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REFEREI'I
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Report of a Study
by a Committee of the
INSTITUfE OF MEDICINE
Division of Health Sciences Policy
M L\!� 0 3 198Z
LIBRARY
NOTICE The proj ect that is the subj ect of thi s repor t was approved
by the Governing Board of the Nat iona l Research Counc i l , whose
members are drawn from the Counc ils of the Nat ional Academy of
Sciences , the National Academy of Eng ineering , and the Inst itute of
Med ic ine . The member s of the ccmm i ttee responsible for the repor t
were chosen for the i r spec ial competence & and with r egard for
appropr iate balance .
The Institute of Med icine was char tered in 1970 by the Nat ional
Academy of Sc iences to enl ist dist inguished members of the
appropr iate professions in the examinat ion of policy matters
pertaining to the health of the publ ic . In th is , the Inst itute act s
under both the Academy ' s 1863 Cong ress ional charter respons ibil ity to
be an advi sor to the federal government , and its own initiative in
ident ifying i ssues of med ical care , research , and educat ion .
Th i s study was suppor ted by the Nat ional Inst itutes of Health ,
Contract No . NOl-oD-0-2114 .
iii
iv
Study Staf f
With the collaborat ion of the Direc tor of the Divis ion of Mental
Health and Behavioral Med ic ine , Fred r ic Solomon , and the assistanc e
of Institute of Med ic ine staff members Bar bara Fllne r , Barbara
Mandula , and Rober t Field .
Consu ltant s
PANELS
Jerome I . K lelnerman
Chairman
Depar tment of Patholog y
Mount Sinal School o f Medicine
Neurobiological I ssues
Harold K alant*
I rwin B . Krakof f
Director
Ve rmont Regional Cancer Center
vi
Reese T . Jones*
P . B . Dews* , Chairman
*Committee membe r .
vii
ACKNOWLEDGMENTS
•
c. Wayne Bardin , Population Council
•
Neal Benowitz , Lang ley Porter Psychiatric Institute
•
Alber t Car lin , Univer sity of Wa shington
•
Sidney Cohen , Alcohol Research Center
•
El len Dempsey , McGill Unive r sity
•
Everett Ellinwood , Duke Univer sity Medical Center
•
Keith Green , Medica l College of Georgia
•
Daniel Both , National Cancer Institute
•
Ll�d Johnston , Institute for Social Researc h
•
Louise Lev , National Cancer Institute
•
Markku Linnoila , Nationa l Institute of Mental Healt h
•
Oriana Kalant and the Documentation Center of the Addiction
Research FOundation
•
Edward Khantzian , Cambridge Hospital
•
Kaye Kilburn , Univer sity of Southern California Schoo l of
Medicine
•
Warren Levinson , Unive rsity of California , San Francisco
•
Raphae l Mechoulam , School of Pharmacy , The Hebrew
University , I s rae l
•
John Mer ritt , Univer sity o f Nor th Carolina
ix
•
Akira Moriah tma , College of Physicians and Surgeons ,
Columbia University
•
Al Munson , Medical Col lege of Virgini a
•
Gabrie l Nahas , College of Physicians and Surgeons , Columbia
Univer sity
•
William Paton , Univer sity of Oxford
•
Bruce Petersen , Lilly Laboratory for Clinical Research
•
Steven Podaa , the Mount Sinai Medical Cente r
•
Lee Robina , Washington University Medical School
•
Har ris Rosenkrantz , EG&G Mason Research Institute
•
Donald Taahkin , University of California , Loa Angeles
•
David Taylor , Centers for Disease Control
•
Carlton Turner , Senior Policy Adviser for Drug Policy ,
Office of Policy Development
•
Ar thur Zimmerman , Unive rsity of Toronto
PREFACE
Thi s repor t i s the wor k of the many people ident if ied in the
preced ing pages , and to all of them I am very g rateful . I
par t icularly wish to thank my d i stinguished colleagues on the study
comm i ttee , upon whose expert knowledge and c r i t ical j udgment this
report rests . They responded consc ient iou sly to all the demand s
placed on them , and they d id so with a promptness and grace that made
my tas k easy .
No study of this kind can be car r ied out without the help of a
s k i l led staff . We were fortunate to have had the ass istance of a
devoted and highly capable staff team led by Enr iqueta c. Bond and
Linda s . Duj ack . They coord inated the efforts of the comm i ttee , the
panel , the consultants , and the Inst itute of Med ic ine staff , and they
played the key role in keep ing everything on schedu le . Moreover ,
t hey carr ied out this formidable task with tact and common sense . On
behalf of the comm i ttee , I wish publ icly to acknowledge ou r
i ndebtedness to the IOM staf f , and I also wi sh to express my personal
thanks to Drs . Bond and Du j ack for the i r unfa i l ing support and
cooperat ion .
F inally , I w i sh to acknowledge my apprec iat ion of the ed itor ial
assi stance of Wallace K . Wate r fall , whose exper t touch is evident
t hroughout this document . Our aim was to wr ite a report in • a clear
and inc i s ive form for the general public . • Any success that we may
have achieved is due in no small measure to his efforts .
Arnold s . Re lman , M . D .
Cha i rma n
xi
CONTENTS
SUMMARY 1
IN'l'RODtx::T ION 6
xU i
APPENDICES 169
xiv
SUMMARY
The Inst itute of Med ic ine ( IOM) of the Nat ional Academy of Sciences
has conducted a 15-month study of the health-re lated effects of
mar i j uana , at the request of the Secretary of Health and Human
Services and the Director of the Nat ional Inst itutes of Health . Th e
IOM appointed a 2 2-member comm i ttee to :
•
analyze ex isting sc ient i f ic evidence bear ing on the possible
hazards to the health and safety of users of mar i j uana J
•
analyze data concerning the poss i ble therapeutic value and
health benefits of mar i j uana J
•
assess federal research prog rams in mar i j uana J
•
ident i fy promising new research d i rect ions , and make
sugggest ions to improve the qual i ty and usefulness of futur e
r e search r and
•
d raw conclus ions f rom this review that would accurately
assess the l imits of pre sent knowledge and thereb¥ provide a factual ,
scient i f ic bas i s for the development of future government policy .
We can say with confidence that mar ijuana produces acute effects on
the brain, including chemical and elec trophys iolog ical changes . Its
most clearly established acute ef fects are on mental funct ions and
behavior . With a seve r i ty directly related to dose, mar ijuana impa irs
moto r coord ination and affects t r ack ing ability and sensory and
perceptual functions important for safe driving and the operat ion of
other machines, it also impa i r s short-te rm memory and slows learn ing .
O ther acute e ffects include feel ing s of euphor ia and other mood
changes, but there also are d i stu rbing mental phenomena, such a s
b rief periods o f anxiety, confusion, o r psychosis .
There is not yet any conclus ive evidence as to whethe r prolonge d
u se o f marij uana cause s permanent changes in the nervou s system or
su stained impairment of brain funct ion and behavior in human being s .
I n a few unconf irmed stud ies in experimental an imals , impa irment of
lea rning and changes in electr ical brain-wave record ings have bee n
o bse rved several months after the ces sat ion of chronic administrat ion
of marij uana . In the j udgment of the committee, widely c i ted stud ie s
purport ing to demonst rate that mar ij uana affects the g ross and
microscop ic structure of the human or monkey brain are not convinc ing ,
much more work i s needed to settle this important point .
Chronic relat ively heavy use of mar ijuana i s assoc iated wit h
behavioral dysfunct ion and mental d i sorder s in human be ing s, but
available evidence does not establish if mar i j uana use under the s e
c ircumstances is a cause or a result o f the mental cond ition . There
are s imilar problems in interpret ing the evidence link ing the use of
mar i j uana to subsequent use of other i llic it drugs, such as heroin or
coca ine . Assoc iat ion doe s not prove a causal relat ion , and the use
of mar i j uana may merely be symptomat ic of an underly ing dispos it ion
to u se psychoac t i ve drug s rather than a • stepping stone • to
i nvolveme�t with more d angerous substances . It is also d iff icult to
sor t out the re lationship between use of mar i j uana and the complex
symptoms known as the amotivat ional syndrome . Self-selection and
effects of the drug are probably both contributing to the
mot ivational problems seen in some chron ic use r s of marij uana .
Thus, the long-term ef fects of mar i j uana on the human brain and
on human behavior r emain to be def ined . Although we have no
convincing evidence thu s far of any effect s per s i st ing in huma n
being s after cessation of drug u se, there may well be subtle but
important physica l and psycholog ical consequences that have not bee n
r ecogni zed .
There is good evidence that the smok ing of marij uana usually causes
acute change s in the heart and circulat ion that are character istic o f
stress, but there is no evidence t o ind icate that a permanently
deleteriou s effect on the normal cardiova scular system occu rs . The r e
i s good evidence t o show that mar ijuana increases the wo r k o f the
heart, usually by ra is ing heart rate and, in some persons, by raising
blood pressure . This rise in wor k load poses a threat to pat ients
with hyper tension, cerebrovascular d i sease , and coronary
a therosc lerosis .
Acute exposure to mar ijuana smoke generally elicits broncho
dilation , chronic heavy smok ing of mar i j uana causes inflamma t ion and
pre-neoplastic changes in the airways, similar to those produced by
smok ing of tobacco . Mar ijuana smoke is a complex mixture that not
only has many chemical components ( including carbon monox ide and
• tar • ) and biological effects similar to those of tobacco smoke , bu t
also some unique ingred ients . This suggests the strong possibility
that prolonged heavy smoking of mar i j uana , like tobacco, will lead to
cancer of the respiratory t ract and to ser iou s impa irment of lung
function . Althoug h there is evidence of impa ired lung funct ion i n
chron ic smokers, no d i rect conf i rmation o f the likelihood o f cancer
has yet been provided, poss ibly because mar i j uana has been widely
smoked in this country for only about 20 years , and data have not
been collected systemat ically in othe r countr ies with a much longe r
history of heavy marij uana u se .
A lthough stud ies in animals have shown that 6 -9-THC ( the maj or
psychoactive constituent of mar i j uana ) lowers the concentrat ion in
blood se rum of pituitary hormones (gonadotropins ) that control
r eproductive funct ions , it is not known if there is a d i rec t effect
on r eproductive t i ssues . Delta-9-THC appear s to have a modest
r ever sible suppressive e ffec t on sperm product ion in men, but there
is no proof that it has a deleter iou s effect on male fertility .
Effects on human female hormonal funct ion have been reported , but the
evidence is not convinc ing . However , there is convinc i ng evidence
t hat mar ij uana inte r feres with ovulat ion in female monkeys . No
sat isfac tory stud ie s of the relat ion between use of mar i j uana and
f emale fert i l i ty and chi ld-bear ing have been car r ied out . Although
6-9-THC is known to cross the placenta read ily and to cause birth
defects when administered in large doses to exper imental animals , no
adequate clinical stud ies have been car r ied out to determine i f
mar i j uana use can harm the human fetus . The re is no conclusive
evidence of teratogen ic ity in human offspr ing, but a slowly developing
or low-level effect might be undetected by the stud ies done so far .
The effects of mar i j uana on reproductive funct ion and on the fetu s
are unclear , they may prove to be negl ig ible , but fur ther research to
establish or rule out such effects would be of g reat importance .
Extracts from mar i j uana smoke part iculates ( • tar • ) have bee n
found to produce dose-related mutat ions in bacter ia J howeve r ,
�9-TBC , by itself , i s not mutagenic . Mar ij uana and 6-9-TBC do
not appear to break chromosomes , but mar ijuana may affect chromosome
segregat ion dur ing cel l division , resulting in an abnormal numbe r of
c hromosomes in daughter cells . Although these results are of
conce rn , the i r clinical signif icance is unknown .
THERAPEUTIC PO'l'EN'l' I AL
The comm ittee also has examined the evidence on the therapeut ic
effects of mar ij uana in a var iety of med ical d i sorde r s . Prel iminary
s tud ies suggest that mar i j uana and its der ivat ives or analogues might
be useful in the treatment of the rai sed intraocular pressure of
g laucoma , in the control of the seve re nausea and vomit ing caused by
cance r chemotherapy , and in the treatment of asthma . There also i s
some prel iminary evidence that a marij uana constituent ( cannabid iol )
might be helpfu l in the treatment of certain type s of epi lept ic
s e i zures , as well as for spast ic disorders and othe r ne rvou s system
d i seases . But , in these and all othe r condit ions , much more work i s
needed . Because mar i j uana and 6-9-THC often produce t roublesome
psychot ropic or cardiovascular s ide-effects that l imit their
therapeut ic usefulne ss , part icular ly in older pat ients , the greates t
t herapeut ic potent ial probably l ies in the use of synthet ic analogues
of mar i j uana der ivat ives with highe r rat ios of therapeutic to
undesirable effects .
The explanation for all of these unanswered que st ions i s insuff ic ien t
research . We need to know much more about the metabol ism of the
var iou s marij uana chemical compounds and the i r biolog ic effects .
Th is will require many more stud ies in an imals , with par t icular
emphasis on subhuman pr imates . Basic pharmacolog ic informat ion
obtained in animal exper iments will ult imately have to be tested in
clinical stud ie s on human beings .
Unt i l 10 or 15 years ago , there was virtually no systemat ic ,
rigorously controlled research on the human health-related ef fect s o f
marij uana and its maj or constituents . Even now, when standard i zed
mar i j uana and pure synthetic cannabinoids are available for
exper imental studies , and good qualitat ive methods ex ist for the
CONCLUSIONS
The sc ient i f ic evidence publ i shed to date ind icates that mar i j uana
ha s a broad range of psycholog ical and biolog ical effects, some of
wh ich, at least under certain condit ions, are harmful to human
health . Unfortunately, the ava ilable informat ion does not tel l us how
ser ious this r i sk may be .
Ou r major conclus ion is that what little we know for certain
about the effects of mar i j uana on human health--and all that we have
r eason to suspect--just i f ies ser ious nat ional concern . Of no leas
concern i s the extent of ou r ignorance about many of the moat basic
and important questions about the drug . Our maj or recomme ndat ion is
that there be a g reatly intens i f ied and more comprehensive prog ram of
research into the e ffects of mar i j uana on the health of the Amer ican
people .
INTRODUCTION
The Inst itute of Med icine ( IOM) of the Nat iona l Academy of Sc iences
ha s undertaken this review and analysi s of the health-related effect s
o f mar i j uana* at the request of the Sec retary of the Department o f
Health and Human Services (DHHS ) and the Di rector of the Nat iona l
Inst itutes of Health (NIH ) .
S c ient i f ic controve rsy and publ ic confusion about mar i j uana
cont inue unabated and perhaps even are expand ing, notwithstand ing
numerous reports on the topic f rom author i tat ive agenc ies and
organi zat ions (Fifth, S ixth, Seventh, and Eighth Annual Reports from
t he Secretary of Health, Educat ion and Welfare to the Cong ress on
Mar ijuana and Health r Fehr, et al . , Cannabis : Adverse Effects on
Health, 1980ar Tink lenberg, Mar ij uana and Health Hazards and
Mar ijuana in the ' 8 0s, a report of the Counc i l on Sc ient i f ic Affa i r s,
t he Amer ican Med ical Assoc iat ion, 1980 ) . Increasing use of th i s
substance and g rowing concern about its poss ible long- and short-term
consequences for human health have added some urgency to the need for
reassessment of the ava i lable data . Interest has been further
h e ightened � recent suggest ions that ma r i j uana may also have some
med ica l therapeutic value, wh ich only intens i f ies the debate abou t
what our publ ic pol icy towards mar i j uana ought to be .
With thi s as backg round, the Secretary of Hea lth, Educat ion, and
Welfare, Joseph A. Cal i fano, Jr . , in a press statement on Apr i l 1 8,
1979, announced the intent ion of h i s department to undertake a review
t hat would • • • • assess the informat ion and sc ient i f ic work now
ava i lable on the effects of mar i j uana . • He followed that with a
memorandum on May 16, 1979, to Donald s. Fred r ickson, Di rector of NIH
i n wh ich he further sta ted z
Following Mr . Cal ifano ' s res ignat ion, subsequent secreta r ie s have
c onf i rmed to the D irector of the NIH the i r des i re to see this review
car r ied forward . Accord ing ly, a contr act between the NIH and the IOM
was executed to provide for a study to commence September 3 0, 19 8 0,
and be completed by Decembe r 2 9, 1 9 8 1 .
The comm i ttee ' s charge spec i f ically excluded the analys i s or
formulat ion of publ ic pol icy .
Pr imary responsibil ity for the conduc t of the study was vested in a
s tee r ing comm i ttee of 2 2 biolog ists, behavioral sc ient i sts, and
clinic ians . Although they all were experts in relevant d i sc ipl ines,
only a few had previously been involved in the study of mar i j uana or
had taken publ ic pos it ions on the subj ect . The comm ittee was d ivided
i nto s ix panels, each concerned with maj or sc ient i f ic areas :
card iovascular and respiratory system effects J neurobiolog ica l
e ffects , epidemiolog ical, behavioral, and psychosoc ial effects ,
reproduct ive biology and ef fects on the fetus J pharmacology, cel l
b iology, a nd immunology , a nd gene t ic and oncogenic ef fects . Each
pane l was cha i red � a membe r of the comm ittee and usually had one o r
more add it ional comm i ttee members and several expert consultants,
whose names appear in the front of thi s report . The comm ittee also
consu lted with many other expe rts in the cou rse of its work and
rece ived valuable help f rom many pe r sons and organ i zat ions .
The full comm i ttee met f ive t imes to coord inate and assess its
prog ress . In the inte rvals between these meetings, the panels held
t he i r own independent sess ions and var ious ad hoc wor k ing g roups met
as necessary . The cha i rman and member s of the comm i ttee staff were
i nvited obse rvers at the Conference on Adverse Health and Behavioral
Consequences of Cannabi s Use, wh ich was sponsored by the Add ict ion
Research Foundat ion (ARF) of Ontar io and the World Health Organi zat ion
(WHO) and held in TOronto, Canada, from March 30 to Apr i l 3, 1981 .
Other members of our comm i ttee served as work ing members of that
conference . We were also fortunate in be i ng able to work closely
with members of the ARF/WHO conference staff and having access to all
the documents prepared for the Canad ian meet ing as well as the
r evi sed d raft of the summa ry report of the conference ( 19 8 1 ) .
The comm i ttee began by systemat ically reviewing all the
l iterature publ i shed s ince 1 975 on mar i j uana and related subj ects,
wh ich had been collected � ou r staff through a Medl ine computer
search . Ear l ier l i terature was select ively examined, as were a
var iety of othe r documents, reviews, and monog raphs on the subj ect .
Our obj ect ive was not merely to compile and summa r i ze, but also to
evaluate the evidence c r i t ically and, with the aid of our consultants,
form some j udgment of the quality and reliabi l i ty of the work . Our
report i s an assessment of what i s and i s not known, based on ou r
best interpretat ions of the sc ient i f ic l i terature . We confined ou r
attent ion to publi shed sc ient i f ic a r t ic les as the pr imary sources of
i nformat ion, rely ing heav i ly on experts in each f ield to select the
re levant paper s and help us interpret the data .
To obtain add it iona l informat ion and opinions from the public and
f rom profess ional g roups on the health-related effect s of mar i j uana,
we sol ic ited wr itten responses in a not ice in the Federal Reg ister of
February 24, 1981 . Responses were rece ived and incorporated into the
r ecords of the comm i ttee . ( See Append ix A for a complete
descr ipt ion . ) The response s fel l into three categor ies :
10
REFERENCES
11
I
CHEMISTRY AND PHARMACOLOGY
OF MARIJUANA
The cannabis plant (Cannabis sat iva ) thr ives under a var iety of
g row ing cond i t ions . I t has been cult ivated for centu r ies , mainly fo r
hemp f iber , but also for its psychoact ive and putat ive medic inal
properties (Abel , 1980 r Turne r et al . , 1 9 8 0 ) . Although the
behavioral and psycholog ical effects were well desc r i bed in
lite rature of the nineteenth century (Kalant and Kalant , 1 9 6 8 ) , the
complex chemistry and pharmacology of the cannabis plant di scouraged
extens ive invest igat ion until about 1 5 year s ago .
Th e most prominent effects o f cannabi s a re o n psycholog ical
phenomena and behavior . Psychopha rmacology and behavioral
pharmacology have developed a s divisions of sc ient i f ic inqu i ry only
ove r the past 2 5 years r therefore , the olde r cannabis literature , no
matter how valuable for observat ions on other matters , does not
prov ide a basis for quant itat ive pharmacolog ical analysi s and
e valuat ion .
E a rly pharmacolog ists could wor k only with crude extracts of the
plant . Althoug h the general structure of the cannabinoids ( Figure 1 )
was known by the turn o f the century , the par t icular cannabinoids
that were ident i f ied early and were available as pure substances wer e
largely devoid of the characte r i s t ic psychoact ive and other
pharmacolog ical effects of cannab i s . Synthetic cannabinoid s with
c annabislike act ivity became ava ilable in the 1930s . It was not
until 196 4 that an active i ng red ient of cannabi s was ident i f ied a s
6- 9 -tetrahydrocannabinol (THC ) a nd synthes i zed ( Figure 1 ) ( Gaoni
and Mechoulam , l964 r Mechoulam and Gaoni , 1 96 5 , 1967 ) . In the
mid-1960s , the i solation and synthe s i s of the mai n psychoact ive
component of cannabi s and related cannabinoids , together with a rapid
increase in the use of ma r i j uana by middle class North American
s tudents , stimulated sc ient i f ic act ivity (Waller et al . , 1976 r Waller
et al . , in press) . Thi s chapter , an overview of cannabis chemistry
and pharmacology , empha s i ze s d i f f icult ies in t he study of th is drug
( explored further in subsequent chapter s ) and in evaluat ing the
l i terature .
12
13
.1-9-lliC Cannabinol
Cannabidiol 11-hydroxy-.1-9-lliC
Cannabis , the crude mater ial f rom the plant Cannabi s sat iva , contains
hund r�s of chemicals . Most of these are found in other plants , bu t
6 1 , termed cannabinoids , a re unique to the cannabis plant ( Table 1 ) .
Natural and most synthetic cannabinoids are relat ively insoluble i n
water , but d issolve in fats and fat solvents and are therefore called
lipid soluble .
A s ingle cannabinoid , A -9-THC , produces almost all the char
acter istic spec i f ic pharmacolog ical ef fects of the complex , crude
cannabi s mixtures . A numbe r of synthetic cannabinoid s have pharmaco
log ical effects s imilar to A -9-THC . Other cannabinoids in the
plant , for example , cannabinol ( Figure 1 ) , are almost inactive
pharmacolog ically or may interact with A-9-THC to modify its
actions . One cannabinoid , cannabid iol (CBD) , can influence the
metabolism of another , A-9-THC ( S iemens et al . , 1976 ) . A few
cannabinoids have effects qu ite different f rom A -9-THC . For
example , cannabid iol ( Figure 1 ) has relat ively little psychoactive
and ca rd iovascular e ffect but is an active ant iconvulsant (Karler and
Turkanis , 1981) .
I nvest igators have chemically altered the A -9-THC molecule in
an attempt to determine which of its structural elements are r equ i red
to produce behavioral or othe r effects ( Mechoulam et al . , 1 9 8 0 ) .
S tud ies of structure-activity relat ionships ind icate that , to produce
14
1 . Cannabinoid s : 61 known
a. Cannabiqerol (CBG) type : 6 known
b. Cannab ich romene ( CBC) type : 4 known
c. Cannab id iol (CBD ) type : 7 known
d. 4-9-Tetrahyd rocannab inol ( 4-9-THC) type : 9 k nown
e. 4 -8-Tetrahydrocannab inol ( 4-8-THC ) type : 2 known
f. Cannabicyclol (CBL ) type : 3 known
g. Cannab ielsoin (CBE ) type : 3 known
h. Cannabinol (CBN ) type : 6 known
i. Cannabinodiol (CBND) type : 2 known
j. Cannab itr iol (CBT) type : 6 known
k. Miscellaneous types : 9 known
1. Othe r cannabinoids : 4 known
6 . Hydrocarbons : so known
1 4 . Terpene&: 1 0 3 known
1 7 . Vitamins : 1 known
18 . Pigments : 2 known
15
16
Nepal.2. 2 . 81
Mex icc£ 1 . 68 1 . 00
Pakistan£ 1 . 30
I nd iat 0 . 46
(g rown above 2 0 0 0 m )
1. 39
(grown below 2000 m )
United States£ 0 . 35
S insemilla
( intermed iate ) g 3. 58
Bashiah
( U . N . standard ) g 2 . 22 ( 7 . 4 0 )� 1.90
NIDA ( c igarette l ) g .0 . 8 4
NIDA ( c igarette 2 ) g 1 . 8 6 ( 2 . 8 ) .i
SOURCES : (!) Jones , 1980 J Q2) Braenden , 197 2 J �) Turner , 1974 J (g)
Turner , 1 9 8 0 J (!) Turner , 1981 J (!,) Turne r et al . , 1979 J (51.)
Rosenkrant z , 1981 J (b) Marshman et al . , 1976 .
17
Marijuana Tobacco
Cigarette Cigarette
(85 mm) (85 mml
A. Cigarettes
B. Mainstream Bllloke
I. GaB £!haae
18
Bes ide s the c r ude plant leaf mate r ial for smok ing , usually called
ma r i j uana , res inou s mate r ia l f rom the plant , called hashish , and
solvent extrac t s of the plant , te rmed ha shish o i l , somet ime s appear
on the i l l ic i t ma r ket . I n many pa r t s of the wo r ld , hash ish is mor e
commonly u sed t han mar i j uana . A s with a l l cannabis prepa rat ions , the
6-9-THC content of ha s h i sh va r ies enormous ly , but the uppe r l im i t s
o f � - 9-THC content are u sua l ly much h igher than for ma r i j uana : 7
pe rcent or h ighe r and even h ighe r for hash ish o i l ( Table 2 ) .
Howeve r , even these gene r a l ly more potent forms of cannabis may
occas ional ly cont ain much less � -9-THC .
The me re des ig nat ion of the nature of a cannabis prepa rat ion i s
an unrel iable pred ictor of its �-9-THC content . The pract ical
consequence of this for the c l i n ical researcher i s that the exposure
to cannabi s u se r s is not known .
Analyt ic Methods
Detect ion and measu rement of cannab inoid s and the i r metabol ite s i n
body f luids i s far more d i f f icult than w ith s uch d rug s as alcohol .
The blood and t i ssue levels result ing from use of ord inary cannabi s
a r e very low--nanog ramst per m i l l i l iter o r lowe r . In add i t ion ,
compounds l i ke steroids , occu r r ing normal ly in body f lu ids inte r fere
with the measurement of cannabinoid s in blood and can ma ke the test
much less sens i t ive t han if pure cannabinoids in an uncontaminated
19
solut ion are be ing analyzed ( Ha r vey et al . , 1980 J Ha rvey and Paton ,
1 980) .
A combinat ion of gas-liqu id chromatography and mass spect rometry
is the most sensit ive d i rec t method of measu r i ng cannabinoids . That ,
howeve r , requ i res s k i l led technic ians and expensive equ ipment not
read i ly ava i lable . Us ing mod i f icat ions of th i s expe r imental
techn ique , one can measure a s l it t le as 5 p icog rams* of 6 -9-THC in
a m i l l i l i te r of plasma ( Harvey et a l . , 1 9 8 0 J Harvey and Paton ,
1 9 8 0 ) . Rad ioimmunoassay and enzyme immunoassay techn iques also ar e
a va i lable , the lowe r l imits of sens it ivity of these methods now are
not adequate for rel iable mea surements of 6-9-THC in human blood
more t han a few hou r s a fter d rug admin istrat ion . A read i ly ava i lable
enzyme immunoassay w i l l detec t cannabi s metabol ite s in the ur ine fo r
a s long as a wee k after the smok ing of a s i ng le ma r i j uana c igarette .
Thu s , a posit ive u r ine test by th i s method i s not necessar i ly
i nd icat ive of u se within the previous few hou r s and does not provide
ev idence of recent intox icat ion as a breath test does for alcohol .
Assays for cannabinoids a re l i kely to rema in far more compl icated
than fo r alcohol and many othe r d r ug s .
PHARMACOLOGY OF CANNAB I S
1 . The concentrat ion of the d rug at the s ites of act ion in the
body . Th i s i s determined by the dose , what the d r ug is d i ssolved i n
o r mixed with , the rou te of admi n i strat ion , and the pharmacok inet ics
of the drug .
2. The sensit ivity of the cells the drug acts upon .
3 . The phys iolog ica l state of the bod i ly systems be ing
a f fected . Th i s , in turn , depends on interactions with othe r systems
and , espec ially for drug s with behavioral and psycholog ical e ffects ,
a s wel l as envi ronmental and exper ient ial factor s , inc lud ing the
presence of other drug s .
W ith cannabi s , many or even most of the se factor s are not always
measurable or unde r the control of an invest igator .
* 1 pg • l o 1 2 g r ams .
-
20
Pharmacok i netic stud ies of the absorpt ion , d istr ibut ion , metabol i sm ,
and e l imination of A-9-THC determine how long A-9-THC and its
metabol ites remain i n the body . Pharmacok ine t ics vary with the route
of drug admini stration and such factor s as l ipid solubi l i ty J
A- 9 -THC tends to rema i n for long per iods of t ime i n fatty t issue .
When smoked , 6 - 9-THC i s rap id ly absorbed by the blood in the
lung . I f taken orally , 6-9-THC is not absorbed into the blood as
rapidly . The r ate of d isappearance of A -9-THC from the blood
var ies with t ime ( Lembe rge r et al . , 1 9 7 la , b , 1 9 7 2 J Ohlsson et al . ,
1 98 0 ) . H igh blood levels fall rap idly for the f irst 3 0 minutes , as
the A-9-THC d i st r ibute s to t i ssue s with h ig h blood f low . After the
init ial d i str ibut ion , the blood leve l falls much more slowly with a
hal f-l ife* of 1 9 hou r s or more (Bunt and Jones , 1 9 8 0 ) . Metabol ite st
of 6 - 9-THC have the i r own i ndependent rates of e l iminat ion .
Typically , metabol ites are e l iminated more slowly , having a half- l i f e
o f approx imately S O hours ( Hunt and Jones , 1 9 8 0 ) .
Afte r an inj ect ion of a s i ng le dose of A-9-TBC , approx imatel y
2 5-30 percent of the compound and its metabolites rema in in the body
at 1 wee k ( Lemberge r et a l . , 197lb r Hunt and Jones , 1 9 8 0 ) .
E s sent ially complete e l iminat ion of a s i ng le dose may take 30 days or
longe r (Jones , 198 0 ) . Thus , repeated admini strat ion of even smal l
doses may lead t o an accumulat ion of drug h igher than levels reached
at any t ime after a s i ng le dose .
Ab so rpt ion
21
evident within a few second s o f inhalat ion . Peak effects occu r abou t
t he t ime smok ing i s completed .
When taken by mouth , cannabinoids usually are in solut ions or
su spens ions . The mate r ia l they are mixed w ith affects the rate of
a bsorpt ion . Por example , blood levels of 6 -9-THC were h ighe r and
lasted longer when g iven in an o i ly solut ion than in an ethyl alcohol
solu t ion ( Perez-Reye s et a l . , 197 3 ) . Th i s suggests that cannabis
e aten i n food mixtures conta ining fat i s better absorbed .
An important di fference between smok i ng and ingest ion i s tha t
when cannabinoida are absorbed from the gut , the blood containing
them f i r st goe s d i rectly through the liver . The l ive r rapidly clear s
t he 6 -9-THC f rom the blood and enzymat ically changes much of the
6 -9-TBC to other metabolites before it reaches the bra in ( Bunt and
Jones , 1 9 8 0 ) . A large amount i s metaboli zed to 11-hydroxy-6-9-THC
( P igure 1 ) . I t i s unknown if the spectrum of effects of this
metabol ite i s ident ica l to that of 6-9-THC . When taken by mouth ,
in contrast to when smoked , two o r three t imes more 6-9-T.RC i s
requ i red t o obtai n equ ivalent acute psycholog ical and phys iolog ica l
e ffects . After oral doses the effects develop more slowly , last
longer , are more var iable , and cannot be controlled by the rec ipien t
once the cannabi s has been swallowed . In contrast , the smoker feels
the effec t s qu ic k ly and can mod i fy inhalat ion at any t ime , althoug h
overdosage i s still poss ible . Unpleasant reac t ions to overdose are
more commo n following ingest ion than inha lat ion .
A var iety of other routes of admini strat ion have been used
exper imentally in humans and in animals , includ ing intravenou s ,
i nt raper i toneal , subcutaneous , intramuscular , topical (on the ak in ) ,
and into the conj unc t ival sac ( eye ) . These var iou s routes inf luence
t he t ime to onset of effect , durat ion and peak intens ity , and the
rate with which the effect d i sappears . Di rect compar i son of f ind i ng s
i n stud ies using d i ffer ing admini stration routes i s d i ff icult and
must take these factor s into cons iderat ion .
Ruman use r s of cannabi s vary in the i r prefer red routes of use .
I n some countr ies and cultures cannabi s i s ma inly taken by ingestion
( for example , India) and in others by inhalat ion ( for example , the
Uni ted States) . Because of the effects of route of admin i stration on
pharmacology , i t i s reasonable to expect d i f ferent health consequences
of the d i fferent route s of admini stration ' therefore , compa r i sons of
health stat ist ics among countr ies must be made with care .
Although smoking avoids many of the absorpt ion problems d i scussed
a bove , a host of other var iables affecting dose are i ntroduced , such
as the s i ze and pack ing of the cannabi s c igarettes , the way the smoke
i s i nhaled , the number of puffs and the interval between puffs , the
temperature produced in the burning c igarette , and whether a c igarett e
i s shared . Because of the prog ressive concentrat ion of cannabis
const i tuent s in the c igarette butt , the last few puf f s y ield con
s ide rably more 6-9-THC and par t iculate matter than do the ear l ier
puf f s . All these and other fac tor s affect the dose rece ived , and
only rarely have they been measured . Only some of these factor s a r e
under the consc ious control o f the cannabis smoker . About half of
the 6-9-THC or ig inally in a cannabi s c igarette i s lost by
22
combust ion , by butt ent rapment , i n smoke not inhaled , and i n smok e
exhaled ( Fehr and K a lant , 1 9 7 2 1 Rosenk rant z , 1 9 8 1 ) .
I t ha s been repor ted that , l i ke nonsmoker s of tobacco , ind i v idual s
i n a poor ly vent i lated room whe re cannabi s i s smoked may pass ive ly
inhale ac t ive components ( Ze idenbe rg et al . , 1 9 7 7 ) . Because only
t race amounts of cannabinoid metabol i tes are present in u r ine of
these passive inhale r s , i t i s unl i kely that the low levels of the
a bsorbed cannabino ids f rom the ambient a i r account for the so-ca l led
•contact h igh . • Expe r ienc ing subj ect ive cannabi s e f fect s in the
presence of cannabi s smoke r s cou ld .be expla ined by psycholog ic
factor s in add it ion to any pharmacolog ic ones . But , because stud ie s
have shown that c h i ldren of parents who smoke tobacco a re more l i kely
to have respiratory infec t ions dur ing the f i r s t yea r of l i fe--wh ich
may be due to t he i r be ing exposed to c igarette smoke in the atmosphe re
( U . S . Depa r tment of Health , Educat ion , and We lfare , 1 9 7 9 ) --the i ssue
of pass ive inha lat ion of mar i j uana smoke i s worth fu rthe r study .
D i s t r ibut ion
The l ipid solubi l ity of A-9-THC and othe r cannabinoid s , inc lud ing
those with h ighest pharmacolog ic act i v i ty , fac i l itates d istr ibut ion
read i ly i nto t i ssue s and ce lls throughou t the body so blood level s
d rop r ap id ly . I n i t ially , cannabinoid concentrat ions a re h ighest in
such t i ssue s as lung , l iver , and k idney that have a h ig h blood flow
( Agurell et a l . , 1 9 6 9 , 1 9 7 0 1 K lausne r and Dinge ll , 1 9 7 1 ) . Delta-9-THC
crosses the placenta and ente r s the fetus of expe r imenta l animals
( Kennedy and Waddell , 1 9 7 2 ) . Cannabinoid levels in the human fetus
have not been stud ied . Small amounts are also found i n the milk o f
exper imental animals and can be t ransfer red t o progeny (Jakubovic e t
al . , 1 9 7 3 1 Chao e t a l . , 19 7 6 ) . Afte r i n i t ia l d i st r ibut ion ,
concentrat ions of cannabinoids in t issue s , cells , and subcellular
compar tments are h ighly nonuniform , determined no doubt by solubi l i t y
a nd other phys icochemical characte r i s t ics . The refore , blood
concentrat ions do not reflect concentrat ions at pharmacolog ically
active s i tes , as they do with alcohol .
23
24
25
CANNAB I S CONTAMINANTS
On occas ion cannabi s has been reported not only to contain the
herbic ide paraquat , but also salmonella bacteria and asperg i llus
fungus . De l iberate add it ion of such drug s as lyserg ic ac i d
d iethylamide ( LSD) , heroin , and phencyc l id ine ( PCP ) has been
c la imed . A plant mate r ial such as cannabi s is not always handled i n
the most sanitary way , and a var iety of contaminants are possible .
Paraquat
26
•
D i sposit ional tolerance resulting from lowe r d rug
concentrat ions at s i tes of action , usually because of increased rates
of drug metabo l i sm or e l iminat ion
•
Funct ional tole rance a r i s ing from decreased sens i t ivity of
the target cells .
27
DRUG INTERACTIONS
28
Cannabi s i s not a s ing le drug , but a complex preparat ion conta ining
many biolog ically act ive chemicals . The psycholog ica l and
physiolog ical e f fects produced by A -9-TRC probably result f rom
actions at s i tes within the central ne rvous system and elsewhe re in
the body , lead ing to the l i kelihood of compl icated effects depend ing
on dose , durat ion of use , and many other considerat ions .
The intens ity of ef fect an i ndividual exper ience s var ie s
c onsiderably according to the cannabis preparat ion and the amount
taken , route of administrat ion , frequency of use , and probably othe r
not-well-recognized biolog ical cons iderat ions . Dose var iabi l i ty must
be cons ide red both in conducting and in interpreting any stud ies of
t he e ffects of cannabi s , par t icula r ly when try ing to pred ict health
consequences .
In research the use of pure A-9-TRC avoids some problems of
dose control but cannot provide a complete picture of cannabis
effects , because the effects of A-9-TRC in crude preparat ions of
the plant may be influenced by othe r components . Other consequences
of cannabi s use , for example , exposure to harmfu l components in i t s
smoke , will have deleter ious health consequences in add it ion to
anything produced by the A-9-THC .
The long persi stence of cannabinoid metabolites in the body may
have delayed effect s or health impl icat ions not yet recogn i zed ,
because , even with relat ive ly infrequent use , there i s chronic
exposure to biolog ically unknown mater ials . In th i s respect ,
c annabis d iffers fundamentally f rom such drug s as alcohol , n icot ine ,
and caf fe ine , which are rap idly metabol ized and eliminated from the
e nt i re body .
C annabinoid effec ts can be mod i f ied by many events , inc lud ing
inte ract ion with othe r drug s and the deve lopment of tolerance . Bot h
tolerance and dependence develop to many effects of the drug . The
health s ignif icance of tolerance and dependence , par t icular ly the i r
impor tance i n drug-see k i ng a nd d rug-using behavior , has not been
stud ied properly .
I t i s unl ikely that adequate epidemiolog ic data will be ava i lable
( soon ) to enable good est imat ion of the health consequences of var iou s
u sage levels .
A pre requ i s i te is that adequate chemical analytical methods be
appl ied on a large-scale bas i s to mon itor actual exposures . COnt inued
s tud ies in exper imental animals will play an essential role in the
assessment of the health r i sks of cannabi s . POr example , the
b iolog ical act ivities of A-9-TRC metabolites can be assessed in
exper imental animals , but these tests a re techn ically more d i f f icult
to do in human beings .
Seve ral research pr ior i t ies are ident i f ied by the preced ing
d iscuss ion :
29
•
Cannabinoids and the i r metabol ite s per s ist for relat ively
long per iod s in the body . More informat ion is needed on the
biolog ica l s ignif icance of that pe r s i stence in human beings . As a
f irst step , the tox icolog ical effects of the var ious metabolites need
to be determined .
•
Drug interactions alte r the act ions of cannab i s . Cannabis
use alters other drug effects . More informat ion is necessary to make
the combined effects of cannabis and othe r l ic i t and i l l ic i t d r ug s
more pred ictable , espec ially with respect to behavioral impa irment
and tox ic ity to lungs , liver , and othe r organa .
•
S tud ies of the mechan i sm of act ion of cannabis should
cont inue . Knowledge of mechanism i s l i kely to provide powerful
ins ights into the potent ial health effects .
•
Improved chemical analyt ical methods are necessary .
Epidemiolog ic appraisal of the health effects of cannabinoids
requ i re s method s suitable for wide-scale assay s of exposures .
Pharmacolog ical ve r i f icat ion of the self-reported extent of use will
make exper imenta l and clinical results much eas ie r to inte rpret . A
c hemical •marker • of the frequent user would be useful . Screening
techniques for the purpose of identifying and d i scou r ag ing
c annabis-impa i red d r iving would also be valuable .
•
Characte r i zat ion of the tox icolog ical s ignif icance of commo n
cannabi s contaminants such as paraquat and other chemicals , fung i ,
and bacte r ia should be cont inued .
•
The development of tolerance is a factor that potent ially
mod i f ies the express ion of all psychoactive drug effects . Add it ional
stud ies on the rate s of acqu i s i t ion and loss of tolerance and the
r e lat ionship of these phenomena to dependence are necessary . The
biolog ical s ignif icance of the changes that under l ie the developmen t
o f tolerance should be establ ished . �e relat ionship , i f any ,
betwe•n tolerance and dependence and drug-seek ing behavior should be
e stabl ished .
•
C annabis products a re var iable and complex . More
informat ion on the amount , nature , and potency of the var ious
prepa rat ions used around the world would fac i l itate calcu lat ions o f
exposures to its constituents . Por example , what i s the biolog ical
and tox icolog ical s ign i f icance of the minor components of cannabi s
smoke?
REFERENCES
Abel , E . L . Mar ihuana : The Pirst Twelve Thousand Yea r s . New York :
Plenum Press , 1 9 8 0 .
Agurell , s . , Nilsson , I . M . , Ohlsson , A . , and Sandberg , P .
El iminat ion o f tr itium-labelled cannabinol& i n the rat wit h
spec ial reference to the development of tests for the
ident i f icat ion of cannabi s u ser s . B iochem . Pharmacol .
1 8 : 1195-1201 , 1969 .
Agurell , s . , Nilsson , I . M. , Ohlsson , A . , and Sandbe rg , P . On the
metabolism of tr itium-labelled delta-1-tetrahydrocannabinol i n
t he r abbit . B iochem . Pharmacol . 19 : 13 33-13 3 9 , 19 7 0 .
30
31
32
33
2
USE OF MARIJUANA
IN THE UNITED STATE S
34
35
The Nat ional Household Surveys found that mar i j uana was the most
common ly used of all the nonlegal psychoact ive drug s invest igated ,
i nc lud ing inhalants , halluc inogens , coca ine , he roin , s t imulants ,
sedat ives , tranqu i l i ze r s , and analgesic s ( Fi shburne et al . , 1 9 8 0 ) .
36
In 1 9 7 9 more than 50 mill ion pe r sons had tr ied mar i j uana at leas t
once in the i r l ives a 6 8 . 2 percent of young adults ( 1 8-2 5 ) , or about
21 million r 30 . 9 percent of youth ( 1 2-17 ) , or more than 7 mill ion r
a nd 1 9 . 6 percent of older adults ( 26 and older ) , or 2 5 million . The
young adult age-g roup ( 18-2 5 yea r s ) has consistently •bowed the
h ighe st rates of current use ( used in past month ) and ever u•e
( l ifetime prevalence ) , and the olde r adult g roup• ( 2 6 and older ) had
the lowest user rate• · Male use r s outnumbered females in all age
groups . Between 1977 and 1 979 , s ignif icant increase s in cur rent us e
and ever use of mar i j uana were obse rved among the young adult and
olde r adult cohorts ( Figure 2 ) . In 1 9 7 9 , in the young adu lt cohor t ,
the most B igni f icant increases in use in the past month were found in
males , wh ites , h ig h school nong r aduates , people in the southe rn
United S tates , and those l iving in nonmetropolitan areas . In the
olde r adult g roup• , the most B ign i f icant recent increa•e i n cur ren t
u se of mar ij uana was ob•e rved in males , white• , college g raduates ,
and people living in the souther n states (Miller and C i s in , 1 9 8 0 ) .
In the early 1960s , illic it drug use in the Un i ted States was
ch iefly a phenomenon of large coastal c it ies . Bu t since then , rate s
i n other reg ions of the country and in c it ies of all s i zes have
rapidly increased unt i l patte rns of u•e are becoming increasing ly
comparable for all sector s in the Uni ted States . At cur rent levels
of u se , some exper ience with mar i j uana in adole scence i s becoming the
norm r ather than the except ion throughout the United S tates . Other
major •urvey stud ies have con f i rmed the f i nd i ng s of the Nat iona l
Bou•ehold Survey for comparable cohort populat ions (Gallup Opin ion
Index , 1976 J O ' Donnell et a l . , 1 976 ) .
37
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s tudents . These f igures show that legal ( for adult s ) drugs are used
much more frequently than i llegal ones . Reports of i l legal use of
d rug s show that exper imentat ion with mar ij uana has , by far , the
h ighest prevalence . It should be noted , also , that •daily • use o f
ma r i j uana ( 9 percent ) among h ig h school senior s is now more prevalent
than •da i ly • dr ink ing ( 6 pe rcent ) of alcoholic beve r ages .
In 1 9 8 0 , for the f irst t ime s ince 1 9 7 5 , when the Mon itor ing the
Futu re data collect ion began among h igh school seniors , the percentag e
o f •daily • users of mar i j uana among seniors in h ig h school decl ined
s ig n i f icantly from 1 0 . 3 percent i n 1 9 7 9 to 9 . 1 percent in 1 9 8 0
( Figure 3 ) , a nd there was a leveling o f l i fet ime prevalence a t
approx imately 6 0 pe rcent . Fur the rmore , the propor t ion of curren t
u se r s among those who ever u sed mar i j uana also showed a stat ist ically
s ignif icant decl ine in 1 9 8 0 as compared to 1979 , f rom 6 0 percent to
5 6 percent . However , •dai ly • user s may be increas i ng ly underrepre-
41
Correlates of Use
Overall levels of use of mar i j uana have been s hown to cor relate with
patterns of use of the drug .
42
stud ies have not sampled th i s popu lat ion in the belief that use o f
mar i j uana d rops o f f sharply in the mid-20 s . Among males , the
prevalence rate for use of mar i j uana in the past month for
over-2 6-year olds went f rom 4 percent in 1977 to 9 percent in 1979 .
I t will be exceed ingly impor tant to monitor the trend s in all olde r
adult age g roups .
One of the key quest ions asked ove r the year s i s , doe s mar i j uana lead
to the use of other d rug s . In any populat ion , the use of var ious
drug s appear s inter related and use r s of any type of drug , whethe r
legal or i llegal , are much more l i kely to use othe r types of drug s
than nonuse r s . POr example , young people who smoke tobacco are also
much more l i kely to have used alcohol or mar i j uana than nonsmokers
( Fishburne et al . , 1980 ) . S imilarly , there i s a strong assoc iation
between the use of mar i j uana and of other i ll ic it drug s . Young
people who use mar i j uana are more l i kely to be consuming othe r
substances , such as alcohol and tobacco , as well as other i ll ic it
drug s ( Johnston et al . , 1980b) . The associat ion increases with
ex tent of mar i j uana involvement and i s espec ially str i k ing among
those young people who use mar i j uana on a •daily • bas i s , as wil l be
d i scussed below .
Results from the Nat ional Household Surveys and f rom samples of
h ig h school senior s had ind icated that the ratio of rates of use o f
i llicit drugs other than mar i j uana to use of mar i j uana declined
throug h 1979 (Kandel , 1980 r Mi lle r and Cisln , 1980 ) . In 1980 ,
however , the ratio started to r i se aga i n . Thus , in 1 9 8 0 , 6 5 percent
of mar i j uana use r s among the h ig h school seniors had also u sed othe r
i l licit drugs as compared to 61 percent in 1979 (Johnston et al . ,
l980a) .
Because any health r isks result ing from the use of ma r ij uana would be
moat l i kely to appear f irst in chronic users of the drug , the young
persons who are chronic and heavy user s are of spec ial interest . The
comm i ttee reports in some deta i l the f ind ing s on this g roup . The
rank s of •daily • users are large . In 1980 they represented more tha n
9 pe rcent of h igh school senior s or ove r 390 , 0 0 0 18-year-olds in the
Uni ted States . One out of 11 senior s f itted the def i n i t ion of
• da i ly • u sers ( 20 or more occas ions of repor ted use within the
preced ing 3 0 days ) . Collection of systemat ic data on such user s
began in 1 9 7 5 with the annual monitor ing of in-school h igh school
senior s . There are many gaps in our knowledge about th i s g roup , bu t
suff ic ient data have been accumu lated that it i s now poss ible to
desc r ibe many of the behavioral attr ibutes of the •da l ly • u ser s .
Most of these data come f rom Mon itoring the Future . Some of the
f i nd i ng s recently repor ted by Johnston ( 1980 , 1981 ) and Bachman e t
a l . ( 1981) are a s follows a
43
Rates of •daily • use d o not vary among reg ions o f the country , but
•da i ly • use shows a strong posit ive relat ionship to the s i ze of the
commu nity and is more prevalent in urban areas . Males are •dai ly •
user s a t almost double the rate o f females ( 1 3 percent ve r sus 7
percent ) . •Dai ly • use among white students i s double that for blacks
( 11 percent ver sus 5 percent ) . • Da i ly • use is spread evenly across
soc ioeconomic levels as def ined in terms of parents ' educat ion .
•Da i ly • use i s only sl ightly h igher among those from homes in wh ic h
one or both parents a re absent .
Dating and soc ial l i fe show strong relat ionsh ips with •da i ly • use of
mar i j uana . Those who spend more t ime on dates have the h ig hest rates
o f •daily • use of mar i j uana . Among those students who go out 6 or 7
n ights a wee k and are pract ically neve r at home , 3 4 percent are
• da i ly • ma r i j uana u sers .
• Daily • mar ij uana users are much more likely than the i r peers to be
extens ive users of other drug s . Thus , of seniors in the class of
1 9 7 9 , 2 7 percent of •da i ly • users of mar i j uana d rank alcohol as
frequently , ve rsus 7 percent for the age-group as a whole J and 5 9
44
S tudent status after h igh school cor relates negatively with •dai ly •
use r that is , full-t ime college students have the lowest rate ( 8
percent) , part-t ime students the next lowest ( 10 percent ) , and
nonstudents the h ighest rate ( 1 3 percent ) . However , althoug h
f ull-t ime students have a lower than average rate of •da i ly • u se ,
they showed the greatest increase after h igh school ( up from 4 . 5 to
8 . 3 percent ) : they s imply star ted from a very low level and in a
sense were •catching up . •
*A cur rent user i s one who has u sed the d rug in the th i r ty days
preced ing the surveys .
45
Living Status
Young people who are l iving away from home have a h ig her proport ion
of •daily • use than those still living with the i r parents ( 1 2 percent
versus 10 percent ) , probably reflecting the result of reduced soc ial
control by parents . Those who remained l iving with the i r parents
( nearly half ) showed relat ively l ittle increase in use ( up 1 . 3
percent) , wh ile those who moved out increased the i r daily use rate
substant ially ( up 3 . 9 percent ) .
Those who are single are almost twice as l ikely to be •daily • users
as those who are mar r ied ( 11 . 4 percent ve rsus 6 . 6 percent ) , and those
without children are somewhat more likely to use mar i j uana than those
with children ( 11 percent ver sus 8 percent ) . I t appear s that these
role respons ibilities have a dampening effect on use . In the face of
an overall 2 . 6 percent increase i n •da i ly • prevalence after h igh
school for the whole sample , those who were marr ied showed virtually
no increase ( up 0 . 2 percent ) and those with ch i ldren actually had a
d ecline i n u se ( down 1 . 5 percent ) .
Type of dwelling
Employment
What reasons do •daily • users g ive for their use of mar i j uana? They
tend to use mar i j uana to produce an intox icated feeli ng , to cope
psycholog ically with feel ings of d i stress , to augment the effects of
othe r drug s , and to part ic ipate in drug-using fr iendsh ips . On a
46
checklist o f 1 3 poss i ble reasons , nearly all o f the senior s who wer e
• da i ly • users chec ked • to feel g ood o r get hig h • ( 94 percent ) and • to
have a good time with my fr iend s • ( 79 percent ) . Two-thi rds said they
u sed it to relax ( 6 7 percent ) and nearly half said they u sed it to
relieve boredom ( 4 5 percent ) . Roughly a quar ter of the •da i ly • user s
c hecked each of the following : • to get away from my problems • ( 2 7
percent ) , •because of anger or frustrat ion • ( 2 3 percent ) , and • to ge t
through the day • ( 2 2 percent ) . These psycholog ical coping motives in
par t icula r seem to d i st inguish the •daily • users from the less
f requent use rs . A fa i r ly h igh propor t ion ( 30 percent ) also said that
they used mar ij uana to increase the effects of othe r drug s , whi le
only 10 percent of the othe r cur rent users gave this reason . Only 11
percent of the •da i ly • users , or 1 percent of the total sample ,
s tated that they used it because they felt • hoo k ed • or had to have
it . All of these responses for senior s were close ly repl icated among
the •da i ly • users in the 19- to 22-year-old sample (Johnston , 1981 ) .
Nea r ly all •da i ly • use r s (over 8 5 percent ) , whether in h igh
schoo l or past high school , say (1) that most or all of the ir fr iends
smoke mar i j uana , ( 2 ) that most or all of the i r fr iends d r ink alcohol ,
( 3 ) that more than a few of the i r fr iends get drunk every week , ( 4 )
tha t more than a few o f the i r fr iends smoke c igarettes , and ( 5 ) that
at least a few of the i r f r iend s use a number of other i ll ic i t drug s .
Thi s deg ree o f immersion in a drug-using fr iendship c i rcle contrast s
sharply to what we obse rve for the i r peer s , even those who are
cur rent but less frequent u se r s of mar i j uana . Clear ly the soc ia l
s uppor ts and the soc ial pressu res are there , both dur ing and after
h igh school , for the •da i ly • use r to continue his or her habit .
A number of use r s of mar i j uana stop using the d rug ( Johnston , 1981) •
47
4 0 percent ) o f seniors who have neve r tr ied mar i j uana reveals concern
abou t phys ica l ( 7 1 percent ) and psycholog ical ( 6 8 percent )
consequences , which are ment ioned far more often than any othe r type
of reason . Soc ial or ideolog ica l constra ints or d i s i nterest in
g ett ing h igh are infrequently ment ioned . There also has been a
signif icant increase in health conce rns among the absta ining segment
s ince 1976 , though not as large as among quitter s .
I n summary , many •daily • u se r s themselves see some negative
consequences of the i r habit , and there perhaps are some consequences
of wh ich they are unaware . The fact that the •da ily • smok ing of
mar i j uana is proving to be more endur i ng and stable than many may
have thought inc reases the probabi lity of cumu lative , long-term
e ffects . The fact that so many young people are becoming •dai ly •
use r s now puts a substantial numbe r o f people at r i sk of whateve r th e
long-term consequences may prove to be .
48
When use of mar i j uana f irst came under research scrut iny in the late
1960s , very few youths had exper imented with illic i t drugs . Much was
made of the deviant status of use of mar i j uana and of the counter
cultural and rebelliou s meaning that came to be attached to using the
d rug ( Suchman , 1 9 6 8 ) . Yet even today , when over 60 percent of all
hig h school senior s have used ma r i j uana , those youths who use
mar i j uana are qu ite d ifferent from nonusers . The mar i j uana users in
1979 show the same patterns of d i saffection from major institution s
t hat characte r i zed the users in 1967 . The most recent data show that
mar i j uana user s per form more poo r ly in school , are less relig ious ,
have per formed more delinquent acts , are in trouble with the law,
have more traff ic acc idents , and use more illicit drugs than nonusers .
Those persons who also use several i llic it drug s show the h ighest
involvement in deviant behaviors . There is a linear relationsh ip
w i th deg ree of involvement with i llicit drug s , such that persons
using mar i j uana exclusively are only quant itat ively d i fferent from
those who have also used harder drug s ( Johnston et al . , 1980b) .
49
50
i ni t ial test ing and throughout subsequent retests . The scores of all
groups of user s converged over t ime so that all three g roups
i ncreased in deviance scores and decreased in the i r ach ievement
or ientat ion over the four yea r s . The sharpest change s in score s
occurred in the year preced ing the drug use .
Peer Influence s
The most consistent and reproduc ible f ind ing in drug research i s the
strong relat ionship between an ind ividual ' s drug behavior and the
concur rent use of drugs by h i s f r iends . The relat ionship is stronger
when based on adolescents ' pe rcept ions of the fr iends ' behavior tha n
on the f r iends ' self-reports (Good e , 1970 J Johnson , 1 9 7 3 J Kandel ,
1973 J Goldste in , 197 5 J O ' Donnell e t al . , 1976 � Brook et al . , 1977 J
Je ssor and Jessor , 1977 1 Kandel et a l . , 1 978a J Orcutt , 1978 J Saart et
al . , 1978 J Huba et al . , 1 9 7 9 ) . On no other characte r i stic except age
and sex i s the s imila r i ty within adolescent fr iendship pai r s as h igh
as it is for use of mar i j uana (Kandel , 1 97 8c ) . Such s imilar ity
r e sults not only from soc ial i zation , the influence of one fr iend on
the other , but also from a process of interper sonal select ion
( assor t ive pai r ing ) , in which adolescents with s imilar values and
behavior seek each other out as fr iends . Long itud inal data on the
format ion and d issolut ion of f r iendships ind icate that selection and
sociali zat ion contr ibute about equally to the simila r i ty in value s
a nd behavior s (Kandel , 1978d ) . Available data on sex d i f ferences in
pee r influence ind icate that females are more suscept ible than male s
to such influence (Jessor et a l . , 1973 J Margulies et al . , 1 9 7 7 ) .
Suscept ibil ity to peer influence i s related to involvement in
peer-related act ivities , e . g . , dat ing or getting together with
f r iends , and to degree of attachment to and rel iance on peer s rathe r
t han parents (Jessor and Jessor , 1978 J Kandel et al . , 1978a J Brook
et a l . , 1 9 8 0 ) . Contact with othe r use r s inc reases the l i kelihood
t hat the ind ividual will have i ncreased opportunit ies to get the
drug . Peer-med iated approaches have been shown to be an effective
vehicle for intervent ions to prevent smok ing of tobacco in
adolescents (Evans , 1977 J Mc�li ster , 1 9 7 9 ) . The powe r ful role o f
peer i nfluence o n the use o f mar i j uana would seem to suggest that it
would be also useful for preventive mar i j uana prog rams .
SUMMARY
Ther e has been a steep r i se in the use of mar i j uana and othe r illic i t
d rug s i n the past decade . S o far i t i s pr imar i ly a youth phenomenon .
Since 1971 there has been at least a doubling of l i fetime exper ience
w ith mar i j uana in every cohort in the 12- to 24-year age group . Of
all psychoactive drug s invest igated ( includ ing inhalants , hallucino
g ens , cocaine , heroin , st imulants , sedat ives , and tranqu i l i zer s ) ,
mar ij uana i s by far the most COIIIDOn ly used illicit drug . Legal drug s
for adults , such as alcohol and tobacco , are the most widely used of
51
52
53
REFERENCES
54
drug use and peer and adult interact ion patterns . J . Consult .
Clin . Psychol . 4 7 : 265-276 , 197 9 .
Jeasor , R . and Jessor , s.L. Problem Behavior and Psychosoc ial
D eve lopment : A Long itud inal Study of Youth . New Yor k : Academic
Preas , 1977 .
Je ssor , R . and Jeasor , S . L . Theory test ing in long itud inal research
on mar ihuana use , pp . 4 1-71 . In Kandel , D. (ed . ) Long itud inal
Research on Drug Use : Empi r ical Find ings and Methodolog ical
I ssues . Washing ton , D . C . : Hemisphe re Publ ishing Corp . , 1978 .
Jessor , R . , Jeasor , S . L . , and Finney , J . A soc ial psychology of
mar i j uana use : Long itud inal studies of h igh school and college
youth . J. Per s . Soc . Psychol . 2 6 : 1-1 5 , 1973 .
Jessor , R . , Donovan , J . E . , and Widmer , K . Psychosoc ial Factor s in
Adolescent Alcohol and Drug Use : The 1978 Nat ional Sample Study ,
a nd the 1974-78 Pane l Study . Final Repor t . Boulder , Colo . :
Univers ity of Colorado Inst itute of Behavioral Sc ience , 1980 .
Johnson , B . D . Mar i j uana Users and Drug Subcultures New Yor k : John
Wi ley , 1973 .
Johnson , B . D . and Uppal , G . S . Mar ihuana and youth : A generat ion
gone to pot , pp . 81-10 8 . In Scarpitt i , F . R . and Datesman , S . K .
( eds . ) Drugs and the Youth Culture . Bever ly H i ll a , Cal i f . : Sage
Publ ications , 1 9 8 0 .
Johnston , L . D . The daily mar i j uana use r . Paper presented at the
Meet ing of the Nat ional Alcohol and Drug Coalition , Washington ,
D . c . , September 1 8 , 1980 .
Johnston , L . D . Frequent mar i j uana use : Cor relates , poss ible
effects , and reasons for using and qu itting . Pape r presented a t
a Conference on Treat ing the Mar i j uana Dependent Per son ,
sponsored by the Amer ican Counc i l on Mar i j uana and Othe r
Psychoactive Drug s , Bethesda , Md . , May 4 , 1981 .
Johnston , L . D . , O ' Malley , P . and Eveland , L . Drug s and delinquency :
A search for causal connect ions , pp . 137-1 5 6 . In Kandel , D . B .
( ed . ) Long itud inal Research on Drug Use : Empir ical Findings and
Methodolog ical Issues . Washington , D . C . : Hemi sphere Publi shing
Corporation , 1 9 7 8 .
Johnston , L . D . , Bachman , J . G . , and O ' Malley , P . M . Drugs and the
Class of ' 78 : Behavior s , Att itudes , and Recent Nat ional Trend s
DBEW Publ icat ion No . (ADM) 79-877 . Washing ton , D . C . : u.s.
Government Pr int ing Off ice , 1979a .
Johnston , L . D . , Bachman , J . G . , and O ' Malley , P . M. 1 9 7 9 Highl ights .
Drugs and the Nat ion ' s H igh School Students . Five Year Nat ional
Trends . DHHS Publ icat ion No . (ADM) 81-93 0 . Washington , D . C . :
u.s . Government Pr inting Off ice , 1979b .
55
56
3
EFPBCTS OF MARIJUANA ON THE RESPIRATORY
AND CARDIOVASCULAR SYSTEMS
RESPIRATORY SYSTEM
The lungs a re the natural target for the harmful effects of smoked
mater ials . Thi s i s as true for ma r ij uana as for tobacco . I n both
i nstances , smoke i s drawn into the lung s where i t can harm not only
the cell a that line the a i rways ( trachea , nasopharynx , bronchi , and
a lveol i ) and constitute the lung t issue , but also impa i r such cella
as lung macrophage& , wh ich are par t of the immune system . As a
r esult , the smoke may inf l ict inj ury d irectly on parts of the system
and also make the lung s vulnerable to agents that normally are held
a t bay by self-cleans ing and self-protecting mechanisms .
Different effects would be expected f rom tobacco and ma r i j uana
smok ing because of the str i k ing d ifferences in the way in which the
two substances are smoked : mar i j uana smoke usually i s drawn deeply
i nto the lung s by one or a few del iberately deep breaths , whereas
tobacco smok ing is gene rally more automat ic , repet itive , and var iabl e
i n pattern . Moreover , because mar i j uana is a • street drug , • it not
only i s inconsi stent i n i t a content but also is subj ec t to contamina
t ion . Also , f i lters are not usually used by ma r i j uana smoker s ,
although water p ipes are used occasionally . Consequently , unde r
natural cond it ions i t is d i f f icult to j udge dosage of act ive
ingred ients , to sort out the influence of contaminants , and to
compare the consequences of ma r i j uana and tobacco smoke .
Exper ience ove r the yea r s with c igarette smok ing has shown tha t
cont inued exposure to tobacco smoke enta ils the r i sk of produc ing
chronic bronchi t i s and/or carcinoma of the lung . But , although
c annabis products have been smoked for centur ies , remar kably little
is r ecorded about the i r effec t s on the lung s . Whateve r contemporary
i nformat ion ex ists i s confounded by the fact that moat mar i j uana
smoker s are also tobacco smoker s .
I n r ecent year s , interest has he ightened i n the smok ing of
mar i j uana as a therapeutic measure . The inhalat ion route takes
advantage of the large sur face a rea afforded by the lung s for
admini ster ing the effect ive const ituent s of ma r i j uana . However , thi s
57
58
Acute E ffects
59
Subacute Effects
Chronic Effect s
A study of 31 Amer ican sold ie r s stat ioned in West Germany who smoked
large quant ities of hashish ( 100 g rams or more per month for pe r iod s
60
61
heavy hashish smokers occ u r red most often in those w ho smoked hash ish
in a pipe without a screen or cotton f i lter J in them , the roof of the
mouth and the back of the throat were inflamed . Per s i stent rhinit is
( inf lamma t ion of the nasal mucous membranes ) was present i n 26
patients . As a rule , allergy could not be implicated in the
nasopharyngeal mani festat ions . Treatment with ant ibiotics ,
d econgestants , and phenylephr ine ( a vasoconstr ictor ) relieved the
symp toms , but they recur red in those who continued smok ing hashish .
Twenty high-dose hashish smokers (more than 50 g rams/month ) had
chronic bronchi ti s as manifested by a chronic sputum-produc ing cough ,
s hor tness of breath , and decreased exerc ise tolerance . On physical
examinat ion , abnormal respi ratory sounds--rhonch i , wheezes , and
r ales --we re present . Chest rad iographs were consi stently normal , but
pulmonary funct ion was abnormal J the vital capac ity ( the maximum
volume of gas taken i n ) was 15 to 40 percent below normal . In s ix of
these subj ects who a.>ked 50 or more g rams per month , biopsy of
bronchial muoosa revealed changes that resembled the abnormalities
that occu r i n older heavy a.>ke r s of tobacco (Auerbach et al. ,
1 961) . The biopsies also turned up atyp ical cells not found in
tobacco smokers .
The s tudy of a respiratory d isease in hashi sh or mar i j uana
smoker s i s d i ff icult because the g reat major i ty also a.>ke tobacc o
c igarettes . Also , the i llegality of mar i j uana smok ing prevents
peop le from volunteer ing informat ion and coope r ating i n exper imenta l
s tud ies . Ba�eline phys iolog ical or clinical studies are d i f f icult ,
beca use the subj ect i s not ident i f ied unt i l he seek s med ical help .
Rats ( Plei acbman et a l . , 1979 ) and dogs ( Ror et al . , 1 9 7 6 ) have
been exposed exper imentally to mar i j uana smoke ove r long pe r iods ( 1
year and 9 00 day s , respect ively ) to determine its morpholog ical
effects on the lung s . At autopsy , the animals demonstrated d amag e of
th• a i rways and also of the lung substance . However , it is d i f f icult
to relate the results of these animal exper iments , in wh ich the
a r t i f ic ial pattern of smok ing d i ffered markedly from that of the
human smoker , to the effects that chronic mar i j uana smok ing might
e lic it in man .
62
The effec t of mari j uana a s a carc inogen for lung , ai rways , and uppe r
r e spiratory organs has not been systemat ically explored . Evaluating
the carc i nogenic i ty of mar ij uana i s d iff icult , because most mar i j uana
smokers alao are tobacco c igarette smokers and because such
carc inogenic ity could have a long per iod of latency , studies o f
tobacco carc inogenesis ind icate that 2 0 t o 30 years of exposure must
occur before tumor s appear in the lung . I t i s under standable that
i nformation concerning the carcinogenic properties of mar ij uana are
not yet ava ilable , part icula rly in the United States , where the agent
has come into extensive use only dur ing the past two decades . An
impor tant problem in evaluating carcinogenic ity i s the fac t that the
leaf is used by igniting it and the inhaled products of its
combust ion may be carc inogen ic , as in the case of tobacco products .
E ven i f i t proved to be carc inogenic , the quest ion would still rema in
as to what constituent in mar i j uana smoke was at fault .
The potency of a substance as a mutagen ( ability to change
genetic mater ial ) can provide a clue as to its possible role as a
c arc inogen . Induct ion of genet ic mutat ions by a substance in test
stra ins of bacter ia cor relates with induct ion of tumor s in test
animals . Fract ions from extracts of mar i j uana smoke part iculates
( • tar • ) have bee n found to produce dose-related mutat ions in fou r ou t
of f ive test stra ins of bacter ia ( Busch et al . , 1979 J Seid and Wei ,
1979 J Wehner et a l . , 19 8 0 ) . By itself , 6-9-TBC was not active as a
mutagen in bacter ial strains ( Glatt et a l . , 1979 ) or in mamma l ian
test systems ( van Went , 19 78 ) .
The extent to which mar i j uana smoke d iffers from tobacco smoke i s
discussed in deta i l in Chapte r 1 . I n general , except for the
p resence of cannabinoids in one and tobacco alkaloids ( n icot ine ) in
the other , the combustion products of tobacco and mar ij uana are
quali tat ively s imilar . On occ a sion , however , d ifferences that may be
meaning ful have been found . For example , one study ( Hoffmann et al . ,
1 9 7 5 ) repor ts that tobacco smoke contains more isoprene and volat i le
phenols , whereas mar i j uana smoke oontains about SO percent more
c arc inogenic hydrocarbons .
Tumorigenicity of mar i j uana and tobacco smoke condensates on
mouse s k i n have been repor ted . In mice pa inted three t imes weekly
w i th a tar suspension of smoke condensate , survival at 74 week s was
better in the ma r i j uana g roup than in the tobacco g roup . S ix of 10 0
m ice pa inted with mar i j uana condensate developed skin tumor s , all of
which were benign , whereas 14 of 100 in the tobacco condensate g roup
d eveloped tumors , two of them malignant ( Hoffman et al . , 197 5 ) .
63
64
custom i n Asia and the Middle East , lung cancer would be expected to
be more prevalent in these parts of the world i f a causal
relationship d id ex ist . Unfortunately , no reliable data have bee n
g athered to settle thi s quest ion . Heavy smok ing of mar i j uana , in
quant itie s canparable to that of tobacco , has been relat ively
uncommon in the United S tates . Therefore , the contr ibut ion of
mar i j uana smok ing to the inc idence of pr imary lung cancer cannot ye t
be answered with any author i tative data .
The most impor tant quest ion about the effects o f mar i j uana o n the
health of the respi ratory system i s whethe r acute or chronic
mar ij uana smok ing cause detectable structural or functional
impa irment of the lung s . Mild but measurable a i rway obstruct ion ,
a ffect ing both large and small a i rways , can be shown to ex ist after 6
to 8 week s of smok ing mar i j uana da i ly , averag ing f ive mar i j uana
c igarettes a day , this decrement in function is reversible , but does
not return to normal within one week of abstaining from smok ing .
In per sons with h i stor ies of heavy smok ing , par t icularly of
hash i sh , chronic inflamma tory changes are seen in the bronchi and
uvula , often in assoc iat ion with chronic sinu s i t i s . These mani festa
tions of uppe r respi ratory d i sturbance have been desc r i bed in
i nd ividuals with hi stor ies of mar i j uana smok ing usually in excess of
3 year s and are reversible when ma r i j uana smok ing is stopped .
Acute exposure of alveolar macrophages in vitro to mar ij uana
smoke causes a reduct ion in phagocytic activity , a cell defense
mechani sm . The agents responsible for this change in macrophage
funct ion are in the vapor phase of ma r i j uana smoke and are not
related to the presence of 6-9-TRC . Also , lung explants exposed to
mar i j uana smoke in vitro show changes in the chromosomal structure of
nuc lei .
There i s as yet no informat ion about the effects of prolonged
smok ing of mar i j uana , that i s , beyond 5 years . Although some
populat ions have been examined for the effects of chronic mar i j uana
smok ing , controlled stud ies are spar se and populations exposed to
mar ij uana smoke only--without exposure to tobacco--apparently are not
avai lable . Par t icularly conspicuous i s the lack of information about
t he effect of chronic mar i j uana smok ing begun in late childhood or
adolescence and oont inued to adulthood . Such stud ies would requ ire
morpholog ical examinat ion of biopsy mater ial from the bronchi and
respiratory passages to determine the presence of structural change s
that ind icate the development of chronic bronchitis and/or lung
cancer . Morpholog ical changes associated with smok ing mar i j uana
could be compared with the morpholog ical abnormalities assoc iated
with chronic tobacco smok ing .
The acute response to inhalat ion of mar ij uana is an apprec iable
bronchodi lat ion , both in normal subj ects and in individuals with
65
One of the g reat uncerta i nt ies about mar ij uana smoking i s its
neoplastic potent ial . No rel iable data are ava i lable concerning the
i ncidence of carc inoma of the lungs and upper respiratory passages in
long-term use r s of cannabi s .
But a var iety of exper imental stud ies has sounded the alert that
mar i j uana smok ing--just as tobacco smok ing--may be carc inogenic and
t hat a combinat ion of tobacco and mar i j uana smoke may have g reater
neoplastic potent ial than e ither one alone . Although the exper imenta l
observat ions have rai sed the suspic ion , long-term observat ions on
human subj ects--and possibly on smok ing animals--will be necessary to
settle the i ssue .
With respect to the per formance and defenses of the lung s , these
studies would be informat ive :
•
the physiolog ical , biochemical , and morpholog ical
interactions of combined exposu res of the respiratory tract to
tobacco and marij uana smoke 7
•
the interact ions of cannabis and alcohol on the funct ion of
the respiratory tract 1
•
t he long -term effects , i . e . , 10 to 30 years , of exposure of
the respiratory tract to frequent use of cannabi s in the absence and
pressure of exposure to tobacco smoke ( for th i s purpose , large-scale
epidemiolog ical stud ies may be requ ired ) 7
•
the phys iolog ical effects and clinical consequences o f
exposure o f alveolar macrophage& and other lung cells to long-term
exposure to mar i j uana smoke 7
•
the immunolog ic effects of mar i j uana smoke exposure on cells
and on the ent ire body .
66
With respect to carc inoma of the lung , these stud ies seem essent ial :
•
an epidemiolog ical survey to determine ove r the next 2 0 to
30 years if there will be an increased inc idence of pr imary lung ,
laryngeal , oropharyngeal , esophageal , nasal , or s inu s cance r in
c hronic mar i j uana smokers r
•
e p idemiolog ic and patholog ical stud ies in humans and
exper imental stud ies in an imals to evaluate the carcinogenic
potent ial of chronic mar i j uana smok ing on the lung , larynx ,
oropharynx , nasal , and s inus epithelium .
CARDIOVASCULAR SYSTEM
W ith respect to the hea rt and c i rculat ion , the most evident effect in
human be i ng s of smok ing mar ij uana , or of ingesting the active
i ngred ient (6-9-TBC ) , i s a brisk increase in heart rate
( tachycard ia ) . Although this i s not threaten ing to the normal
hear t , the rapid hea r t act ion can be harmfu l to the heart in wh ic h
t he c irculat ion i s compromi sed by atheroscleros i s or i s on the verge
of f a i l ing .
The responses of the card iovascular system to acute exposure to
mar i j uana d if fe r between human be i ng s and most other mamma l s in that
the human subj ect typically responds with an increase in heart rate
(Br ight at al . , 1971 J Beaconsfield et a l . , 1972 J Perez-Reye s et al . ,
1 9 7 3 ) , whereas most mamma ls show a slowing in rate ( bradycard ia)
(Cavero at a l . , 19 7 3 J Graham and Li , 1973 J Rosenkrant z and Braude ,
1 974 1 Vollmer et a l . , 1974 r Adams et a l . , 1976 J Hardman and Rosko ,
1976 J Kawa sak i et al . , 198 0 ) . Ruman blood pressure usually increase s
moderately on acute admini strat ion of 6-9-TBC , but in monkeys and
dogs acute administration is followed by a decrease in systemic
ar ter ial pressure . Typical effects on hea r t rate and blood pressur e
have been attr ibuted to altered autonomic funct ion ( Loewe , 1944 J
Joachimoglu , 19 6 5 J Ames , 1968 r Gill and Paton , 197 0 ) .
Effects on the card iovascular system are to some extent a
function of dose , route of administration , and durat ion of exposure .
Tolerance to s�e of the card iovascular effects in human be ing s
develops with chronic use ( Benowitz and Jones , 19 7 5 , 1977a , b J Nowla n
and Cohen , 1977 ) , but cont inued use does not result in any per s i stent
alterat ion in card iovascu la r func t ion after cessat ion of exposure
( Dornbush and Kokkevi , 1976 ) .
E ffects on Hea rt Rate In healthy young adults , acute admini strat ion
of ma r i j uana by smok ing ( 1 0 mg tota l dose ) cause s a prompt increase
i n heart rate ( increasing by up to 90 beats/minute ) for about 1 hour .
67
68
because i t has not been poss ible to oontrol separately the severa l
var iables that modify left ventr icular funct ion and are changed �
administration of 6-9-TBC . Changes in heart rate , after load
( systemic vascular resi stance , blood pressure ) , or preload (plasma
volume , venous return ) individually can cause changes in heart s i ze
and ventr icular per formance . In spite of these l imitat ions ,
conclusions can be drawn f rom the observat ions on human beings .
Def initive animal studies of 6 -9-TBC e ffects on ventr icular
per formance have not been done .
I nd ices of card iac performance usually improve after mar i j uana or
6- 9-TBC . Almost invar iably this improvement can be att r ibuted to
the i ncrease in hear t rate ( Gash et al . , 1 9 7 8 ) . The acute
administrat ion of 6-9-TBC ( 2 5 Pg/kg intravenously ) to healthy
young males elicits , i n assoc iat ion with the inc rease in heart rate ,
changes i n the ventr icula r contract ion pe r iods (an increase in
e j ect ion t ime and shortening of the preinj ec t ion per i od ) , whi le
systemic arter ial pressure i s unaffected (Wei s s et a l . , 1972 J Kanak i s
e t a l . , 1976 ) . Beta-adrenerg ic blockade by propranolol i s followed
� less str i k ing changes i n the contraction t ime intervals . Anothe r
s tudy of 17 subj ects who smoked two to three c igarettes ( 2 0 mg
6- 9-TBC pe r c igarette ) found card iac output increased by 2 8 percen t
and heart rate � 30 percent , in conj unc tion with a slight decrease
in stroke volume , wh ich affects pulse pressure ( Tashk in et al . ,
1 977b) .
69
reflex adj ustments in the heart and systemic c i rculat ion . Finally ,
o ther possibilities , such as desens i t i zat ion or blockade of
per ipheral adrenerg ic receptor s , have not been examined .
Although the data on human beings are not adequate to determine
how ma r i j uana inf luences autonomic funct ion , evidence that it doe s
has been obtained . Por example , 6 - 9-� appears to reduce a number
of autonomic reflexes a After mar i j uana , the typical changes in hear t
rate and blood pressure elic i ted by the Valaalva maneuver ( a forced
exhalat ion effort aga inst the c losed g lott i s ) are decreased , and so
are the reflex c i rcu latory responaea to immer aion of the hand in cold
water ( Beaconsfield et a l . , 1972 J Benowi tz et al . , 197 9 ) . However ,
dur ing chronic administration of 6-9-TBC , no change occur a in the
reflex decreaae in hear t rate cauaed by infua ion of a doae of the
vaaoconstr ictor phenylephr ine suf f ic ient to increase the blood
p resaure ( Benowitz and Jonea , 1975 J Benowitz et a l . , 1979 ) .
Exerc i se
Although amok ing mar i j uana or the introduction of 6-9-TRC into the
body ia apparently wi thout deleter ious effect on the normal heart and
c i rculat ion , the poss ibility is g reat that the abnormal heart and
c irculat ion will not be as tolerant of an agent that speeds up the
hea r t , aomet imes unpred ictably raises or drops the blood pressure ,
70
and mod i f ies the act ivit ies of the autonomic nervous system .
Therefore , it is pert inent to examine the prospects that mar i j uana
(or 6-9-THC ) may be ha rmfu l in individuals with coronary hea rt
d i sease , cerebrovascular d i sease , hyper tens ion , and heart failu re .
Moreover , it may be impor tant to determine i f 6-9-THC interacts i n
its effects o n the abnormal heart or c i rculat ion with othe r agents
that are be ing administered for therapeutic purposes .
D ata on this top ic are sparse , presumably because of the relat ively
shor t t ime that mar ij uana has been ava i lable in th i s country . Those
who have smoked mar i j uana a re j ust ente r i ng the age when coronary
athe roscleros is is common . Howeve r , it has been shown both in norma l
i nd ividuals and in ind ividuals w ith coronary artery d isease that the
acute administration of 6-9-THC by smok ing or inject ion can cause
changes in the electrocard iog ram ( ECG) (Johnson and Domino , 1971 1
Beaconsf ield et al . , 1972 1 Kochar and Rosko , 1 9 7 3 ) . Premature beat s
have a lso been noted . The reasons for the changes are unclear . Also
not understood i s the contr ibut ion of the increase in heart rate
i tself to the ECG changes and to the premature beats .
In some patients with coronary artery d i sease , increased
c atecholamine& can induce arrhythmias . It seems l i kely that in such
pat ients 6-9-THC could have the same effect . Also , in pat ients
with coronary artery d i sease a large increase in heart rate can
induce ang ina (pain) and even i schemic damage f rom insuf f ic ient
oxygen as a result of an obstructed blood vessel . If 6 -9-THC were
to increase hea rt rate markedly in such pat ients , and at the same
t ime increase the need for cardiac perfusion because of the increased
c ard iac wor k and because of the i ntensi f ied effect of catecholamine&
on the heart , it seems reasonable that there oould be induct ion of
ang ina and potent ially prec ipitat ion of ischemic damag e . Furthermore ,
i f 6-9-THC dulled the apprec iation of pai n and the appropr iate
responses to pai n , the pat ient might not take su itable measure to
relieve the ang ina , thereby increasing the r i sk of damage or
a r rhythmias .
A decrease in oxygen-carrying capac i ty of blood because of
format ion of carboxyhemog lobin could also be troublesome . Exerc i s e
tolerance has been repor ted t o decrease in individuals with ang ina
after smoking ma r i j uana 1 this dec rease i s in contrast to the
u naffec ted exerc ise tolerance after smok ing a placebo mar ij uana
c igarette (Aronow and Cass idy , 19 7 4 ) . Oral ingest ion of 6 -9-THC o r
smok i ng mar i j uana apparently can cause mar ked hyper tension in
assoc iat ion with an increase in systemic vascular res i stance
( Benowitz et a l . , 1979 ) , which would place the heart with coronary
artery d i sease at r isk of damage .
These observat ions concur i n i nd icat ing that mar i j uana and
6-9-THC increase the wor k of the heart , often in many ways . The
conc lus ion seems inescapable that this increased work , coupled with
st imulat ion by catecholamine& , may tax the heart to the point of
c linical hazard .
71
Cerebrovascular Disease
There are few , if any , ind icat ions that 6 -9-THC has d i rect effects
on the cerebral c i rculat ion that would be impor tant in pat ients with
cerebrovascular d i sease . I n the occas ional pat ient who develops
hyper tens ion after smok ing , there would be an increased r isk of a
cerebral vascular acc ident ( stroke ) . Also , because 6-9-THC
admini stered after at ropine can cause marked increases in blood
pressure , thi s combinat ion would place the patient with cerebro
vascular d i sease at r i sk , as would smok ing after ingest ion of othe r
muscarinic blockers . In some pat ients , postural hypotens ion could be
a problem , not only for persona with abnormal cerebral c i rculat ions ,
but also with abnormal corona ry ci rculat ions .
Hypertens ion
Hear t Fai lu r e
Few stud ies evaluate interact ions between 6 -9-TRC and other drugs
that act d i rectly or indi rec tly on the heart . Propranolol usually
attenuates the increase in heart rate caused by 6-9-TBC . Atropine
72
can g reatly potent iate the abi l ity o f 6-9-THC to inc rease sy stemi c
arter ial pressure ( Benowitz and Jones , 1 9 7 7a , b) . A number of poss ible
interact ions can be iaag ined . I f a pat ient were tak ing a d rug that
blocked uptake of catecholamine& by nerve terainals , then those
effects of 6-9-TRC that are med iated by catecholamine & would be
intensi f ied . Because a g reat many psychotropic and ant ihypertens ive
drug s mod ify aetabol ism of neurot ransmitters in the central nervou s
system and per iphery , a wide var iety of interact ions with 6 -9-TBC
seems possible .
The smok ing of mar i j uana causes changes in the heart and c i rculat io n
that are character ist ic of stress . But there i s no evidence to
ind icate that it exerts a permanently deleter ious effect on the
normal card iovascular system . Ne i ther is the re convi ncing evidence
that mar i j uana would be of particular benef it in treat ing any of the
major foras of card iovascular d isease .
The s i tuat ion i s qu ite d if ferent for those with an abnormal hear t
o r c irculat ion . Evidence abounds that mar i j uana increases the wor k
of the heart , usually by increas ing heart rate , and in some per son s
by i ncreasing blood pressure . Thi s increase in workload poses a
threat to pat ients with hypertens ion , cerebrovascular d i sease , and
coronary atheroscleros is . The magni tude and inc idence of the threat
rema ins to be deterained because mar i j uana smok ing has largely been
conf ined to younger adults who are only now entering the age of
ser iou s compl icat ions of atherosclerosi s on the heart , brain , and
per ipheral vessels .
M ar i j uana also can cause postural hypotens ion . Th i s drop in
blood pressure could be hazardous in those ind ividual s with
compromised blood f low to the heart or bra i n , espec ial ly if they are
volume-depleted (dehydrated ) or i f other drug s have impai red reflex
control of the i r blood vessels .
M ar i j uana appear s to intens i fy the effects of the sympathetic
nervous system on the heart , an undes i rable consequence in pat ient s
w ith coronary artery d isease. and in those susceptible to arrhythmias .
Many of the undes i rable effects of mar ij uana on the card iovascular
system seem to become less seve re following chronic exposure . Whether
the relat ive pauc ity of repor ts of the i ll-effects of mar ij uana on
the abnormal cardiovascular system is a consequence of adaptat ion to
chronic u sage or to lac k of exposure to mar i j uana of a popu lat ion
t hat is suff ic iently advanced in years to be susceptible to its
untoward effects remains to be determined .
Add it ional stud ies are needed both ( 1 ) to provide informat ion on the
mechanisms respons ible for the observed effects of mar i j uana on the
card iovascular system and ( 2 ) to provide new data on the ef fects of
mar i j uana in patients with known forms of card iovascular d i sease .
73
•
The aanner in which A-9-TBC acta on the heart to chang e
tbe rate and force of contract ion needs c lar if icat ion . Direct
effects on the hear t are not l i kely to d iffer among spec ies , and thu s
exper iments can be planned for a • standard • heart preparat ion .
•
Direct effects on electr ical act ivity , which might relate t o
reports of changes in e lectr ical activity and product ion of preaature
impulses a a well aa changes in s inus rate , should be evaluated with
s tandard methode and standard preparat ions .
•
Di rect effects of A-9-TRC on vascular smoot h muscle should
be explored . Por this purpose , i t would be essent ial to use 8Cile
veaaela that d id , and other s that d id not , .have funct ioning nerve
terminals . It would be impor tant here to include stud ies on selected
coronary vessels and on veaaela which play a dominant role in the
r egulat ion of systemic vascular resistance .
•
A number of related studies are needed before the effects on
humans can be explained in ful l , par t icularly the effects of
A-9-TRC on the renin-ang iotensin ayatea in the k idney , wh ich
provides control of arterial pressure , and on the seve ral sequences
of prostag land in metabol i 81l .
S tud ies also are i nd icated to obta in new data about the effects
of aarij uana on a
•
persona with hypertens ion , coronary artery d i sease , and
cerebrovascular d isease '
•
i ncreases in systemic arter ial pressure in low- and
h igh-renin hypertens ion and the interact ions betwee n A -9-TRC and
several c laaaea of ant ihypertensive med icat ions ,
•
the interact ions between the salt and water-retaining effect
of A -9-TIIC and d iuret ics that could be employed both in
hypertensives and those with heart fai lure .
REFERENCES
74
75
76
77
78
79
4
EI'PEC'l'S OF MARIJUANA ON 'l'HE BRAI N
The moat c learly e stabli shed effects of cannabi s are upon behavior .
These effects , descr ibed in Chapte r 6 , ind icate that aajor act ions o f
c annabinoids are upon the bra i n . The ways in which mar i j uana alters
the brain to produce ita behavioral ef fects are not known .
Efforts to d iscover the causes of the behavioral effects have
included stud ies on brain morphology , physiology , and chemi stry to b e
r eviewed in t h i s chapter . Effects o f mar i j uana o n brain electr ical
act ivity and on brain chemistry have been measured , but the i r
s ignif icance for brain funct ion i s not known because o f our l imited
knowledge of brain-behavior re lat ions . Ma r i j uana causes temporary
i ntox icat ion and results i n changes in brain phys iology and chemistry
s imi lar to those caused by othe r intox icat ing drugs . Although these
k inds of stud ies may u lt imately shed l ig ht on the way mar ij uana
produce s ita behaviora l changes , they do not provide answers to
impor tant clinical quest ions . Does mar i j uana cause long-term changes
in the brain that lead to chronic psychiatr ic or neurolog ical
d isorder s ? So far , the stud ies reviewed below provide no convinc ing
evidence for long-term changes because of u se of mar i j uana .
BRAIN MORPHOLOGY
Gross Morphology
D ata suggesting that use of mar ij uana causes brain atrophy were
obta ined by pneumoencephalog r aphy ( inj ec t ion of air into spaces i n
a nd sur round ing the brain) on 1 0 u sers o f mar i j uana who had sought
med ical attent ion because of neurolog ic complaints (Campbell et al . ,
1 97 1 ) . The s i ze of the largest brain cavities ( ventr icle s ) was
80
81
mel�aured to dete rmine whether loss of brain t issue had oceurred . The
author s interpreted the i r data as showing that atrophy was present .
One of the f irst c r i t ics of thi s report quest ioned the
inte rpretat ion of the rad iolog ic techniques u sed (Bull , 1971) . Th e
results also have been ser iously c r i t ic i zed because of the mar ij uana
user s stud ied . They had neu rolog ical symptoms or s igna suff ic ient to
j ust ify an i nvas ive and painful d iagnost ic teat , but there is no
evidence that such neu rolog ical complaints occur with g reater
f requency in u sers of mar i j uana than in the general populat ion .
Further , Campbell ' s pat ients d id not only use ma r i j uana , but also
u sed such behavior-alter ing drug s , as lyserg ic ac id d iethylamide
( LSD ) and amphetamines .
More recent evidence has been provided by computed tomog raphy
(CT) scans of the brain . Thi s technique , wh ich i s noninvasive ,
painless , and y ields more prec ise and quant i f iable measures of brain
atrophy , has replaced pneumoencephalography as a d i agnostic teat .
Using CT methods , two stud ies fai led to f ind evidence of cerebral
atrophy in healthy chronic mar ij uana u se r s (Co et al . , 1977 J Keuhnle
e t al . , 1 9 7 7 ) . These latter results suggest that the ear l ier
f ind ing s were attr i butable to the impr ec i s ion of convent iona l
pneumoencephalography , or to the fact that a g roup with neurolog ic
compla ints was stud ied , or to the use of mult iple psychoactive drug s
by these i nd ividuals . This last possibi l i ty i s reinforced by CT
scans of animals who rece i ved a var iety of paychoactive drugs .
Mar ij uana a lone produced no evidence of brain atrophy , whereas other
drug s , such as amphetamines , d id produce changes ( Rumbaugh et a l . ,
1980) .
Microscopic Morphology
Three post mortem stud ies on monkeys in the same laboratory have
r epor ted changes in the mic roscopic morphology of the brain at the
ultrastructural level (Harper et al . , 1977 J Meyer s and Heath , 1979 J
Heath et a l . , 1 9 8 0 ) . No s imi lar stud ies on human bei ng s have been
repor ted . The monkeys rece ived e i the r chronic exposure to mar ij uana
smoke or chronic inj ect ions of A-9-TBC . Changes repor ted to have
occu r red in the brains included alterat ion in synapt ic* cleft width ,
increased dens ity of synapt ic cleft mater ial , a decrease in volume of
rough endoplasmic ret iculum , presence of clumping of synaptic vesicles
in axon terminals (where impu lses travel away from the cell body ) ,
and an increase i n intranuclear i nclus ions . These changes appear
dramat ic , but they must be interpreted with caut ion . The three
stud ies a re baaed princ ipally upon exami nat ion of two l imited bra in
areas only i n three treated monkeys , two rece iving mar ij uana smok e
* A synapse i s the reg ion of commu nicat ion between nerve cella ,
forming the place where a nervous impulse i s transmitted from on e
nerve cell to another .
82
and one intravenous 6-9-THC ; a fou rth treated anima l was added to
the last study and more brain areas were analyzed in it ( Heath et
al . , 19 8 0 ) . Further , althoug h the mate r ial was eva luated
• doublebl ind • after e lectron microg raphs had been made , it wou ld
appear that f ixation , tissue preparat ion , and photog raphy were
c a r r ied out before these safeguards aga inst bias were applied . I t i s
possible that unknown but systematic d i f ferences occu r red between
exper imental ( treated ) and control animals in f ixat ion and
preparat ion of t i ssue or i n se lect ion of sample s for micrography . I n
add i t ion , i t should be noted that a t least one o f the changes noted ,
clumping of synapt ic ves icles (Harpe r et al . , 1977 ) , i s a normal
var iant in the synapt ic morphology of axon terminals in mamma lian
brain ( S ipe and Moo r e , 1977 ) and does not represent a patholog ica l
c hange . Also , these s tud ies have not been replicated and , beCause
the basi s for interpretat ion is such a l imited sample , it is con
c luded that no definit ive interpretat ion can be made at this t ime .
However , the poss ibility that mar ij uana may produce chronic , u ltra
s tructural changes i n brain has not been ruled out and should be
inve st igated .
NEUROPHYSIOLOGY
One sou rce of informat ion on the mechani sms of act ion of a d rug , such
as ma r i j uana , i s the study of its phys iolog ical e ffects . Effec ts of
ma r i j uana on the e lectr ical act ivity of the brain have been
d emonstrated by means of the e lect roencephalog ram ( EEG ) . The
standard , or clinical , EEG measu res t iny va r iations at the scalp o f
voltages produced by the e lectr ical activity o f the brain . Voltage
d i f fe rences between two points on the scalp , or between the scalp and
an inactive reference s i te , are recorded on moving paper , produc ing a
g r aph of voltage over t ime . The waves observed are class i f ied
accord ing to frequenc ies as delta , theta , alpha , and beta . Whi le the
changes i n EEG desc r i bed below are of interest , the i r biolog ical
s ig n i f icance is unknown .
83
o f cannabi s on the wak ing EEG . FOr a fur ther review of thi s
l iterature , see Fr ied ( 1977 ) .
One can employ computer averag ing to retr ieve from the EEG cer ta i n
i nformat ion that i s not detectable by vi sual inspection . In this
way , the electr ical events that follow a st imu lus may be stud ied in
subj ects who are at rest , asleep , or car ry ing out certain tasks .
These computer -averag ed potent ials provide clues to the sequent i a l
processing of informat ion by the brain .
Althoug h the literature i s incons i stent , i t i s clear that cannabi s
c an produce effects on event-related potent ials ( EPa ) · ( Berning et
al . , 1979 ) . Effects on ampli tude are more often reported than effect s
84
Drug s often produce marked effects on the EEG dur ing sleep , bu t
p roduc ing l ittle or no change in the wak ing EEG . Th i s i s the case
with ma r i j uana and 6-9-THC .
In relat ively h ig h doses ( 70-210 mg/day ) , 6-9-THC and mar i j uana
extrac t produced ma r ked effects on sleep EEG ( Fe inberg et al . , 19 7 5 ,
1 97 6 ) . On initial administrat ion , the t ime spent i n REM sleep*
( stage REM durat ion) was reduced be low base line levels (placebo) by
1 8 percent and the number of eye movements by 49 percent . Some
tolerance ( return toward base line levels ) was apparent du r ing the
per iod ( 12-16 days) of drug administrat ion . On withdrawal , REM
durat ion was increased above basel ine by 4 9 percent and rapid eye
movements were increased by 67 percent . Whi le these effects are
qu ite large , the i r clinical s ignif icance is unknown . They were not
accompanied by such unusual behavioral changes as ha l luc inat ions or
d i sor ientat ion , although there wa s evidence of withdrawal-
i r r itab i l i ty , inc reased reflexes , and mild ag itat ion . With much
smaller doses of 6-9-THC , e ithe r a small reduction i n REM sleep
( Pivik et al . , 1 9 7 2 J Freemon , 1 9 7 4 ) or no change has been repor ted
(Bar ratt et al . , 19 7 4 J Bosko et al . , 1 9 7 3 J Prani koff et al . , 197 3 ) .
* A stage in sleep dur ing which Rapid Eye Movements may be detected
and vivid dreaming u sually occur s .
85
The f ind ings of several animal stud ies car r ied out to investigate the
effects of ma r i j uana on EEG d i f fer in some respects to those in human
be ing s . Spec ies d ifferences are thought to be responsible for some
of the var iat ions found f rom spec ies to spec ies . FOr example , 5 and
1 0 mg/kg 6 - 9-THC administered acutely to rata suppressed REM ,
reduced slow-wave sleep , and increased wakefulness (Moreton a nd
Davi s , 1 9 7 3 ) . Chronic admini strat ion caused an init ial suppression
of REM , which returned to baseline after 4 days and remained at
basel ine levels for a further 1 6 days . I n contrast to the human
s tud ies , there was no withdrawal increase in REM above baseline
dur ing a 10-day withdrawa l pe r iod . S imilar result s we re obtained i n
a abor t-term study that employed intravenous doaea o f 6 - 9-THC ( 0 . 5
and 1 . 0 mg/kg ) to rabbits ( Fuj u imor i and B�ich , 19 7 3 ) .
Apprec iable qual i tat ive d i fference s in sleep EEG response to
6- 9-TRC have also been detected in pr imates when compa red with
human stud ies . When 1 . 2 mg/kg 6- 9-THC i a admini stered to squi rrel
monkeys i n a s i ng le oral dose , da i ly for 6 0 days , no s ig n i f icant
e f fects on REM sleep durat ion occu r red r i nstead , a dec rease in EEG
stages 3 and 4 was noted ( Adams and Bar ratt , 1 9 7 5 ) .
86
E lec trode implantat ion i s rarely possible in man , but i s a rout ine
and essent ial technique for the study of brain e lectrophys iology in
animals . Animal exper iments also permit use of h ig he r doses and more
prolonged administrat ion than is possible with human subj ects . FOr
these reasons , animal exper iments can yield impor tant data that
cannot be obtained in human stud ies . In general , EEG record ing s
a fter short-term admini strat ion o f mar i j uana are s imi lar from sur face
(cor tex ) or from deep brain ( subcor tex ) reg ions . However , after
c hron ic administration of h ig h doses of � - 9-THC , abnormal record ing s
have been observed in subcor t ical r eg ions o f some animals , read ing s
not seen i n the cor tex . Althoug h these f i nd ing s have not been
r epl icated , they are of par t icular concern , beCause they r a i se the
poss ibi lity that chron ic exposure to h ig h doses of mar i j uana produce s
long-lasting effec ts on brain phys iology .
Afte r intravenous admin i strat ion of a range of � - 9-THC dose s
( f rom 0 . 0 5 to 1 2 . 8 mg/kg ) to r hesus monkeys , a general increase in
EEG synchrony was observed J and at hig her dose ranges , there wer e
spec i f ic EEG changes i n the l imbic system , f rontal cor tex , thalamus
and fast ig ial nuc le i (Martine z et al . , 197 2 ) . I n thi s study , the
i nc rease in h ig h-voltage activity showed a good dose-response
relat ionship . In a second study , oral dos ing of three rhesus monkey s
w ith a c rude mar i j uana extract containing 2 5 percent � - 9 -THC
produced dose-related EEG changes , includ ing slow waves in the
h ippocampu s , amygdala , and septum ( S tadnick i et al . , 197 4 ) .
Tole rance to the behavioral and EEG changes occurred with daily
treatment , which was stopped after 51 days . Behavioral withdrawa l
e ffects were noted , but EEG changes dur ing wi thd rawal we re min imal
and there was no evidence of EEG changes pe r s ist ing beyond the pe r iod
of �-9-THC ingestion .
Two stud ies that monito�ed EEG record ing f rom deep brain s i tes
afte r chronic administrat ion of h ig h dose s of ma r i j uana found change s
i n EEGs f rom deep brain s i tes that were not observed in sur face areas
after drug withdrawa l ( Feh r e t a l . , 1976 J Heath , 1976 J Heath et al . ,
1 97 9 ) . Stud ies of two rats w i th electrodes implanted in the anter ior
neocor tex , dorsal h ippocampus , and mesencephal ic ret icular format ion
1 year after exposu re to 20 mg/kg for 6 months ( Fehr et al . , 1 9 7 6 )
yielded h ippocampa l record ing s w i t h • epi lept iform • abnormalities , i n
contrast t o one control and t wo alcohol-t reated an imals .
The second study was carr ied out on thi r teen feral-ra i sed rhesu s
monkeys ( Heath 1976 7 Heath et a l . , 1 9 7 9 ) . Ten monkeys had electrodes
implanted in deep s i tes and i n brain cor tex . Fou r monkeys were made
to smoke mar ij uana three t imes a day , 5 days per week for 6 months 7
two othe r monkeys with implants were g iven 0 . 6 mg/kg 6-9-THC each
day , 5 days per week for 6 months 7 s t i ll other monkeys were used as
controls or rece ived smaller doses of ma r i j uana . In three h igh-dose
monkeys , two smok ing and one ingest ing � - 9-THC , changes in EEG
could be detected in record ings from deep brain s i tes , the changes
continued 7 months after cessat ion of ma r i j uana exposure . No EEG
a bnorma l i t ies were present in record ings f rom the bra in sur face .
87
One of the major c r itic i sms of both these stud ies i s the i r u se of
small numbers of animals . Fu r the rmore , there have been no attempts
a t repl icat ion by other workers . Never theless , because these
finding s provide some of the only ev idence for a poss ible
i r reve r s ible effect of chron ic h igh dose s of mar i j uana , they are
ment ioned here with a st rong urg ing for add it ional stud ies in an
e ffort to repl icate these f ind ing s .
EPILEPSY
Because of the e f fects of mar i j uana on brain e lectr ical act ivity ,
quest ions have been raised about its assoc iation with ep i lepsy . Two
quest ions are raised in the l i terature . First , does mar ij uana
produce se i zures? Second , doe s ma r i j uana or a der ivat ive prevent
sei zures? The f i rst quest ion will be d i scussed here . The second i s
reviewed in Chapter 7 , wh ich i s concerned with the potent ial
t herapeut ic u ses of cannabis .
There are anecdotal reports in the l i terature that suggest
se i zures may be induced by ma r i j uana in some pe r sons with a known
s e i zu re d i sorder . A r igorous study , using adequate numbers of
pat ients with documented se i zure patterns , has not been done .
Reports of exper imental animal stud ies a re conflict ing and var ied
( Feeney et al . , 1 97 3 , 1979 7 Lemberger , 1 9 8 0 ) . There are some
c i rcumstances i n which cannabi s admini strat ion does not alter certain
type s of se i zures such as the photosens i t ive se i zures in the baboo n
( Meldrum et al . , 1974 ) , and others in which it seems that se i zures
are induced . A sing le rabbit that responded to 6-9-THC adminis-
trat ion with sei zures was bred to establ i sh a colony of rabbits with
s imi lar response (Consroe and Fish , 1981) . I t will be of consider
able i nte rest to determine mechani sms of se i zure induct ion and
pharmacolog ic response patterns in thi s unusual animal model .
However , as descr ibed furthe r in Chapter 7 , the bulk of the animal
l i terature and some data from human stud ies suggest that the mor e
p rominent effect of mar i j uana der ivat ives , espec ially cannabinol and
cannabid iol , i s to decrease rather than i nc rease se i zure suscept i
b i l i ty ( see Karler and Turkanis , 1981 , for review) .
NEUROCHEMISTRY
Our knowledge of the effects of mar i j uana on brain chemistry has come
largely f rom stud ies in animals . cannabi s and some of its
d erivat ives have been shown to cause chemical effects in the brain ,
as demonstrated by effects on neu rotransmitters and on nuc leic
acids . The evidence i s reviewed below .
Neurotransmitter s
88
A very few stud ies have examined the ef fects of mar i j uana o n
neurochemical var i abless other than neurotransmitters ( Luthra and
Rosenkrantz , 1 9 7 4 r Luthra et al . , 1 9 7 5 , 1 9 7 6 ) . Afte r chronic
adm ini strat ion to rats e ither of 6 -9-THC or mar ij uana smoke ( for
89
SUMMARY
90
dete rmine whether any per s i stent abnorma l i ties have been produced . A
systematic approach to these que st ions u s i ng modern methods of
measu rement and analy s i s cou ld extend ou r present knowledg e
substant ially .
REFERENCES
91
92
93
5
EFFECTS OF MARIJUANA ON
OTHER BIOLOGICAL SYSTEM S
A var i ety of stud i e s ind icate that mar i j uana and some of it s
d e r ivat ives have reve r s ible , suppr e s s i ve e f fects upon test icular
func t ion in an imals and men . The se have been measured in terms o f
d imini shed we ights o f the prostate g land , semina l ve s icle s , or
testes , and in dec reased leve l s of te stoste rone ( the male hormone ) in
b lood plasma or suppress ion o f spe rmatog ene s i s following chronic o r
acute adm i n i st r at ion o f cannab i s o r � -9-THC . App ropr i ate obse rva
t ion s have i nd icated that the e f fect s of cannabinoids on the ma le
reproduct ive t r act and on test icu lar funct ion were completely
r eve rsed 1 month a fter d r ug withd rawal .
Ther e i s no gene r a l ag r eement as to the cause or magnitude o f
t hese e f fects . The maj or reasons for this lac k o f ag r eement re late
to major d i f fe rences in study des ign , inc lud ing spec i e s stud ied (man ,
monkey , or rodent ) , route of drug admini strat ion , and pu r ity of the
drug u sed .
Human Stud i e s
94
95
( FSH ) , gonadotrop ins that cont rol the g rowth of the ovar ies or testes
and the i r hormonal act ivit ies , were in the normal range ; howeve r , in
men smok ing more than 1 0 mar ij uana c igarettes per wee k , the FSH leve l
was s ign i f icantly lowe r than for those who smoked 5 to 10 mar i j uana
c igarettes per week . Because only random samples of blood were
obta ined for gonadotropic measurements , small but s ig ni f ican t change s
could have been missed . Levels of prolact in , the female hormone
involved in lactat ion and also present in small quant itie s in men ,
were all in the low normal range . In add i t ion , the men who smoked
more than 10 mar ij uana c ig a rettes per wee k had s ignif icantly lowe r
sperm counts than those who smoked the lesser quant ity ( 26 ver sus 6 8
mill ion/ml ) . These individuals obtained mar i j uana from a var iety of
sources , and there was no way to determine whethe r they were tak ing
othe r drug s that could lowe r plasma te stosterone .
Later in 1974 , another study reported that plasma testosterone
levels were not suppressed in 27 men stud ied in a research ward
( Mendelson et a l . , 1974 ) These ind ividuals smoked mar i j uana
c igarette s suppl ied by the federal government . For unexplained
r easons , the mean testosterone levels in these individuals were
greater than 1 , 0 0 0 ng/dl ( h ighe r than the normal mean ) before and
dur ing the smok ing pe r iods . Thi s is in marked contrast to the mean
value of 7 4 2 ng/dl for nonsmoker s in the study of Kolodny et al .
ment ioned above . The re was no report of gonadotropic values or semen
analysis in the Mende lson Study .
A study of 1 6 pat ients on a metabolic ward who smoked NIDA
cigarette s ( Hembree et al . , 1979 ) showed that 5 to 6 week s o f
h igh-dose ( 2 percent ) mar i j uana administ rat ion ( 8-20 c igarettes/day)
wa s assoc iated with a decline in sperm count dur ing the f i fth a�d
s ixth week s a fte r init iation of drug exposure . Thi s was preceded by
a decrease in sperm mot i l ity and an increase in abnormal forms of
sperm . Once a week dur ing the study f ive blood samples were obtained
at 1 5-minute inte � vals for measurement of testosterone , LH , and PSH .
No change in these hormone levels was noted throughout the s tudy
( althoug h no values were reported ) . The relationship in t ime of
.
these samples to the last previous c igarette was not ment ioned ,
therefore the test would not have excluded a trans ient decline i n
hormonal leve ls after each c igarette . However , because hormonal
suppression of spermatogenesi s takes longer than 4 weeks and usually
i s not assoc iated with an increase in the n�ber of abnormal forms
and a dec rease in mot ility , the author s concluded that the effec t
upon the seminiferous tubular epithelium was d irect rather than by
suppress ion of gonadotropins . Th i s i s the only reported study in ma n
that measured the hou r-to-hour fluctuat ions in gonadotropic levels .
Anothe r study (Cogg ins et al . , 1976 ) evaluated the health statu s
·
of 84 mar i j uana smoke rs who had used the agent three or more t imes
per week for a min imum of 10 yea r s . Testosterone levels were
measu red in 38 u sers and 38 nonuse r s . The mean levels and ranges
were virtually ident ical . Thi s hete rogeneous group of men pat ients
s tud ied in Costa Rica was not recruited for the purpose of study ing
the pitu itary-gonadal ax is . No gonadotropic levels or semen sample s
were stud ied .
96
Endoc r ine funct ion stud ies are br iefly mentioned in a pape r by
Cohen ( 1976 ) . Subj ects were recruited on the basis of heavy ma r i j uana
use and were stud ied in a metabolic wa rd . They smoked an average of
f ive mar i j uana c igarettes per day , which was bel ieved to be the
equ ivalent of 103 mg of �-9-THC . Dur ing acute admini strat ion , mea n
leve ls of plasma testosterone decl ined f rom 7 54 to 533 ng/dl over a
3-hour per iod . After 9 week s of smok ing , plasma testosterone levels
had decl ined f rom 7 4 0 to 509 ng . Plasma LH levels were reported to
have fallen afte r the fourth week ' however , no absolute values we r e
g iven . In add i t ion , no standard errors a re g iven for any o f the
means presented in this paper . The refore , it is imposs ible to
evaluate the s ignif icance of the repor ted f ind ing s .
In Greece , a populat ion of 4 7 ch ronic hashish users was stud ied .
E lectron microscope stud ies of the acrosome , the head of the spe rm ,
showed abnormality in some pat ient s ( Issidor ide s , 1979) . I t i s
d if f icult t o evaluate the study because no quant itat ive data were
pre sented .
All of the studies mentioned be low are substant ially d i fferent from
t hose of human beings because , with one except ion , the act ive agent
(usually �-9-THC ) was admini stered intrape r itoneally at a dose of
2 . 5 to 2 5 mg/kg . Based on calculat ions g iven by Cohen ( 1976) , 3 to 6
mg/kg/day would be cons idered a large dose in human beings . * Also ,
human be ings self-administer the drug ove r many hou r s r ather than as
a s i ng le dose .
In castrated rhesus monkeys , plasma LH and FSB fell acutely
following acute admini strat ion of �-9-THC ( Smith et a l . , 1980 ) .
Dur ing this suppress ion per iod , both gonadotropins could be
st imulated by luteni z ing hormone-releas ing factor ( LHRF) , which
c auses the release of LB . The effect o f � -9-TRC was t o suppress
prolact in release , which , in turn , could be st imulated by
thyrotropin-releasing hormone ( TRB ) . Studies in othe r spec ies have
tended to confirm these observat ions in monkeys .
The results are compat ib�e with the hypothes i s that the ef fec t o f
mar i j uana and its der ivatives is on gonadotropic secret ion ( Ha rcle rode
et al . , 1979) . Test icular cytochrome P-4 5 0 (an enzyme ) dec reased in
the rat following 2 to 9 weeks of treatment . The concentrat ions of
thi s enzyme , plu s a var iety of other testicular markers , were restored
w i th FSB and LB therapy . The effect of var ious cannabinoids has been
stud ied on sperm morphology in the mouse ( Z immerman et al . , 1979) .
97
Mice were g iven f ive daily intrape r itoneal inj ect ions of �-9-THC ,
cannabid iol , or cannabinol at doses approaching or exceed ing the
LD s o ( the dose necessary to kill SO percent of the an imals ) .
Thi rty-five days a fter the last treatment , animals were k i lled and
sperm were evaluated by scann ing e lectron microscopy . Control
animals had 1 . 5 percent abnormal forms . Animals that received LDs o
dose s of the var iou s der ivat ives had 2 . 4 to s . o percent abnormal
forms .
Only a few stud ies have examined the effects of cannabi s on
spermatogenesis ( Huang et al . , 1979) . Mar i j uana wa s administered t o
r ats in a smoke machine . After 30 days of exposure , mar ij uana smoke
lowered the sperm counts in animals s ignif icantly , as d id
c annabinoid-free smoke . By 7 5 days , however , only the mar i j uana
smoke g roup ma intained a low sperm count . In the mar ij uana-treated
g roup , there was an increased number of abnormal forms , par t icular ly
with an increase in d i ssoc iat ion of sperm heads and tails . In the
d iscussion of this paper , the authors reported elevated serum FSH
levels following ma r i j uana exposu re , but d id not present data . They
concluded that mar i j uana has a d i rect effect on the test is . A
var iety of in vitro stud ies support thi s suggest ion (Jakubov ic e t
a l . , 1977 , 1979 ) .
Mar i j uana and its der ivat ives also have been shown to be
antiand rogenic ( antagonistic to male hormones ) ( Puroh i t et al . ,
1 9 8 0 ) . Several const ituents , includ ing �-9-THC , can bind to the
receptor for androgen . Mar ij uana also has been demonstrated to be
estrogenic ( like female sex hormone s ) in vivo , and recent stud ie s
suggest that these effects may be med iated via the est rogen
receptor . These observat ions have been d i sputed by other s ( reviewed
by Purohit et al . , 1980 ) . The abi lity to inh ibit or mimic the act ion
of sex steroid s provide s one mechan ism by which these agents can
produce the i r e ffects . There obviously are many othe r s .
The e ffect of cannabi s on female reproduct ion has been stud ied in
rats , mice , rabbits , and monkeys . The work in rhesus monkeys is o f
part icular importance , because of the s imilar ity in the menstrual
cycle among pr imate spec ies , includ ing human be ing s .
Human Studies
98
99
An imal Studies
* B ibl iog raphy ava i lable upon request from the Inst itute of Med ic ine ,
Nat ional Academy of Sc iences .
100
GENETIC EFFECTS
Mutagenic ity
101
Cytogenet ic Effects
102
les s exposure pe r week ) and heavy (more than two exposu res pe r week )
u sers of mar ij uana ( Stenchever et al . , 1974 ) . One problem in this
study i s the poo r dose characteri zat ion . Fur thermore , the increase
i n the numbers of breaks in both l ight and heavy use r s of mar i j uana
was not dose-related , the same frequency of breaks wa s observed i n
both g roups . Although the evidence i s inconclus ive , it suggests that
mar i j uana doe s not cause ch romosome break s .
Doe s mar ij uana interfere with cell d ivis ion and chromosome
seg regat ion , the reby result ing in abnormal numbe r s of chromosomes ?
There i s conflict ing evidence in the l i terature . On the one hand , no
sign i f icant effects of mar i j uana smoke or 6-9-TRC on chromosome
complement have been reported us ing the micronucle i test in mice or
in cytogenet ic stud ies in dog s (Genest et al . , 1976 J Legator et a l . ,
1 97 6 ) . On the other hand , more extensive stud ies have demonstrated
aneuplo idy resulting f rom in vitro exposu re of cells to mar i j uana a s
well as i n vivo studies of animals and human be ing s .
Human Studies
S tud ies of lymphocytes cultured f rom human mar i j uana smokers def ined
e ither as •moderate • use r s ( at least one ma r i j uana c igarette per
week , range 1-10 for a minimum of two years) or •heavy • users (more
than three t imes per week ) all of whom consumed between 12 . 9 and 15 . 3
mar i j uana c igarettes per day dur ing the exper iment , turned up a
s ignif icantly large r numbe r of cells with les s than 3 0 chromosome s
t han would be found in normal cont rol cultures (Mor ishima et al . ,
1 9 7 9 ) . These posit ive f ind i ng s suggest that mar i j uana may affect
c hromosome seg regat ion dur ing cell d ivis ion and result in cells with
fewe r than the normal numbe r of chromosomes . What these findings
mean in terms of r isk for abnormalit ies in offspr ing or pos sible
disease is not known . Findings in lymphocyte cultures may not be
r elevant to what is happen ing in the germ cells ( sex cells) .
103
TH E IMMUNE SYSTEM
The immune system funct ions in protec t i ng the body ag a i nst v i ruses ,
and othe r i nfect ions �
bacte r ia , I t also play s a maj or role i n
p revent ing the g rowth and d i ssem inat ion of cancerous cells .
Ther e have been repo r t s that cannabis i s immunogen ic , capable o f
a c t i vat ing components i n the immune system . These components inc lude
such cells as lymphocytes , some of wh ich produce ant i bod ie s i n
r e sponse to i nva s ion by a fore ign ag ent , and mac rophag e & , wh ich can
be st imu la ted by i n f lamma t ion to i ngest i nvader s .
An imal Studies
A numbe r of s tud ies have shown that � -9-THC and other cannabinoids
i nduce immunolog ical defects i n rodents ( Peter sen and Lemberger ,
1976 ; Lefkow i t z and K lage r , 1978 , Le f kow i t z et a l . , 1978 ; Preuss an d
Lefkowi t z , 1978 ) . The doses var ied f rom 5 to 25 mg/kg ( intra
per i tone a l ly ) to 1 0 0 mg/kg (orally ) . At the h igher doses the re wa s a
d iminut ion of immune response , as measured by standard immunolog ica l
assay s . De lta-9-THC had t h e same effect s o n ce lls g rown i n vitro .
O ther c annabinoids also have been tested for the i r e ffects .
Cannabinol , �-8-THC , and 1-methyl-6-8 -THC had the same
immu nosuppress ive e f fec ts as � -9-THC , but c annabid iol had no
immunosuppress ive effec t . Immun i z ing rabb i t s with � -9-THC
r e sulted in t he produc t ion o f ant i bod i e s (Ch i arott i et al . , 1 98 0 ) .
104
BODY TEMPERATURE
SUMMARY
I n animals , mar ij uana and its der ivat ive s can acutely lower
gonadotropic secretion when admini stered intrape r itoneally . There i s
a lso some evidence i n animals to suggest that these agents can
d irectly affect the semini ferou s tubule . In man , sperm numbe r and
mot i l i ty are decreased dur ing chronic mar i j uana use . From the
avai lable stud ies , it appear s thi s was due to a direct effect of the
c annabinoids e ithe r on the semini ferous tubular epithelium or the
epid idymal spe rm . Due to conf l icting and incomplete evidence , it i s
not possible to conclude at the present t ime whether mar i j uana
smoking has a s ignif icant effect upon gonadotropic and testosterone
concentrat ions in humans . Whether the decrease in spe rm numbe r or
mot i l ity has any effect on fe r t i l ity i s not known .
105
Genet ic Effects
The data from animal studies suggest that A-9-THC and some of its
analogues have a mild , trans ient , immunosuppressant e ffect in both jn
vitro and in vivo systems , the effects are mild compared with known
immunosuppressant drug s . The stud ies i n human be ings are contrad ic
tory , some demonstrated mild , immunosuppress ive effects , but others ,
u sing the same or s imi lar method s , d id not f ind any d i fferences in
the tmmu ne system between normals and chronic marij uana smokers . At
the present t ime , there have been no human or animal stud ies that
have determined if mar ij uana smokers are more prone to infect ions or
other d i seases . Because of the widespread use of mar i j uana , even
weak immunosuppress ive ef fects are a conce rn . S i nce further researc h
may not demonstrate definit ive f ind ing s , immunolog ic effects should
be studied along with othe r var iables in a larger investigat ion . I f
mar ij uana i s t o be used o n immunosuppressed pat ients ( for example ,
for ant iemetic purpose s dur ing cancer chemotherapy) , even minor
add i t ional suppress ion might be dangerous .
• Fur the r obse rvations should be made regard ing the relat ion
of mar i j uana u se to r eproductive defects in human be ing s , espec ially
10 6
on young users whose reproduct ive biology is unde rgo ing rapid change .
The pr inc ipa l need i s fo r assessment of endocr ine prof iles and seme n
analysis in male users versus nonuse r s , with adequate cont rol of
confound ing var iable s--for example , d iet , alcohol , othe r d r ug use .
I n women , the princ ipal need i s for more data on endoc r ine and
menstrual patte rns in user s ve r su s nonuse r s , with part icu lar
a ttent ion to the leng th of cycles , the pre sence or absence of
ovulat ion , and the exi stence or absence of subfe r t i l i ty . More
s tud ies a re needed to detec t subtle , low-f requency , or cumu lat ive
effects on reproduct ive funct ion in long-term , heavy u se r s .
Although routine test ing of teratogenic ity in human be ing s
•
i s not recommended at this t ime , the col lec t ion of prec ise
epidemiolog ic informat ion on the outcome of human preg nancy i n
mar i j uana use r s is of g reat importance and must be carefully
cont rol led .
The re are no good an imal mode ls for study ing the e f fec ts of
•
smok ing mar ij uana , but cytogene t ic stud ies in an imals after exposu re
to �-9-THC by othe r route s than smok i ng wou ld be of some value .
The most relevant s tud ies s t i l l would be in vivo human stud ies .
Mar ij uana has been found to have mild immunolog ical effect s
•
in a var iety of test systems , but stud ies of its inf luence on the
body ' s immune defense ag ainst microorgan i sms are lac k ing and need to
be conducted .
C r i tical exper iments are needed to test the hypothe s i s that
•
widely recogn i zed . Th i s type o f var iat ion must be eva luated i n
respect t o suscept ibil ity t o ma r i j uana .
REFERENCES
107
108
110
111
6
BEHAVIORAL AND PSYCHOSOC IAL EFFECTS
OF MARIJUANA USE
112
113
Acute Effec t s
The stud ies repor ted here cove r the range o f commonly used doses*
from ve ry low up to 0 . 2 5 0 mg/kg of �-9-THC in ma r i j uana c igarette s
at a s ing le s i tt ing . The se are acute e ffects--changes that can be
seen after a s i ng le dose . The effects beg in to be seen at abou t the
same dose level at which a • h igh• i s perce ived ( 0 . 0 50-0 . 1 50 mg/kg
6-9-THC ) . Generally the effects are dose-related . In othe r word s ,
low dose s have small e ffect s , h igher dose s tend to have g reater
effects .
* Dose s are repor ted in m i l l ig r ams per k i log r am (mg/kg ) where provided
by the author s or as total dose s in m i l l ig r ams with the route of
admin i stration .
114
Mar ij uana has been found to impa i r motor coord inat ion at dose s
commonly used i n soc ial setting s by both na ive and ch ron ic use r s .
The f unc t ions s tud ied inc lude : hand stead ine s s (Mayor ' s Commi ttee on
Ma r i huana , 1 9 4 4 : Clar k et al . , 1 9 7 0 : Mi lste i n et al . , 197 5 ) , body
sway ( Mayor ' s Comm i ttee on Mar ihuana , 1 9 4 4 : K ip l i ng e r e t al . , 1971 :
Evans et a l . , 197 3 ) , and acc u r acy of execut ion movements ( Rafae 1 se n
e t al . , 1 9 7 3 : M i l s te i n e t a l . , 1 9 7 5 : K valse th , 1977) . Stud ies have
also s howed a dose-related inc rease in impa irment of postu r a l
s tabi l ity as measu red by inc reased body sway (K ip l i ng e r e t a l . , 1971 ) .
React ion t ime i s def i ned as the t ime lag between a s ig nal and the
response a subj ec t make s to that s ignal . Most stud ie s examine the
t ime t hat i t takes a subj ec t to r e spond to a v i sual or aud itory
s ig nal . The ef fec t s of ma r i j uana on e i ther speed of i n i t i a l
d e tect ion of the s ignal or speed of response have been incons i stent
at dose s common ly u sed i n soc ial sett i ng s ( • low to mode r ate • ) . The
same subj ects are impa i red at some t ime s , but not at othe r t ime s
(Mayor ' s Comm i ttee on Ma r i huana , 1 9 4 4 : Clar k et al . , 1 9 7 0 1 Dornbus h
1 9 7 1 1 Mo skowitz et a l . , 1 9 7 2 , 1 9 7 4 : Borg et al . , 1 97 5 :
e t al . ,
Schaefer et al . , 1 9 7 7 : Pee k e e t a l . , 1 9 7 6 1 S t i llman et al . , 1 9 7 7 ) .
The mean i ng of th i s i ncon s i stency is unc e r ta in , but it probably
involve s an effect on attent ion mecha n i sms . When a subj ec t i s
i ntox icated with mar i j uana , he i s probably le s s l i kely to attend to
the reac t ion t ime task . Per haps it is when he doe s pay attent ion to
t he task that f unct ion on t h i s te st is not impa i r ed .
Trac k i ng
115
task s d i f fer from reac t ion t ime stud ies , because the subj ec t mu s t
cont inuou sly pay attent ion t o the task . S ince reac t ion t ime tests
are intermittent , cont inuou s at tent ion i s not requ i r ed , and th i s may
expla in why r eac t ion t ime s tud ies fail to show cons i s tent mar ij uana
effects .
Tests that measu re a subj ect ' s abi l i ty to detec t a br ief flash of
l ight show s ignif icant impa i rment by low to moderate dose s ( 2- 3 mg
a r e examples ) of smoked mar i j uana ( Sharma and Moskowi t z , 19 72 , 1 9 7 3 ,
1974 ; Moskowitz et al . , 1972 , 1 9 7 4 ; Ca sswell and Marks , 1 9 7 3 1 Jone s
and S tone , 1 9 7 0 ) . Sustained attent ion is r equ i red in s ignal
detect ion tasks , and the relat ion between this susta ined attent io n
r equ i rement and mot ivat ion e ffects has not been explored . S ig nal
detect ion tas k s a r e prototypes of pe rceptual demand s found in
man-machine i nteract ions . The large reduct ions in s ignal detect ion
that occu r unde r the inf luence of mar ij uana may suggest a substant ial
r isk for users who are operating machine s . Other visual funct ions ,
such as v i sual search , that depend on eye movement s are not impa ired .
Lea r n ing and Memory When studying the effects of drug s on learning ,
i t i s d i f f icult to control all of the factors that might influence
the results , for example , as noted above , how ha rd a subj ect tr ies t o
per form can make a big d i fference even in the presence of a sedating
drug . Thus , it i s not surpr i s ing that ear ly studies of mar ij uana ' s
e ffects gave incons istent results .
More recently , several stud ies have demonstr ated that a sing l e
moderate dose of mar ij uana impa i r s shor t-term memory . Thi s effec t i s
espec ially not iceable in the phases of shor t-term memory tha t are
heavi ly dependent on attent ion , such as informat ion acqu i s i t ion and
stor age (Abel , 1970 , 1 9 7 1 1 Dornbush et al . , 1 9 7 1 1 Dittr ich et al . ,
1 97 3 ; Melges et a l . , 1 9 7 4 ; Belmore and Miller , 1 9 8 0 ) . Rxamples of
the type s of impai red task s wou ld be remember ing a sequence of
numbers or syllables or memor i z ing and following a sequence of
d i rect ions .
Phys iolog ical changes have been mon i tored in some of the same
stud ies in which inte llectual impa i rment has been repor ted . Mille r
116
Marij uana use in low to mode rate doses impairs oral communicat ion ,
espec ially clar ity of sequent ial dialogue with other pe rsons
( Dornbush et al . , 1971 1 Paul and Car son , 1973 1 Zeidenberg et al . ,
1973 1 Crockett et al . , 1976 1 Miller et al . , 1977a-d , 1978a , b , 1979 1
Pfefferbaum et a l . , 197 7 1 Mi ller and Cornett , 1978 r Natale et al . ,
1979 r Belmore and Mi ller , 1 9 8 0 ) . Mar i j uana at moderate doses
d isrupts continu ity of speech by impa i r i ng shor t-term memory ( 6-18
seconds duration ) ( Belmore and Miller , 1980 ) . Commu nication while
i ntox icated i s also impaired by the intrusion of irrelevant words and
idea s into the stream of commun icat ion . When a list of words i s
learned and then the cubj ects a r e asked t o recall those words without
regard to sequence , words that were neve r in the or ig inal l ist ar e
i nserted dur ing recall more often by subj ects g iven � -9-THC than by
those who were d rug-free ( Pfefferbaum et a l . , 1977 1 Mi ller and
Cornett , 1978 1 Mi ller et al . , 1978a , b) . Ze idenberg et al . ( 1973 )
administered 5 mg � -9-THC orally and found that , in a soc ial
context , phrases bec ame shor ter , speech became slower , and there was
117
greate r lag t ime between the cue to talk and the actual onset o f
talking . These subj ects were also less able t o recog n i ze three
lette r nonsense syllables to wh ich they had previously been exposed .
Further , when expe r imental subj ects were all g iven the same dose of
�-9-TRC , they repor ted d i f ferent subj ect ive levels of intox ication .
Those who repor ted more intox icat ion showed g reater d i srupt ion of
two-per son commu nication ( Pau l and Car son , 1 97 3 ) .
Exper imental subj ects who were asked to tell stor ies about
ambiguous pictures ( the Themat ic Appe rcept ion Test ) demonstrated drug
impaired organ i zat ion and integ ration of stor ies . The authors
reported • a t ime less , nonnar rat ive quality , with g reater d i scontinuity
i n thought sequence and more f requent inclus ion of contrad ictory
ideas • ( Roth et al . , 197 5 ) . When asked to talk for f ive minute s o n
any topic , subj ects under � -9-THC demonst rated decreased var iabil i ty
of language and an i ncrease in per sonal references , a s well as less
deta i l ing of items ment ioned in the monologue and less cr i t ical
evaluat ion of those i tems ( Natale et a l . , 1 9 7 9 ) .
118
Exper imental stud ies of the e ffects of mar ij uana on closed course
automobile dr iv ing per formance show that this s k i l l is impa ired by
mar i j uana . Car handling sk ills were reduced , as shown by object ive
measu res (Klonoff , 1974 ; Hansteen et al . , 1976 ; Attwood , in press) .
I t should be noted that these stud ies , involving subj ects under the
inf luence of mar i j uana , exami ned per formance in less complex
s i tuat ions than are actua lly met in r eal-l i fe d r iving situat ions .
However , a closed course has the advantages of standard cond itions
and safety factor s . I n real-l ife dr iving s i tuat ions , the perceptual
and cogn it ive demand s are cons ider ably more complex . The K lonoff
( 19 7 4 ) study of dr iving per formance on city streets ind icates that
smoked mar ij uana ( 5-10 mg �-9-THC ) impairs j udgment and
concentrat ion in add i t ion to impa i r i ng car hand ling sk ills .
119
not had an acc ident or othe rwi se come to pol ice attent ion . I n
add i t ion , many u sers o f mar i j uana also u se other drug s so that data
are avai lable on only a few subj ects who only used ma r i j uana .
In an e ffor t to obta in some reference point for the assoc iat ion
of mar i j uana with acc idents as compa red with othe r drug s , War ren e t
al . ( in press) reanalyzed the C imbura e t al . ( 1980 ) data . Twelve
percent of the fatally inj ured d r ivers and pedestr ians in that study
had been found to have �-9-TRC in the i r blood . The pre sence of
othe r drug s was also determined and a culpabi l i ty index was deve loped .
A culpabi l ity index compares the frequency that a drug is found in
d r ive r s assigned respons i b i l ity for cau s i ng a coll is ion with the
frequency in individual s from the same sample who had not caused a n
acc ident .
Aspir in was found to have a culpabi l i ty index of 1 . 0 . That i s ,
it was no more frequent in ind ividuals ass igned respons ibi l ity for a
coll i s ion than on those who were not . Th is is of some s ignif icance
because it serves as an internal chec k on the technique , ag ree ing
w ith the a pr ior i assumpt ion that i t would be unl i kely for aspir in
use r s to be overrepresented among those respons ible for acc idents .
In contrast , subj ects with cannabinoids pre sent in the ur ine were
found to have a culpabi l i ty index of 1 . 7 , the same culpabi l i ty leve l
found for the presence o f a lcohol . Th i s ind icates an excess of
�9-THC-pos itive dr iver s in the category responsible for
acc idents . The presence of antihistamines produced a culpability
index of 1 . 5 , and tranqu i l i zer s/ant idepressants , 1 . 8 .
Given the d i fficult ies in executing epidemiolog ic stud ies where
it is so d i f f icult to obtai n adequate control groups , it would appea r
that only tentat ive conclus ions about mar i j uana ' s role in acc idents
can be reached . Suppor t ive ev idence that ma r i j uana is a contr ibuting
c ause of acc idents comes from surveys of mar i j uana users who repor t
they rece ive a h igher-than-average numbe r of t ickets for dr iving
v iolat ions and are involved in a h igher-than-average number of
acc idents (Johnston , 1 9 8 0 ) . Never theless , the problems descr ibed
above are yet to be solved . But the culpabi l i ty index model presents
a methodology that may be refined and ut i l i zed i n future stud ies .
Surveys show that mar ij uana and alcohol are frequently consume d
together ( Fishburne et al . , 1980 1 Johnston et al . , 1 9 8 0 ) . Thu s , it
is impor tant to determine what interact ions , if any , occu r betwee n
these two drug s . As both drug s have sedative propert ies , an add it ive
effect would be expected and has been found in the few systemat ic
i nvestigat ions of the effects of this combinat ion . One study
repor ted that 0 . 0 5 percent blood alcohol leve l concentrat ion ( BAC )
i ncreased the impa i rment produced by 5 mg of smoked � -9-TRC on
track ing behavior (Manno et a l . , 1971) . In a study using two doses
of a lcohol and two dose s of mar i j uana , even the low dose of alcoho l
( 0 . 0 7 percent BAC ) and the low dose of � -9-TRC ( 1 . 4 mg ) impa ired
complex tracking in an add i t ive fashion (Bansteen et al . , 1976) .
120
Ch ron ic Effects
Animal Studies
121
chronic mar ij uana users before and after 21-9 4 days of chronic
i ntox icat ion in a research hospital sett ing . None of the
invest igator s found any psycholog ical changes dur ing postdrug
testing . However , 2 months of u se i s a relat ive ly short per iod of
time for a change to be detected , and the subj ects had already been
u s ing marij uana for at least a year pr ior to enter ing each study
(Fehr et a l . , 19 76 ) .
The ava ilable stud ies of chronic behavioral effects lead to no
clea r conclusions . Althoug h some animal studies demonstrated a
learning def ic it that pers i sted for months after da ily mar i j uana
exposure wa s d i scont inued , the human stud ies have such methodolog ica l
weaknesses that they cannot be interpreted . A prospective concur rent
cohort study and a retrospect ive case-control study of possible
outcomes of and r isk factor s for u se of mar ij uana could add useful
informat ion . ( See research recomme ndat ions at the end of this
chapter . )
CLINICAL SYNDROMES
I n thi s sect ion we will d i scuss both acute and chron ic behaviora l
changes that have been repor ted in the clinical l i terature to be
associated with the use of mar i j uana . An association based on cas e
r eports does not imply causality . Stud ies o f appropr iate control
groups are necessary . In general , acute or immed iate clinical
e ffects of drug s can be determined sc ient i f ically much more read ily
than chronic or delayed effects . Th i s i s as true for mar ij uana as i t
i s for a lcohol and other drug s . Thus , the acute effects of mar ij uana
are based on more sol id evidence than are the reported chron ic
e ffec ts .
Acute Effects
The acute clinical effects of mar i j uana seem to occu r on a cont inuum
f rom mild dysphor ia to acute bra in syndrome . In the l i terature ,
three d i f ferent syndromes have been descr ibed , although there i s
blurr ing o f the boundar ies i n this classif icat ion and no general
ag reement as to d iagnostic cr iter i a .
A maj or por t ion of the evidence for this effect comes from repor ts by
mar i j uana users themselves . Mar i j uana ' s popu lar ity notwithstand ing ,
a surpr isingly h igh proport ion of user s report react ions that they
regard as unpleasant or undesi rable . FOr example , 3 3 percent of
regular u sers reported that wh i le intox icated they occas ionally
exper ienced such symptoms as acute pan ic , paranoid react ion ,
halluc inat ions , and unpleasant d istor t ions in body image (Tar t , 1970 1
Neg rete and Kwan , 197 2 ) . Another study repor ted that 16 percent of
122
regular users reported anx iety , fear fulness , confu sion , dependency ,
o r agg ress ive u rges as a •usual occurrence • (Hal ikas et al . , 1 9 7 1 ) .
S imilar finding s in g roups of stable , well-adj usted , mode rate use r s
have been found by other invest igators (Annis and Sma r t , 19 7 3 1 Marcus
et a l . , 1 9 7 4 ) . First-t ime users are more l i kely than are exper ienced
u se r s to r eport adver se react ions . The frequency of such react ions
appears to be higher when the sett ing for use is not a favorable one J
for example , when the u se r sees the envi ronment as threatening .
These adverse psycholog ical react ions also have been observed i n
s u bj ects of laboratory exper iments with mar ij uana . Such control led
observat ions of persons whose immed iate pr ior mental statu s and whose
dosage were known g ive a bas i s for conclud ing that acute adverse
psycholog ical react ions can occu r unde r sing le moderate doses of
mar ij uana . These e ffects are more l i kely at higher doses . They
usually last no longer than 2 to 4 hou r s . Acute paranoid react ion s
unde r these controlled cond it ions have been reported (Mendelson and
Meyer , 1 9 7 2 1 Tassinar i et al . , 1 9 7 3 1 Frank et al . , 1976 1 Me lges ,
1 97 6 ) . Ingest ion , in which t itration of dose (dose adj ustment as
occurs dur ing smok ing ) is d i f f icult , may be more l i kely to produce
adve r se effects than administrat ion by smoking mar i j uana . However ,
chronic use and inte raction with other psychoact ive substance s a r e
not required .
As frequent ly as these adverse react ions are observed and
self-repor ted , med ica l treatment i s rarely sought . FOr example , a
college student health clinic repor ted only s ix students per year
sought med ical treatment for an adverse react ion to mar ij uana out o f
a student populat ion of 2 0 , 0 0 0 (Pi llard , 197 0 ) . In the general
popu lat ion , a diagnos is of acute cannabis reaction was found in only
1 0 cases out of 700 , 0 00 hospital admiss ions in the Un ited States
(Lundberg et al . , 1971) . In the u . s . Army , only 18 such cases we r e
treated over a several-year per iod f r om a military populat ion of
3 3 , 0 0 0 (Tennant and Groesbeck , 1 9 7 2 ) . There are no recent f igure s
showing requests for medical treatment now that the use of mar ij uana
is more intense , wide spread , and reaching younger ag e-groups .
However , a unique monitor ing of drug causality behavior document ing
emergency room encounte r s conducted by the Drug Enforcement
Administrat ion and the Nat ional Institute on Drug Abuse ( U . S .
Depar tment of Health and Human Services , 1 9 7 9 ) may i n the futur e
provide addit ional information about the frequency of adver se
react ions to use of mar ij uana .
Therapeut ic tr ials have been car r ied out test ing 6 -9-THC as a
poss ible treatment for mood d isorders ( see Chapter 7 ) . Severe
dysphor ic react ions character i zed by d i sor ientat ion , catatonial i k e
immobi lity , acu te panic , and heavy sedat ion have occu rred in several
pat ients . The dysphor ic symptoms appeared at moderate doses compa r
able t o those used in soc ial setting s . They lasted only a few hour s
and responded t o d i scont inuation o f the drug and reassurance o f the
pat ients (Kot in et a l . , 1973 1 Ablon and Goodw in , 197 4 ) .
123
S imilar dysphor ic react ions have been repor ted i n cancer pat ients
who were on a the rapeutic tr ial of 6-9-THC to control the nau sea
assoc ia ted with chemotherapy . The symptoms , course , and response to
ceasing use of the drug were ident ical to those descr ibed above .
I nvest igators have suggested that the dysphor ic response is more
likely to occu r in older pat ients not accustomed to drug use for whom
the mood-altering effects are unantic ipated and unwelcome (Shil ing
and Sti llman , 1 9 8 0 ) .
D iagnost ic criter ia for the syndrome now cal led de lir ium and
prev iously called acute brain syndrome appear in Diagnost ic and
S tat istical Manual of Mental Disorders , Thi rd Edi t ion , 1980 (DSM
I I I ) . These include : ( a ) a cloud ing of consc iousness as man ifested
by impa irment of abi l i ty to susta in attent ion to environmental
stimuli , or impai rment of abi l i ty to sustain goal-d i rected th ink ing
or goal-d irected behavior r ( b) a d i sorder of memory or or ientat ion r
(c ) perceptual d i stur bances r and (d) a change in sleep pattern and/o r
a change in psychomotor act ivity . The symptoms develop over a short
per iod of t ime and f luctuate rap idly .
Both the symptom pattern and the course of the acute brain
syndrome fit the descr ipt ions of one type of behavior d i sorde r
a ssoc iated with u se of mar ij uana . I t has been reported to develop in
per sons who have a history of prolonged , regular , heavy use of
marij uana . I t is def ined as an • acute • brain syndrome beCause it
come s on dur ing the per iod of drug use and i t gradually d i sappear s
a f ter the d rug i s stopped . The maj or ity o f case repor ts have come
from Eastern countr ies where the cannabis products customarily used
have h igh potency ( Spencer , 1970 r Chopra and Smi th , 1974 r Meyer ,
197 5 ) . I t has also been reported in u . s . Army pe r sonnel stat ioned i n
Viet Nam ( Talbott and Teague , 1969 ) a nd i n Europe ( Tennant , 19 7 2 ) ,
where sold iers had access to very h igh 6-9-THC concentrat ions in
cannabi s substances . I n contrast to the Ind ian publ ic mental hospital
pat ients who were hospitali zed for many weeks , u . s . soldiers recovered
i n 3 to 11 days and returned to duty . Th i s d i f ference in durat ion
may reflect soc iocu ltural d i fferences in length of in-pat ient
t reatment more than a d ifference in the d isorder .
Withdrawal Syndrome
S tud ies of animals and human subj ects g iven moderate to h igh doses of
mar i j uana orally or by inhalat ion several t imes pe r day have
demonstrated tolerance to many of the effects of mar i j uana ( see
Chapter 1) . When such use of mar i j uana is stopped after several days ,
a wi thdrawal syndrome occurs . I n human subj ects , this resembles the
typical mi ld wi thdrawal symptoms seen after prolonged sedat ive use
( Jones and Benowitz , 197 6 ) . Subj ects show i r r itabi l i ty , ag itat ion ,
insomnia , and BEG changes ( see Chapter 4 ) . These symptoms are
self-l imiting r they peak at 3 0 hours and d isappear by 9 0 hour s .
124
Chron ic Effects
Cannabis Psychos i s
C l inic ians coined the term • amot ivat ional syndrome • to describe a
characte r i stic set of personal i ty changes seen in some da i ly users o f
mar ij uana (McGlothlin and West , 1968 J Smi th , 1968 ) . The changes
include apathy , loss of amb it ion , loss of effect iveness , d iminishe d
ability to carry out long-term plans , diff iculty in concentrating ,
and a dec l ine in school or work pe rformance . As usually described ,
t hese changes are seen in frequent or da i ly users , and thu s they may
be cons idered a form of chron ic intox icat ion . The term •amot ivat iona l
syndrome • is not an off ic ial d iagnos is , but there is agreement among
many clinic ians who treat young people that this constellat ion of
symptoms is common . It may . a l so be seen in nonmar i j uana users , and
da i ly use of mar ij uana i s not always assoc iated with los s of
mot ivat ion .
The evidence presented for the l ink ing of this syndrome with
mar i j uana cons ists of case repor ts . For example , Baker and Luca s
( 19 6 9 ) descr ibed the case of a man whom fr iend s descr ibed as
previously consc ientious , capable , and effective J but after smok ing
hashish daily for 3 years , he changed into a person for whom use of
drug s wa s a way of l i fe and in whom a ser ious deter iorat ion of soc ia l
function was observed . Other r epor ts cons ist of g roups of cases with
s imilar h istor ies (Thur low , 1971) . The symptoms ment ioned , in
add i t ion to loss of motivat ion , include falling g rades , difficult ies
in concentrat ion , intermittent confus ion , and impa i red memory . Some
authors repor t improvement when use of mar i j uana is stopped (Kolansky
and Moor e , 1971 , 19 7 2 ) .
125
126
s ig n i f icant assoc i a t ion with the prec ip itat ion o f LSD flashbac k s
among f ive c lasses of abused d rug s . C l i n ical s tud ies also have
prov ided ev idence that mar i j uana prec ip i tates a recu r rence of the LS D
f lashbac k s expe r ience ( Holsten , 1 9 7 6 1 Abr aham , 1 9 8 1 ) .
The ex i s tence of flashbac k s fol lowing use of e i the r LSD o r
mar ij uana i s ent i r e ly based o n self-repo r t s , because the re are no
d i st inc t ive phy s ical s igns or tes t s , suc h as EEG changes , to ident i f y
t h i s cond it ion . The re i s no cur rent pha rmacolog ical explanat ion o f
the phenomenon , and data regard ing dose and t ime par amete r s d o no t
exist . Still , the repo r t s by u se r s a re reasonably cons i stent . Thu s ,
the r e i s c l inical ev idence that use o f ma r i j uana by those who have
p reviou s ly u sed LSD i nc reases the l i ke l i hood of recu r rence of the LSD
expe r ience .
Mood Cha ng e s
127
pas t expe r ience , att i tude , expectat ions , and sett i ng . FOr example ,
i nd ividuals who u sed ma r i j uana in i solat ion tended to be relaxed and
s l ightly d rowsy , i n cont rast , when the use r was i n a g roup s i tuation ,
mar i j uana was a s soc iated with euphor ia and lack of sedat ive e ffec t
(Jones , 1971) . Fu r the r ev idence that mood changes are not attr ibu t
a ble sole ly t o t he pha rmacolog ical act ion of mar i j uana comes f rom a
study that found that e levat ion in mood occu r red immed iate ly befo r e
u se of mar i j uana and immed iately a fter , bu t t h a t mood was not
cor re lated with othe r ind icat ions of the subj ect ive leve l o f
i ntox icat ion ( Ros s i e t a l . , 1978 ) . Instead , mood was cor re lated
s ig n i f icantly with the mood s of othe r s , whethe r or not the othe r
per sons we re intox icated .
I t appears that preex i s t ing mood can inf luence the dec i s ion to
use ma r i j uana . H ig h schoo l students who exh i b i t symptoms of
d epress ion a re more l i kely than are othe r s to beg in u s i ng mar i j uana
a s we l l as othe r i l l ic i t d r ug s ( Paton et a l . , 1977) . There is some
e vidence that students u se the d rug as a self-presc r i bed remedy for
the i r own mood problems , often report ing that they use ma r i j uana a s a
means of psycholog ical coping ( Johns ton et a l . , 1980 J Kaplan , 198 0 ) .
A bel i e f that ma r i j uana can be u sed to a l leviate c l i n ical
d epre ss ion is not suppor ted by othe r s tud ies , i nclud ing one in wh ich
6-9-THC wa s carefu lly tes ted a s an ant idepre ssant . It wa s g iven to
depressed pat ient s a s an exper imental treatment wi thou t success
(Ablon and Goodw in , 1974 ) ( see Chapte r 7) .
Adolescent s and young adu lts often report that they u se mar i j uana to
fac i l i tate inte r ac t ion in new soc ial s i tuat ions (Mi r i n and McKenna ,
1975 ) . In a su rvey of 704 m idwestern und e rg raduate s tudents , most
repor ted that ma r i j uana was a mean i ng f u l • tool of soc ial bond i ng •
( Linn , 1 971) . The re seems to be a widespread be lief that mar i j uana
smok i ng ha s seve r a l fac i l i tat ive e f fects , i nc lud ing enhanced soc i a l
e ffec t ivene ss , c lose r soc ial bond ing , he ig htened i nte rpersonal
sens i t i v i ty and empathy , and enhanced sexual pleasu re . The
s ubcu ltu ral lore on one of the se measu re s of inte rpersonal behavior-
sexua l effec ts--ha s not been stud ied systemat ically e i the r i n survey s
or i n expe r imental stud ies . The e ffects on sex hormones are
controve r s ia l ( see Chapter 5) . Stud ies in expe r imental s i tuat ion s
have f a i led to show any enhancement of soc ial inte rac t ion and , in
fact , some dec rement s were noted ( Ga lante r e t al . , 1974 J Clopton et
al. , 1979 J Janowsky et al . , 1979) . Data f rom natu ral sett ings rathe r
tha n expe r imenta l sett i ng s are not ava i lable .
Because mar ij uana u sers have been i nvolved in delinquent behav ior , a
numbe r of i nvest igators have que st ioned whethe r use of mar i j uana
e nhances agg ress ivene ss in human be i ng s . The re are spec i f ic concerns
128
abou t potent ial links of use of mar i j uana to agg ress ion . Bot h
r etrospective and expe r imental stud ies in human be ings have fa i led to
y ield evidence that mar ij uana use lead s to increased agg ress ion .
Most of these stud ies suggest qu ite the contrary effec t . Mar i j uana
appears to have a sedat ive effect , and it may reduce somewhat the
i ntens ity of angry feelings and the probability of interpersonal
agg ress ive behav ior (McGu i re and Megaree , 1974 1 Tink lenberg , 1974 J
Salzman et al . , 19 7 6 J Taylor et al . , 1976 1 Tinklenberg et al . , 19 7 6 b J
Hemphi l l and Fisher , 1980 ) .
SUMMARY
• coord inat ion as examined by hand stead iness , body sway , and
accuracy of execut ion of movement J
• track ing per formance ,
• perceptual tasks 1
• vig i lance ,
• per formance on automob i le dr iving and flying s imulators , and
• ope rat i ng automobiles on test roadways .
129
130
REFERENCES
131
132
133
134
135
136
137
138
1
THERAPEUTIC POTENTIAL AND
MEDICAL USES OF MARIJUANA
The re ha s been g rowing interest in the possibil ity that cannabi s and
i ts der ivat ive s will be valuable for the treatment of several med ical
and psychiatr ic cond i t ions . The 97th Cong ress , for example ,
introduced a b i l l ( H . R . 4 4 9 8 ) • to provide for the the r apeut ic use o f
ma r i j uana in s ituat ions involving l i fe-threatening or sense-threaten
ing i l lness and to provide adequate suppl ies of mar i j uana for such
use . •
Most of the putative therapeut ic effects of cannabis are believed
to be med iated by the central nervous system . These inc lude e f fect s
o n appet i te , nausea a nd vom it i ng , epi lepsy , muscle spastic i ty ,
anx iety , depre ss ion , pain , and o n g laucoma , asthma , and the symptom s
of wi thdrawal f rom a lcohol and narcot ics . The l iterature on these
and othe r therapeut ic act ions be l ieved med iated by the central
nervous system will be reviewed in thi s chapte r .
I n general , the comm i ttee f ind s that cannabis shows promi se i n
s ome o f these areas , although the dose necessary to produce the
des i red therapeutic effect is often close to one that produces a n
unacceptable frequency of tox ic ( undesi rable ) s ide-effects . What is
perhaps more encou rag ing than the the rapeutic effects obse rved thu s
far i s that cannabis seems to exe r t its bene f ic ial e f fects through
mechanisms that d i f fe r from those of othe r ava i lable drug s . Thi s
r a i ses the poss i b i l i ty that some pat ients who would not be helped by
convent iona l therapies could be treated e ffective ly with cannabi s . A
second poss ibility i s that cannabis could be combined with othe r
drug s to achieve a therapeut ic goal , but with each drug be i ng used a t
a lowe r dose than would be requ i red i f e i ther we re used alone . As a
result , fewer s ide-ef fect s would be expected to occur . It may be
possible to reduce s ide-effects by synthe s i z i ng related molecules
that could have a more favorable ratio of des ired to undes i red
act ions , thi s l ine of investigat ion should have high pr ior ity ,
because such synthet ic der ivat ive s may ult imate ly have widespread
t herapeu t ic use .
1 39
140
GLAUCOMA
G laucoma i s the lead ing cause of blindne ss in the Uni ted States. The
term i s used to desc r i be a group of ocular d i seases character i zed by
a n i ncrease in i ntraocular pressure , which damages the opt ic nerve
and leads eventually to loss of v i s ion . The d i sease affects over two
m i llion Amer icans of age 3 5 or older . Although there i s increas ing
r is k of g laucoma with increasing age , the re are forms that develop i n
i nfancy . The Nat ional Soc iety to Prevent Blindness ( 1980 ) also
estimates that 3 0 0 , 0 0 0 new cases are d iagnosed each year .
Treatment of g laucoma depends on the type and cause . I t may be
pharmacolog ical or surg ical . Surgery i s useful treatment in
r e lat ively few cases , there i s a h igh inc idence of fa i lure and
ser iou s compl ications may occur . Avai lable antig laucoma drugs a r e
e ffect ive in regulat ing intraocular pressure in many patients , and
are the ma instay of treatment in the most common form of g laucoma ,
but there are some adverse s ide-effects . Some pat ients are refrac
tory to present forms of treatment and become bl ind as the d i sease
p rog resses ' for them, there i s a par t icularly urgent need to f ind
effect ive drugs .
Cannabis ( the crude drug ) , A-9-TBC ( the pure compound ) , and
some other cannabinoid der ivat ives lowe r intraocular pressure when
admini stered by var ious routes , such as inhalat ion , oral , or
i ntravenous . However , adver se a ide-ef fects of cannabi s and A -9-TBC
also have been reported . Most pat ients with glaucoma are elder ly ,
and have a reduced tolerance for many of these s ide-effects . Even
without the adverse s ide effects , smok ing , oral , and intravenous
route s of administrat ion are not su itable for the long term . POr
e xample , to g ive adequate control for intraocular pressure , four
mar i j uana c igarettes per day of 2 percent A-9-TBC would be
nece ssa ry , this amount i s cons idered heavy usage and could pose a
ser iou s health problem in long-term use . The refore , topical
appl icat ion would be the moat salutary route of administrat ion for
the pat ient who needs cont inuous treatment .
Human Studies
14 1
A-9-TBC content were obse rved for 3 5 days and another 29 subj ects
were observed aa in-pat ients for a total of 94 days . There was a
cons istent drop in intraocular pressure in those smok ing the 2 percen t
cannabis and the reduct ion appeared to last 4 to 5 hours (Hepler et
al . , 1976a) . The author s noted that there d id not seem to be much of
a cuaulative effect on a i se of pupils or upon intraocular pressure
response . Studies by other invest igator s have conf i rmed this effect
o f cannabis and A-9-TBC in causing reduct ion of intraocular
pressure in humans ( Shapiro , 197 4 J PUrnell and Gregg , 197 5 ) .
Peres-Reyes et al . in 1976 investigated the effect of intravenou s
i nfus ion of s ix cannabinoida in healthy volunteers . Delta-8-THC ,
A-9-TBC , 11-hydroxy-A-9-THC , cannabinol , cannabid iol , and
8-8 -hyd roxy-A-9-TBC were tested on healthy subj ects with normal
intraocula r preaaure J A-8-THC , A-9-TBC , and 11-hydroxy-TBC caused
the g reatest reduct ion in pressure . Of these A-8-TBC caused the
largest decrease in intraocular pressure , with the least number o f
psycholog ical a ide-effects .
I n a prelimina ry study of 11 human g laucoma pat ients who smoked
aar ij uana ( 1 , 2 , and 4 percent ) or ingested A-9-TBC ( 15 mg ) , intra
ocular pressure was lowered an average of 30 percent in 7 out of 11
pat ients ( Hepler et al . , 1976a) . Another study showed that moat
pat ients had a decrease in intraocular pressure after ingest ion of
15 , 20 , or 3 0 mg of A-9-TBC and after smok ing cannabi s containing
1 , 2 , and 4 percent A-9-TBC (Hepler et al . , 19 76b) .
Ideal ly , the synthe s i s of a preparat ion that could be appl ied
topically to the eye would be moat desirable for humans , beCause this
wou ld allow for self-administrat ion . However , initia l stud ies in
humans with a topical preparat ion of A -9-TBC have not shown a
cons i stent effect on intraocular pressure (Mer r i tt et a l . , 1981) .
More wor k needs to be done on thi s possibility .
While animal stud ies have supported the observat ion that A-9-TRC
lowers intraocu lar pre ssure after oral and topical admini strat ion in
rabbits (Green et al . , 1977a , b J 197 8 ) , and after intravenous adminis
t rat ion in the cat ( Innemee et a l . , 197 9 ) , the reduct ion in intra
ocular pressure ia not completely under stood . It may result in par t
f rom a central nervous system e ffect , and i n part through act ion on
the adrenerg ic system in the eye , probably med iated by the neuro
t ransmitter norepinephrine .
S ide-Effects
142
o n the othe r hand , some of these e f fect s may d i sappear as tole rance
( decreased response with repeated use ) develops .
Summary
ANTIEMETIC ACTION
143
mo r e effect ive than prochlorperaz ine in certain s i tuat ions and seems
promi s ing ( Gralla e t al . , 1981) .
The suggestion that cannabis might have some useful ant iemetic
act ivity i n thi s setting arose about 19 7 3 , when pat ients rece iving
i ntensive chemotherapy for acute leukemia obse rved that the i r
• soc ial • u s e o f cannabi s appeared t o reduce the i r customary nause a
and vomiting .
Several controlled stud ie s have been repor ted . In one of the early
ones ( Sallan e t al . , 1975) , 6-9-THC in 15- or 20-mg dose s by mouth
was compared with a placebo i n a randomi zed double-bl ind crossover
tr ial in 22 pat ients whose nausea and vomit ing had been shown
r efractory to other antiemetic s . In 14 of 20 courses of treatment ,
pat ient s obtained •complete or par t ial rel ief • with 6-9-THC J in
none of 2 2 courses d id pat ients report bene f i t with the placebo. It
was observed that the ant iemetic effect o f 6-9-TBC occur red only i n
assoc iat ion with the • h igh , • and it was necessary to mainta in the
•high • in orde r to ma intai n the ant iemetic effec t .
In another controlled t r ial (Chang et al . , 1 97 9 ) , 14 of 15
pat ients with osteogenic sarcoma treated with h igh-dose methotrexate
had less nausea and vomiting with 6 -9-THC than with the placebo .
In that study , patients with other tumors be i ng treated with cytoxan
and adr iamyc in d id not respond aa well . That repor t and others like
i t suggested that the ant iemetic effect of 6 -9-THC against those
chemotherapeut ic agents that are moderate in their emetic potent ial
( e . g . , methotrexate ) was pronounced , but that 6-9-TRC was less
e f fective against those agents with severe emet ic propert ies . In a
similar study ( Luca s and Laszlo , 1 9 8 0 ) , 3 8 of 5 3 pat ients with nause a
and vomiting refractory to other ant iemet ic& repor ted good results
with 6-9-THC . Among the failure s were those treated with
ciaplat in , which has been character i zed aa one of the moat emetic
agent s used in cancer chemotherapy .
In compar i son with prochlorperaz ine , 6 -9-THC has also been
repor ted to be more effective in prevent ing nausea and vomiting
(Eke r t et a l . , 1979 J Sallan et al . , 1980 ) .
In a larger study ( Frytak et a l . , 197 9 ) , of 116 pat ients treated
with 5-fluourac i l and methyl-ccNO , 6-9-TBC was said to be no more
effective than prochlorperazine . In that study , in which near ly all
pat ients were older than those in the othe r reported tr ials , the
major ity of pat ients considered the other s ide-effects of 6 -9-THC
so unpleasant that they preferred e ither prochlorparaz ine or the
placebo .
Another cannabinoid , a synthetic , nabi lone , has been provided to
several invest igator s for eva luation an an ant iemetic agent J it ha s
been l icensed for use in Canada for treatment of nausea assoc iated
with cancer treatment . In the largest clinical study to date ( He rma n
e t a l . , 1979 ) , nabi lone was compared with prochlorperaz ine in a
double-blind c rossover tr ial . I t was found more effect ive than
144
prochlorperazine . The pat ient s in that study prefer red nabi lone to
p rochlorperaz ine J the predominant s ide-effects were somnolence , dry
mouth , and d i z z iness . Halluc inat ions occurred in a few pat ients .
Euphor ia of the type assoc iated with cannabis was infrequent in that
study . However , a study in dog s has revealed previously unrecogni zed
late neurolog ic e ffects of nab i lone at high dose s ( Arche r et al . ,
1981) . Monkeys and rats d id not show s im i la r tox ic e f fects with long
t erm admin istrat ion of nabi lone ( Archer et a l . , 198 1 ) , and further
stud ies will be necessary to c la r i fy the safety of th i s new agent .
Levonantradol i s yet another synthet ic cannabinoid , related to
A-9-THC , which has been shown i n pre l iminary clinical stud ies to
have ant iemet ic act ion in pat ients with refractory chemotherapy
induced eme s i s ( Diasio et al . , 1 9 8 1 ) .
In r esponse to publ ic and pol i t ical pressures , the Nat ional cancer
Inst itute , the United State s Drug Enforcement Agency , and the POod
a nd Drug Administrat ion have ag reed to a program whereby the Nat ional
Cance r Inst itute is mak ing A-9-TBC ava i lable through the pharmac ies
of approximately 500 teaching hospitals and cancer centers to
physic ians who wish to use A-9-TBC in treating the nausea and
vomi t ing of pat ients rece iving cance r chemotherapy . Th i s broad ,
uncontrolled prog r am , in wh ich no data other than the report ing o f
severe react ions a r e t o be col lected , may make it extremely d i f f icult
to obtai n continuing valid evaluat ions of the effec t i veness of
A- 9-TBC in the management of nausea and vomiting due to cancer
chemothe rapy . Although the extent of use of A-9-TBC under thi s
prog ram i s d i f f icult t o evaluate , informa l commu nicat ion with the
Nat ional Cancer Inst i tute ind icates that A -9-TBC has been suppl ied
in substant ial quant i t ies to several hundred hosp ital pharmac ies .
The problem i s fur the r compl icated by the fact that the leg islature s
o f 2 3 states have author i zed the use of cannabis by any physic ian for
the management of nausea and vomit ing due to cancer chemothe rapy . It
i s expected that l i ttle rel iable informat ion will be der ived from
such use .
Summary
145
APPETITE STIMULANT
I t has been stated by • soc ial• users that the smok ing of cannabis
increases appet ite . On that bas i s , there have been sporad ic attempt s
to use i t in pat ients with advanced cancer to overcome the i r
customary debil itating weight los s .
I n several of the stud ies in which A -9-THC was used as an
ant iemet ic in pat ients rece iving cancer chemotherapy , they were
reported to have increased appetite and food intake . At thi s t ime ,
i t i s not certain whether that increase was due merely to rel ief of
nausea and vomit ing or to st imulat ion of appet ite . One compar i son o f
habitual mar ij uana users a nd cont rols matched for age and educat ional
backg round showed increased calor ic intake and we ight gain among the
u sers (Greenberg , et a l . , 197 6 ) . Fur the rmore , a double-bl ind
controlled study (Holliste r , 1971) of smokers of cannabi s or placebo
c igarettes provided with unl imited quant it ies of a h igh-calor ic
beverage ind icated an increase in calor ic consumpt ion in those us ing
cannabi s compared with those using the placebo , however , the
var iabi l ity was very large and there was some quest ion that cannabi s
could be cons idered a clinically s ign if icant appetite stimulant .
In another study of the psycholog ical effects of A-9-TRC i n
pat ients with advanced cancer , i t was observed that A-9-THC
appeared to st imu late appetite and retard we ight loss (Regelaon e t
a l . , 197 6 ) . In that study many pat ients refused to complete the
2-week tr ial because of unacceptable s ide-ef fects from A-9-THC .
The evidence to date suggests that there may be some influence of
cannabi s on appet ite . However , i t i s not possible to separate that
f rom the effect on nausea and vomiting . Furthe r stud ies are in
prog ress in cancer pat ients whose course is not compl icated by nause a
and vomi t ing .
ANTICONVULSANT ACTION
A large number of animal stud ies have been conducted us ing cannabi s
as an ant iconvulsant . These can be d ivided into several categor ies .
The f i rst to be d i scussed will be max imal electroshoc k se i zures
(MES) * both i n the rat and mouse ( Loewe and Goodman , 1947 J Sofia et
al. , 1971 J Fuj imoto , 1972 J Consroe and Man , 1973 J Karler et al. ,
1 9 7 3 J Chesher and Jackson , 197 4 J Karler et a l . , 1974 J McCaughran et
al . , 1974 J Karler and Turkan i s , 1976 J Consroe and Wol k in , 1977 J
Turkanis et al. , 197 7 ) . In these stud ies the re i s a c lear dose
re sponse effect in the protec t ion to MES confer red by cannabinol
( CBN) and cannabid iol (CBD ) . Tolerance to the effept has frequently
been reported . However , the tolerance noted with cannabinoids i s
s imilar to that seen with phenytoin ( DPH) . Further , even though
tolerance to phenytoin develops with MES , this has not been shown to
*Electr ical shock of max imum intens ity to cause a major se i zure .
146
SUDDa ry
147
AN'l'IASTHMATIC EFFEC T
148
p lacebo cannabis smoke were not suff ic ient to agg ravate o r perpetuate
ex ist ing acute bronchospasm to an extent g reater than that wh ich
m ight result from the i r r itant effect of inhaled sal ine . The results
also demonstrate that inhaled A-9-THC causes a prompt and complete
sustained reversal of methacholine-induced bronchospasm and cor rection
of the associated hyperinflat ion . These effects were not s igni fi
c antly different f rom those observed after isoproterenol , although
there was a tendency toward a g reater degree of bronchial di lat ion
a fter i soproterenol . S imilarly , after inhalat ion of A -9-TRC , there
was a prompt return of a irway conductance and thorac ic gas volume
dur ing exerc ise-induced bronchospasm to the preexerc ise value . Afte r
exerc ise the effects of 10 mg A-9-THC was not as eff icac ious as
1. 2 5 mg isoproterenol .
The way in which A-9-THC induces bronchial dilat ion has not
been determined , but previous stud ies have shown that this effect is
not med iated by beta-adrenerg ic st imu lat ion or inhibit ion of muscar ine
r eceptors ( Shapi ro et al. , 1 9 7 3 ) . A vagolyt ic mechanism is possible ,
as suggested by othe r stud ies carr ied out on the dog sal ivary gland
( Cavero et a l . , 1972 ) and on guinea pig i leum (Gill et al . , 1970 ) .
Although ingest ion of A-9-THC in a sesame oil vehicle has
produced bronchod ilat ion in asthmatic pat ients ( Tashk in et al . ,
1974) , less d ilat ion was noted than after smaller doses of A-9-THC
de livered by smoking . I ts s ignif icant bronchod ilator effect
notwithstand ing , A-9-THC does not appear to be su itable for tha t
therapeutic use , because of its psychotropic effects and poss ibly
othe r s ide-effects . However , othe r cannabinoid compounds such as
c annabinol and cannabid iol do not produce the central nervous system
effects of tachycard ia character i st ic of cannabis (Holli ster , 1973 )
and deserve fur ther invest igat ion for possible bronchod ilator
ac tivity .
ANTIANXIETY EFFECT
Users of cannabis have often reported that the drug produces feel ing s
of relaxat ion and calmness , and some have reported its use to reduce
anxiety . A problem with evaluating cannabi s as an ant ianx iety drug ,
however , i s that some subj ects report increased anx iety or pan ic
afte r using cannabis ( see Chapter 6 ) . FOr example , Regelson et al .
( 1976 ) found less tens ion and apprehension in cancer patients after
cannabi s use r but 6 of 50 subj ects rece iving A-9-THC reported such
s ide-effects as severe dizz iness , confused thinking , dissoc iat ion ,
and concer n over loss of sanity . In normals , Pillard et al . ( 1974 )
found no effects of cannabis on exper imentally induced anxiety .
Nabi lone , a synthetic cannabinoid , was found to reduce exper imentally
i nduced anx iety in normal volunteers but it was less effective than
diazepam (Nakano et al . , 19 7 8 ) . Nabi lone was found to be more
e ffective than placebo in pat ients with psychoneurot ic anxiety ( Fabre
et al. , 1978) .
There are very few stud ies of cannabis effects on anx iety .
There is no ind icat ion at th is t ime that cannabi s or nabi lone are
149
more effect ive or rel iable than cu r rently ava ilable ant ianx iety
med icat ion .
ANTIDEPRESSANT EFFECT
ANALGESIC ACTION
ALCOHOLISM
OPIATE WITHDRAWAL
150
SUMMARY
Cannabis and i ts der ivat ives have shown promise in the treatment of a
var iety of disorde r s . The evidence is most impress ive in g laucoma ,
where their mechanism of act ion appears to be different f rom the
standard drugs , in asthma , where they approach i soproterenol i n
e ffect iveness , and in the nausea and vomi t ing o f cancer chemotherapy ,
whe re they cOmpare favorably with phenoth iaz ine& . Smaller tr ials
have suggested cannabis might also be use ful in se i zu res , spast icity ,
and othe r nervous system di sorders . Effect ive doses usually produce
psychotropic and card iovascular effects and can be troublesome ,
particularly in older patient s .
Although mar i j uana has not been s hown unequivocally super ior to
any ex ist ing therapy for any of these condit ions , several important
a spects of its therapeut ic potent ial should be apprec iated . First ,
its mechanisms of act ion and its tox ic ity in several diseases are
d ifferent f rom those of drugs now being used to treat those
cond itions J thus , combined use with other drugs might allow greate r
t herapeut ic eff icacy without cumulat ive tox ic i ty . Second , the
d ifferences in act ion suggest new approaches to unde r stand ing bot h
the diseases and the drugs used to treat them . Last , the re may be an
opportunity to synthesize der ivatives of ma r i j uana that offer bette r
therapeut ic rat ios than mar i j uana itself .
The comm i ttee bel ieves that the therapeut ic potent ial of cannabis and
its de r ivat ives and synthet ic analogues warrant s further research
a long the l ines desc r ibed in this chapte r . The re also may be
s igni f icant heur ist ic benefits to be derived f rom the study of the
b iolog ical mechanisms by which these compounds act .
151
REFERENCES
152
153
154
155
8
FEDERAL SUPpORT OF
RESEARCH ON MARIJUANA
I n this chapte r the comm i ttee has examined sources and amounts o f
federal support for research o n cannabis a nd the areas o f research
support . The comm i ttee has not analyzed the sc ient i f ic substance of
the work , nor has it examined the strategy of research support or
reviewed cur rent unpubli shed research .
The overall federal support for research on cannabis for the
f i scal year s 1977 , 1978 , and 1979 has averaged slightly more than $ 4
million pe r year i n real dollars ( Table 4 ) . Dur ing these years , 11
federal agenc ies allocated funds for this purpose . Of these , the
Nat ional Inst itute on Drug Abuse ( NIDA) has been the pr inc ipal agency ,
account ing for over four-f i fths of the total , therefore , our analys i s
will focus pr imar ily on this agency .
FOr f i scal year s 197 5 through 198 0 , NIDA ' s support of research on
c annabis amounted to $ 4 . 5 , $ 2 . 9 , $ 3 . 9 , $ 3 . 6 , $3 . 5 , and $ 3 . 8 million ,
respect ively , in real dollars , but in constant 1981 dollars , cor recte d
by the GNP deflator , the same f igures were $ 7 . 0 , $4 . 2 , $ 5 . 4 $ 4 . 6 ,
$4 . 2 , and $4 . 1 (Table 5 ) . Although the total research budget of th i s
agency for those years increased by approx imately $12 mill ion ( real
dollars) , the percent spent on cannabis declined f rom 14 . 2 to 8 . 2
( Table 5 ) . Dur ing the same per iod , the total numbe r of proj ects on
cannabi s supported by NIDA was reduced by approx imately SO percent r
however , the cost per proj ec t increased f rom $ 4 2 , 700 to $ 71 , 400 ( real
dollars) . This increased coat pe r proj ect is still somewhat lowe r
t han the mean coat o f all proj ects funded by the Nat ional Inst itutes
of Health in 1980 ( Leventhal , 1981) .
Table 6 shows the NIDA extramu ral research prog rams for f i scal
years 1975 through 1981 , allocated according to the type of drug being
s tud ied . In FY 1975 research on cannabi s was allocated only 13
percent of the total ext ramural budget , whe reas na rcot ics and
narcot ic antagonists rece ived more than 4 0 percent . The reafter , the
percentage devoted to cannabi s decl ined , to a low of 8 percent in FY
1 979 , but started to r ise again slightly in FY 1980 and FY 1981 . In
the last year , an est imated 1 1 pe rcent of the budget wa s spent on
cannabis research . The percent of the budget allocated to narcot ics
and narcotic antagon ists has declined stead ily , wh ile the percentage s
156
1 57
N IAAA 2 8 !. 5 85 2 6 1 22 3
NIH
NC I 91 2 2 80 2 2 85 2
NBI 0 3 68 2 1 36 1
N ICHD 0 1 13 !. 1 15 !.
N I RR 0 2 26 0 0
NIGMS 0 0 1 9 !.
OTHER AGBNC I BS
VA 7 52 1 6 26 1 8 25 1
DOT 5 55 1 1 !. 2 104 2
USDA 1 41 1 0 1 85 2
l"Y '73 l"Y ' 74 l"Y ' 75 py '76 F lt ' 77 py ' 78 Flt ' 79 l!'i ' ci O /!l{ ' 8 J.
Tot a l N I DA research budget 3l , 6 0 0 3 4 , 000 3 4 , 046 3 3 , 760 3 3 , 994 3 3 , 986 4 2 , 930 4 5 , !1 7 2 40, 400
( r ea l dol la r s , thou.and s )
To t a l N I DA r esearch budget 58, 500 5 8 , 700 5 3 , 500 4 9 , 600 4 6 , 800 4 3 , 800 5 1 , 0UO 50 , 300 4 0 , 4 00
( con s tant 1 9 8 1 dol lars ,
t housand s )
Po1ydrug ,
u nspec i f i ed , othe r 1 0 , 169 32 8 , 166 26 6 , 731 22 6, 723 22 1 2 , 286 32 l J. , 8 7 5 211 8 , 008 .10
TOTAL 31 , 5 7 5 100 31 , 198 100 31 , 4 9 1 100 31 , 1 38 100 38 , 1 7 5 100 42 , 024 100 4 0 , 408 J. O O
!Bst iJNte .
160
Cannabi s research essentially began in the late 1960s with a Nat iona l
I nst itute of Mental Health progr am to produce •ped ig reed • cannabis
for research invest igator s . NIDA , which was created in 1972 , started
w i th an extramural budget of $ 2 9 . 6 million and an i ntramu ral budget
of $4 . 0 million for f i scal year 1973 ( Ludford , 1981) . In the ear ly
1 970s , NIDA ' s major thrusts were ( a ) supplying ( to researchers)
standard i zed mar i j uana of a known concentrat ion of 6-9-TRC and of
known genet ic stock , (b) fac i l itat ing administrative mechanisms , and
( c ) attempting to under stand the problem of drug abuse , e . g . , how
many people use the drug , what are the acute effects , and what are
it s impl ications (Peter sen , 1 9 8 1 ) .
Recently , NIDA ' s emphasis has shifted to study ing certain g roups ,
e . g . , children , adolescents , and pregnant women , espec ially with
r e spect to the long-term effects of cannabis on these g roups
( Petersen , 1981) . The NIDA prog r am plan for f i scal year 198 2
stresses that chronic and acute stud ies need to be conducted on the
effects of cannabi s and othe r drug s of abuse on women and adolescents ,
w ith a spec ial emphasis on : ( a ) i n-depth behavioral and b iolog ical
stud ies of the amot ivat ional syndrome ( • burn-out • ) , and ( b ) the
development of approaches to t reatment . Also spec i f ically targeted
are stud ies of the effects on brain funct ion and structure .
Table 7 presents the NIDA proj ects on cannabi s for f i scal years
1978 , 1979 , and 1980 stratif ied by research goal . These research
goals are def ined in the footnote to the table . POr f iscal years
197 8 , 1979 , and 198 0 , most of the money devoted to research on
cannabis ( approx imately $3 million annually) was spent in three areas :
( 1 ) hazard s of cannabi s use , ( 2 ) basic research , and ( 3 ) research
suppor t . Thi s last goal includes the g rowth , process ing , packag ing ,
and d istr ibut ion of cannabis , as well as the development of the
6- 9-TRC capsu le . It is instruct ive to compare this d istr ibut ion of
cannabis funds with the d istr ibut ion of the total research funds of
NIDA . In FY • s o , research o n hazards took only 12 percent o f the
total NIDA research budget , basic research 42 percent , and research
suppor t 19 percent ( Pollin , 1981) .
The allocat ion of funds , by research topic , for f i scal years
1978 , 1979 , and 1980 is presented in Table 8 . The largest proportio n
o f the funds has been allocated t o two research topics : ( 1 ) drug
161
1. Epidemiology 238 54 61
3. Prevent ion 77 48
162
Psychophysiology 54 76 16
Immunology 69 85
Drug interactions 64 97
Cu ltural/ethnic 195 45 69
Abuse liability 76 48
!Due to round ing o f numbers , the total value i s not exactly the
same as in Table 7 .
163
* NIDA has r equested that the NIH take over the cost and d istr ibut ion
of the drug s for clinical stud ies ( Snyde r , 1 9 8 1 ) .
164
ADAMHA
N I DA 55 2, 267 16 1 , 6 29 4 44 75 3, 940
N IAAA 2 8 2 8
N IH
NC I 4 91 4 91
NEI
NCHD
N I RR
NIGHS
OTHER AGENC I ES
VA 7 52 7 52
DOT 2 55 2 55
USDA 1 4l l 4l
SUMMARY OP FINDINGS
165
ADAMilA
N IMH 5 1 58 3 56 8 214
N IAAA 5 85 5 85
NIH
NC I 2 80 2 80
NB I 3 68 3 68
NCHD 1 13 1 13
NIRR 2 26 2 26
NIGHS
0'1'HBR AGENC I ES
VA 6 26 6 26
DOT 1 .! 1 .!
USDA
166
TABLE 1 1 ca n n a b i no i d Research by Ag en cy : FY 1979
( r ea l dolla r s i n thousand s )
ADAMHA
N I DA 54 2, 6 08 10 925 1 3 65 3, 536
N I AAA 6 122 6 1 22
NIH
NC I 2 85 2 85
NE I 1 36 1 36
N ICHD 1 15 1 15
NIRR
N I GHS 1 9 1 9
OTHER AGENC I ES
VA 8 25 8 25
USDA 1 85 1 85
!F Y 1 8 0 : RFP 1 2
FY ' 81 : RFP 1 4
167
TABLE 1 2 Drug Abuse Research Gr ant Award Rate s and Pr ior ity Score s
Emphasis should be on stud ies of human be ings and other pr imates , and
investigator-initiated research g rants should continue to be the
p r imary vehicle of support .
RECOMMENDATIONS
•
More support of cannabis research is needed . Proper ly
allocated , it could pay large d ividends in new knowledge and could
help to d i spe l present ignorance in many c r i t ical areas . Withou t
this new informat ion , the pre sent level o f publ ic anxiety and
controversy over the use of mar ij uana is not li kely to be resolved i n
t he forseeable future . Furthermore , we are not l i kely to improve ou r
present slow prog ress in deve lop ing informat ion about possible
therapeut ic u ses of cannabis and its analogues without the stimulus
of increased research grant suppor t . At the end of each of the
c hapter s , we have pointed out opportunities or problems that are r ipe
at thi s t ime .
•
A larger proport ion of NIDA resou rces could j ust i f iably be
allocated to cannabis research . Without wishing to minimize the
value of any of the other drug research prog rams now supported by
N IDA , we believe that the magnitude and soc ial u rgency of the
mar ij uana problem war rant a h ighe r pr ior i ty for cannabis researc h
168
than it has apparently rece ived to date . A drug that is cur rently
u sed by about a third of all Amer ican high school sen ior s , and daily
by about one in eleven , dese rve s more study than we cur rently are
g iving it . No other i llicit drug is used as widely by our youth , and
yet NIDA spent only 9 percent of its research budget on it in FY • so .
•
NIDA would be advised to cont inue its recent policy of
reducing the relat ive proport ion of contracts and emphas i z ing
g rants . Although we bel ieve that there is need for fede ral
i nit iat ives in st imulat ing work in neg lected areas of cur rent
conce r n , the bulk of research supor t should cont inue to go to
i nvestigator- init iated proj ects .
•
The durat ion for invest igator-initiated research should be
lengthened beyond the average 3-year per iod in order to attract and
hold good researcher s .
•
Other agenc ies should contr ibute funds for the product ion ,
processing , and d istr ibut ion of cannabis .
•
A sc ient i f ic advisory g roup should be formed to ass ist i n
provid ing sc ientif ic evidence and gu idance to the d irector o f NIDA .
•
An increased interagency effor t targeted toward spec i f ic
problems not read i ly add ressed by other approaches is required .
These would include , for example , human long-term stud ies , as well a s
stud ies i n epidemiology , prevent ion , and treatment . Funds should be
contr ibuted by all agenc ies .
•
Research on human be ing s and other pr imates should be
encouraged , par ticularly stud ies in the young . There i s a spec ial
need at th i s t ime for good epidemiolog ica l stud ies that follow
ident if iable cohorts of mar i j uana users over a per iod of t ime .
REFERENCES
Hurd , Susan . Nat ional Hear t , Lung , and Blood Inst itute . Bethesda ,
Md . Per sonal commu n icat ion , 1981 .
L ittle , Franc ine . Nat ional Cancer Inst itute , Bethesda , Md . Pe r sonal
commun ication , 1981 .
L eventhal , Car l . Nat ional Inst itute of Arthr it is , Metabolism, and
Digestive Diseases , Bethesda , Md . Pe r sonal commu nicat ion , 1981 .
Ludford , Jacqueline . Nat ional Institute on Drug Abuse , Rockvi lle ,
MD . Per sonal commu n icat ion , 1981 .
Peter sen , Rober t . Nat ional Inst itute on Drug Abuse , Rockvi lle , Md .
Per sonal commu nication , 1 98 1 .
Pollin , w . Statement on Drug Abuse Research before the Subcomm i ttee
on Alcoholism and Drug Abuse , Comm i ttee on Labor and Human
Resources . United States Senate , July 2 7 , 1 981 .
Snyder , Marvin . Nat ional Inst itute on Drug Abuse , Bethe sda , Md .
Personal commu nicat ion , 1981 .
Append ix
A
WORK OP TBB COMM I 'l'TBE
The steer ing comm i ttee , i n the meant ime , nominated add it ional
cand idate s for membership on the panel s and comm i ttee at its f ir s t
meeting o n December 1 , 1980 . Subsequently , four more meet ings were
169
170
Append ix
B
ACCESS '1'0 �-9-THC AND MARIJUANA
FOR RESEARCH AND TREATMENT
The invest igat ional u se in human subj ects of �-9-THC and ma r i j uana
are controlled by the Fede ral Food , Drug , and Cosmetic Act and the
Investigat iona l New Drug Regulat ions issued unde r that Act . In
add i t ion , � -9-THC and mar i j uana are controlled under the provis ions
of the Cont rolled Substances Act and cur rently are cont rolled in
Schedule I of the Cont rolled Substance s Act . Schedu le I drug s ar e
t hose that have a ( 1 ) h igh potent ial for abuse , ( 2 ) no cur rently
accepted med ical use in treatment in the Un ited States , and ( 3 ) lac k
of accepted safety for use unde r med ical superv i s ion .
Basically two agenc ies wor k together for enforc ing the cont rol s
o f the Act a the Food and Drug Administrat ion ( FDA) in the Department
of Health and Human Service s and the Drug Enforcement Administ rat ion
( DEA) in the Department of Just ice . The Depar tment of Just ice was
pet it ioned to recons ider the re schedu ling of �-9-THC and mar i j uana
in 1 9 7 2 , but to date there has been no change . Howeve r , DEA and FDA
are now under court order to recons ide r thi s situat ion . An FDA
advi sory meet ing , held in June 1981 , cons idered the scheduling status
of the �-9-TBC capsu le only (Federal Reg i ster , 1981 ) . The
comm i ttee recomme nded that the � -9-THC capsule be changed from
Schedule I to Schedule I I status when a new drug appl icat ion fo r
�- 9-TBC i s approved by FDA . Schedule I I drug s a re those that
have : ( 1) a h igh potent ial for abuse , ( 2 ) a cur rently accepted
med ical use in treatment in the United State s or a cur rently accepted
med ical u se with seve re restr ict ions , and ( 3 ) abuse that may lead to
severe psycholog ical or phy s ical dependence .
COmpla ints and concerns were expressed to the study comm i ttee
abou t the supply and d i str ibut ion of mar i j uana and �-9-TBC for
treat ing chemotherapy s ide-effects in cance r pat ients . On the one
hand , phys ic ians said that there was poor cooperat ion f rom federal
agenc ies engaged in controlling and supply ing the drug (Koller , 1981 J
Monsma , 1981) , par t !cu larly with respect to ( 1 ) potency of �-9-THC
rece ived ( concentrations we re too low to be effective ) , and ( 2 )
unce rtainty and irregular ity of the sh ipments of the drug . On the
othe r hand , some cl inic ians felt that it was premature to release
A-9-TBC for use in cance r pat ient s (Moertel , 1981 J Cook , 1981)
because :
171
17 2
•
spec i f ic ind ications have not been established , in that the
way in which chemothe rapeut ic agents cause nausea and vomiting is not
known ,
•
spec i f ic populat ions of pat ients have not been establ ished ,
•
effect ive dose schedules have not been establ i shed r
•
safety of treatment at doses effect ive for ant iemet i c
purposes rema ins in quest ion r
•
r eported peer-rev iewed exper ience i s contrad ictory and st ill
fragmentary , and
•
c ontrolled , r andomi zed , prospect ive stud ies have not been
conducted .
Depend ing upon the use of the drug , two d i fferent agenc ies are in
charge of supply ing mar i j uana c igarettes and �-9-THC capsules r the
Nat ional Institute on Drug Abuse (NIDA) controls the supply of
mar i j uana c igarettes and/or �-9-THC capsules for basic research ,
and the Nat ional Cancer Inst itute (NCI ) controls the supply of
6-9-TBC capsules for cancer treatment . The processes of obtaining
supplies f rom each agency (or for each purpose ) d if fer .
173
anorex i a , the phy s ic ian aust g o through the bas ic r esearch route . In
v iew o f the poss ible contaminant problems with asperg i llus and
salmone l la , it may be necessary to provide ste r i l i zed ma r i j uana
c igarettes to pat ients .
174
REFERENCES
Abraham , Dav id . Invest igat iona l Drug Br anch , Hea lth Sc ienc e
Administrat ion , Nat ional Cancer Inst itute , Bethesda , Md .
Per sona l commu n icat ion , 1981 .
Cook , D . A . Pr ivate pract ice , Bay City , Mich . Per sonal
commu n icat ion , 1981 .
Davignon , Paul . Ch iei , Pha rmaceut ical Resou rces Branch , Nat ional
Cance r Inst i tute , Bethesda , Md . Pe r sona l commu nicat ion , 1981 .
Federal Reg ister , Volume 4 6 , Number 3 1 , Februa ry 2 4 , 1981 . Study of
the health-related effects of mar ij uana use , pp . 13816-13 818 ,
1981 .
G roup C Gu idelines for the use of �-9-Tetrahydrocannabinol
NSC1 3 4 4 54 for nau sea and vomi t ing induced by ant ineoplast ic
chemothe rapy . Investigat iona l Drug Branch , Cance r The rapy
Evaluat ion Prog r am , Div i s ion of Cancer Treatment , Nat ional Cancer
Inst itute , Bethesda , Md . , September , 19 8 0 .
Gunby , P . Many cancer pat ients rece iving TRC a s ant iemet ic . JAMA
2 4 5 : 1515-1518 , 198 1 .
K oller , C . A . Ass i stant Professor o f Internal Med ic ine , Divis ion of
Hematology and Oncology . Un ivers ity of Mich igan , Ann Arbor ,
M ich . Per sonal commu nicat ion , 1981 .
Moe r tel , C . G . Director , Mayo Comprehens ive Cance r Cente r 1 Professo r
of Oncology , Mayo Med ical School , Cha i rman , Depar tment of
Oncology , Mayo Clinic , Rocheste r , Minn . Per sonal commun icat ion ,
1981 .
Monama , Stephen v. Senator , State Senate of Mich ig an , Lansing ,
Mich . Per sonal commu nicat ion , 19 8 1 .
Tocus , Edward c . Chief , Drug Abuse Staff , Food and Drug
Administration , Rockville , Md . Pe r sonal commu n icat ion , 1981 .
Turner , Car leton . Di rector , Research Inst itute of Pha rmaceut ical
Sc iences , University of Miss i s s ippi , Oxford , Miss . Per sona l
commu nicat ion , 1981 .
Append ix
c
LONGITUDINAL STUDIES
Append ix C i s a rev iew of prospective long itud inal stud ies of drug
use in normal populations listed by complet ion status , type of sample
( schoo l sample , commu nity sample ) , age of respondents , and year of
first contact . Some of the stud i e s are ongoing .
175
Characte r i s t ic s of Long itud inal Stud ie s of Drug Use in Normal Populat ions Listed by Completion
S tatus , Type of Sample , Age of Respondents , and Year of First Contact .
Pr inc ipal Population Gcade/Age at Year of Year of Total Interval S he of S he of Methode of Da ta Dr119a Inqu i red About
Inveat igator a Characte r i st ics '1'1 of Sallp le Fi rat L.. t llullbe r Betwee n S�le '1'1 Matched Collect!�
E l ig ible for Contact Contact of Con tecta Bllg i ble Pane l
Panel Contacts for Pane l
lellaa All ente r ing public Grade 1 1966 1975- 5 3 tiM• 1 , 2U 705 aa.e interv ieva 1 Cigarette s , bee r or
and parochial schoo l 1976 dur i ng schoo l te sta ( IQ , vine , hard liquor ,
f irst-g rade children f i rst achie-nt) and .. r i j uana , LSD,
i n a black �ni ty g rede g radea 1 ratings othe r paycbade lica ,
i n Chicago with low 2 years by teacher , cli upper s , downe r s ,
inco.e and high un 7 yea r s nician , -the r tranqu i l i aera , co
e�I.oy.ent ('1'1-'1'5 ) 1 pollee ca ine , heroin and
recorda , quea other opiate a, glue ,
tlonna irea ( '1'5 ) cough syrup
S.ith Students froa g redea Gredea 1969 1973 2-5 1 year 12 , 000 Var iable Self-�ini atered C igarette s , l iquor ,
c-12 i n 6 schoo l c-11 (approx . ) quest ionnai res in .. r i j uana , ups ,
ayateaa i n g reater claaarooaa , achoo l downs, psychedelics
Boston a rea , pre record a , peer s ' op iates , inhalant s ,
doai nantly wh ite and rat ings of atu- nonpre scr iption
• iddle-claaa dents ' person- dr119 stor e products ....
alitiea ....,
0\
laplan Seventh g rade stu- Grade 7 1971 1973 3 1 year 7 , 6 20 3,U8 Self-�ini atered Bee r or vine , liquor ,
dents f roa 18 of 36 quest ionna ires in .. r i j uana , na rcot ics
j unior high achoo l a claaaroo.a
of the Houston
I ndependent Schoo l
Diatr ict
Jea110r and High schoo l atudy a Grades 1969 1972 ' 1 year 589 C83 Belf-aCJ.in iatered Bee r or vine , hard
Jea110r randoa �le of 7-9 que stionna i re• li quor , .. r i j uana ,
students f roa g rades outs ide of claaa , �hetaa inea , LSD ,
7-12 of 3 junior and Grades 1969 1972 2-3 1 yea r 26 2 Var i able schoo l recorda other paychede l ica ,
3 sen ior h igh schoo l s 10-11 cocaine , and heroin
i n a ... 11 c ity in
the Rocky Mountains ,
a�t all of Ang lo
�r ican , •idd le-
claaa backg round
B U..- and Students f roa 5 Grades 1971 1973 2 2 years 18 , 363 8 , 136 Belf-�ini atered Cigarette s , bee r or
JoaephiiOn j unior and 18 aen ior 7-10 questionna i res in vine , hard liquor ,
high schoo l s purpose- claaa roo.a .. r i j uana or hash ish,
fully aelected to uaphetaai nea , •the
r epreaent va ried dr ine , barbiturates,
r eg ions , �nity LSD , other payche
a i ae a , aoc ioac:onc-ic de llca , cocaine ,
leve l s , and racial hecoi n , i nha lants
c011p0a l t lona but not
to r epreaent tha
Un ited State s
Annie and Student• of l public Grade 9 (llot (llot 2 ll 110ntha 915 886 &elf-ad8iniatarld Alcohol , aar i j uan� ,
Wataon high acboo l a i n a Givan) Given) queationn� i raa in tobacco , aolventa ,
northern Ontar io claaa1 intarviawa hallucinogana , bar-
city and dropouta witb dropouta biturata a , op iata a
f raa .... claaHa at T2
Kandel ( 1 ) Mult i a tage ran- Gradea 1971 1972 2 6 110ntha 8 , 206 5 , 423 Se lf-ad8in i aterad C igaratta a , bear o r
d aa aa.ple o f llaw 9-12 quaationn� i rea in wine , hard l iquor ,
Yor k State public claaaroaaa (ado- .. r i j auna , haahiah ,
aecondary acboo l leacanta ) . Ma i led a.phatu inaa, Mtha-
atudanta fraa 1 8 quaationna i raa d r i ne , barbitura�aa ,
acboo la and data (parental tranqu i l i zara , LSD ,
f raa 110thara o r other paychada lica ,
fathara 1 beat acbool cocaine , heroin,
fr iend in aubaa.pl a other narcot ica , in-
of 5 acboo l a halant a , cough ayrup
( 2 ) 1972 Senior Grade 1 2 1971 1973 3 7-12 2 , 3 86 l r 635 &a lf-ad8in iatarad s ...
claaa ( Th i rd wave) 110nt:ha qua ationna i raa
(Tl , T2 ) 1 .. U ad
queat ionna i raa (T3 )
--
Johnaton Yout h in Trana i t ion Grade 10 1966 197 4 5 2 yeara 2 , 2l 3 1 , 60 8 Interviawa (Tl , Cigaretta a , bear ,
cohort--A national l year T2 , T4 1 1 aa lf-ad- wi ne , bard l iquor
rando. •UIPle of 1 year aini aterad quaa- aa r i j uana , a.phata-
boya i n 8 7 publ ic 4 yeara t ionna i raa (Tl- ainea , barbiturataa ,
high acbool a in T4 ) 1 aa i lad ha llucinogana , Mtha-
cont inental Uni ted quaat ionna i raa qualona , coca i ne ,
Stataa i n 1966 1 drug ( T5 1 1 ability heroin
caaponenta added in teata (Tll
1970 and 1974 ....
....!
B r itt and ....!
North Carol ina h igh Grade 12 1961 1962 2 1 year 2 , 300 1 , 420 Self-adainiatarad Alcohol
Cupball acboo 1 nniora who queat ionna i rea ,
axpraaaed an intan- (unclear whether
t ion to attend in or out: of
collage in fall claaa)
Gulaa and Sen ior a at Dart.outb Collage llot Rot 2 4 yaar a 90 90 Ma i led quaation- Ma r i j uana , UIPhata-
Ung Collage ..tcbad fraahMn Given Givan nai ra• ainea , barbitu rataa ,
retroapactive1y to (pr ior ha lluci nogen•
t he i r fraabaan - to 1976)
year recorda
Beagan Collage j un ior• at Collage 1965 1968 2 3 yean 70 70 &alf-adaini atarad 'l'Obacco , alcohol ,
Maalayan univer aity f raahaen quaat ionna i raa 1 .. r i j uana , hallucino-
aatchad ratroapac- teat data on f i la gena
t iva1y to the i r at Off ice of
f raahaan ·and- Paycholog ical
aop�ra-yaar Sar v i�
record a
Ga r f ield and Randaa aa.pla at Collage 1966- 1970- 4 1 year 300 T2 -100 Par aonally adain- Alcohol, ..r i j uana ,
Ga r f ield large pr ivata aubur- atudanta 1967 1971 T3•201 laterad quea- haahiah , LSD, M aca-
ban raa idential T4-100 tionna i raa Una
waatarn univeraity
!.Tha aaaa Mtboda -r• uaed in all wavea of data collection of a atudy , unlaaa apac i f ic t t.. a are i nd icated .
Character istics of Long itud inal Studies of Drug Use in Normal Populat ion s Li sted by Complet ion Status ,
Type of Sample , Age of Respondents , and Year of First contact .
Princ ipal Populat ion Grede/Age at Year of Year of 'rotal Interval S he of She of Methode of Data Dr119• Inquired About
In,..t igaton Character iet ice '1'1 of Suple Firat La at IIUIIbe r Bet-n Suple '1'1 Matched Collection
BU g ible for Contact Contact of Contecta BUg ible Panel
Panel Con tecta for Panel
Grupp Randca auple of n College 1969 1973 3 2 years 127 '1'2-120 Pe nonal inter- Mar i j uana
of etudente at · undergraduate• '1'3-103 vi-• at Tl , T2 r
I l linoia State and g raduate .. t led quest ion-
Unive r s i ty not etudente na i ree for those
reporting .. r t j uana out of area at T2 ,
UH and for everyone
at T3
Gold ate i n Student• enrolled College 1968 1 97 2 4 Appr ox a 770 u7- Se lf-�ini etered Bee r , hard liquor ,
at Carnegie-Mellon f reet.en 9 11011 th8 queet ionna i ree , .. r i j uana ( inc l .
Univereity (claea 16 11011 t he outeide of cla•• ha e h i e h ) , tranqu i l -
of 1972) 20 11011 the (.. 11 technique i aere and ber bi-
preHrving enony- turetea , uphate-
•tty) •inee , hallucinogens , ....
narcot ice , tobacc o ......!
(I)
Grovea Full-tiee etudente College 1970 1971 2 1 year 7 , 948 3 , 961 Ma i led question- caffe i ne , alcohol ,
at predaa i nant1y freet.en na i r•• .. r i j uana , baeh i eh
wbite nonapecie1- end •thedr i ne , othe r
i aed colleges with j uniors uphetu i nee , berbi-
projected enroll- tu retee , aedetivee ,
••nt of over 1 , 000 trenqu i l i ae r e , LSD ,
( 1970 ) other peychede l ice ,,
coca i ne , op i ue ,
he roi n , o t ha r nar -
cot ice , COIJ9 h eyrupe
llell inger (1) Probabi lity College 1970 1973 2 2 1/2 960 834 Pereonal i nte r- 'I'Obacco , a lcohol ,
auple of .. le freet.en year a vi-• and Hlf- .. r i j uana or haah-
f reeheen of Uni- �in ietered ieh , uphetuinee ,
vere ity of Cal i- for-. 1 acboo l ber bitur etee , aeda-
fornia at Be rkeley recorder .. ned t i vee , peychede l ice ,
in Fall 1970 questionna ire• coca i ne , ha roin ,
op i ue , o t he r opiatee ,
inha lants
Jeeeor and College etudy--ran- College 1970 1973 4 1 year 276 226 Self-�inietered Bee r or wine , ha rd
Jeeeor doe eaeple of arts freehMn questionna ire• • liquor , .. r i j uana ,
and eo lence unlver- ecbool recorda uphatM i ne e , LSD ,
eity etudenta in a other peychede lice ,
a .. ll Rocky Mountain coca ine, heroin
city
SciNck it � UIIPl ea of
incaa i ng f rea�n at a
( 1 ) Waab tngton Uni- College 1970 1974 4 1 year 158 Not s-iatructured TObacco, alcoho l ,
varaity in S t . Louie freat.. n Givan interviawa a aa i lad aa r i j uana , baab i ah ,
quaat ionna i rea to uopha taine a , apeed ,
nonrea identa LSD , MIICaline ,
( 2 ) Univera ity of College 1971 1975 4 1 yea r 22 2 188 pai locyb i n , STP , MDA ,
California at San frea'-tl opiatea , .ad ic inal
Diego drug a
G inabarg and Student• enrolled at College 1971 197 4 2 2 year• 319 274 Ma iled queation- Mar i j uana
Greenley Un ivara ity of Wia- freat.. n and nairea
conain-Madi8on aop�rea
1971-1974
Sadava ( 1 ) College f rea�n College !lot llot 2 6 .antha 358 319 Self-adaini aterad cannabi a , paycha-
in an Bng l iab-lan- frea�n Givan G ivan queat ionna irea in del ica , uophatainea ,
g uege Ra.an Catholic (prior claaaroc.a a lcohol
college in province to 1973)
of Quebec
( 2 ) Undergreduatea College 1972 1973 2 6 .ontba 467 3n self-adaini aterad Alcoho l , tobacco ,
at a aaa l l Ontar io frea'-n and queat ionna i rea .. r i j uana and othe r
univaraity i n intro- aop�rea i llicit druga
ductory paychology
cou r a e
. -
lt ay � UIIP le o f College 1971 1974 -- 4 -- 6 .antba a
-- 1 30 68 Self-adaini aterad Ma r i j uana
..le atudanta freat.. n 1972 1974 3 1- '1'2 1 1 24 85 queat ionnaire a , ....
ente r ing Labigb 1973 1974 2 1 yeao ll2 98 ad jective cbeck ......!
univara ity '1'2-T3 , liat , California 10
T3-T4 Paycholog ical
Inventory
Mooa Enter i ng claaaea of College Not llot 3 9 11011 th a 1 , 296 T2-886 &elf-adaini aterad Alcohol
two univaraitiea fre�n Ghan Ghen 3 yaara TJ -567 queat ionna i rea,
outa ide claaa
Characteristics of Lonq itud ina l Stud ies of Drug Use in Norma l Populations Listed by Completion Status ,
Type of Sample , Age of Respondents , and Year of First contact .
Part 2 . eo-plated Studiaa o CU..U n ity Sa-plea
P r i nc ipal Popu lation Grade/Age at Year of Year of Total Interval She of st .. of llathoda of Data Dr119a Inqu i red About
Inveat igatora Characta r i at ica '1'1 of SUIPla Firat La at Rllllba r Ba�n SUIPle '1'1 Matched Collection
Elig i ble for COntact COntact of Contacta llig ibla Panel
Panel Contacta for Panel
( 1 ) Children 13-17 yra 1973 1 9 7 5- 2 3 yean 403 183 &ouaahold inter- Ma r i j uana , upa ,
1976 viawa downa , paychede l ica ,
heroin
B runawick Rapraaantativa co.- 16-17 1969- 1975- 2 6 yean 664 536 Bouaahold inter- Alcoho l , -r i j uana , ....
Q)
.unity aaapl a of yaar a old 1970 1976 viawa a��pha t-i nea, bar -
0
Barl .. youth bi turata a , acid ,
coca i ne , heroin, g lue
Sieber 19 year old con- 1 9 yean 1971 1974 2 3 year a 1 , 413 841 Self-adainiatarad Alcohol , tobacco ,
acr ipta born in quaationna i rea 'I'l l -r i j uana
canton of Zur ich .. ilad quaation-
who report - na i raa '1'2
alcohol/drug uaa
at i n i t ial contact
Robina ( l l Viatnaa veterans 20 yaara 1972 1974 2 2 yean 605 571 Intar.iawa 1 urine Cigarattea, a lcohol ,
randca aaapla of a� (-nl 1975 aaap laa 1 • 1 1 itary .. r ij uana , a.phata-
anli atad .. laa wbo and v.tarana ' Ad- •inea , ha r biturataa ,
retu r ned fraa Viatnaa •ini atration tranqu i l i za r a , hal -
to the Un ited Stataa recorda 1uc inogana , cocaine,
in Sept.-bar 1971 , narcot ics
and a auppl...ntary
randaa aaap le f raa
to
r2
id
:Ill
raatr 1ctad to ..n
i nducted a ince 1 969
and fraa the 25 �r•
populou• lbte a
Cahalan ( 1 ) Nat ional proba- 21 and 1964- 1967 2 2 year• 1� 810 1 , 359 aou .. bold inter- Dr inking patterna ,
et a l . b i l i ty ..-ple of over 1965 viewa (Tl ) l .. il practicea , and
Un ited State• adult queationna irea probl-
population, ( � )
a aJIPled f rc. reduced
Il target population
N•l , 810 , with ab-
atainera and very
infrequent d r i nker •
aubaaJIP led at a
leaHr rate
( 2 ) National proba- 2 1-59 1969 1973 2 4 yean 978 725 SaM SaM
b i l i ty ..-ple of year a old
white .. lea aged 21-
59, with ove r...-
pUng of urban a rua
Character ist ics of Long itud ina l Studies of Drug Use in Normal Popu lat ions Li sted by Complet ion Status ,
Type of SaJDple , Age of Respondents , and Year of First Contact .
Pr incipal Populat ion Grade/Age at Year of Year of 1'otal Interval Siaa of Sba of Method• of Data Druga Inquired About
Inveat lgaton Charactar iat lca '1'1 of Supla Pint Laat Hwlber llat-n Supla '1'1 Matched Collection
BUg ibla for Contact Contact of Contact a BUg ibla Panel
Panal Contac:U for Panel
Buba and Student• in the Grade a 1976 1980! 4 1 year 1 , 6 34 768 Salf-a&.iniaterad C igarettea, bee r ,
Bentler greate r Loa Angel•• 7-9 2 yean quaat lonna i raa vine , l i quor , .. r i -
area vitb over...- 1 year fro. the atudanta , juana , haahiah, cof -
pUng of lower aoc i o- paranu ( '1'1 , '1'4 1 fH , •inor and .. jor
econc.ic achoo l a and paa r a ( '1'1 , '1'2 1 tranqu i l i aar a , barb i -
turate a , aadati vea ,
antldapraaaanta ,
upheta. ine a , non -
uphet .. inaa , uppe ra ,
LSD, other payche- ....
Q)
da l i ca , an i f f ing ...,
atu f f , aay l nitrate ,
nonpreacr ipt. ion •
alHping pUla I
atbu lan ta, coug h
� ic i ne , cold
� ic i ne , coca ine ,
heroin, other na r -
cot ica , PCP , coca
paate
Lukoff Quota aa.pla fro. 6 Grad•• 1979 19al 2 2 yean 932 Not yet Se lf adaini aterad Alcoho l , c igarettea,
and Brook atatea (Connec ticu t , 9-10 co.platad quaatlonnairea .. r i j uana , upheta-
Kanaa a , Nav Jeraey , •inaa , barbi turatea ,
Nav Yor k , Oh io , and LSD , othe r payche-
South Carolina) • delic a , heroi n , other
App r oxiaataly equal narcot lc a , tranqu i -
n Wibe n o f .. lea and l i aa r a , quaalude a ,
f ... lea , blacka and coca i ne , inhalant•
vh i te a of •iddle
soc i�ic atatua
Clayton Nat ionally rapre .. n- 20-JO 1974- 1982 2 6-7 4 50 Not yet Pe r aonal inte r- Cigar ettaa , alcohol ,
and Voaa tat iva aa.pla of .. n year• old 1975 yea r• co.platad viava aa r i j uana , payche -
born bat-n 1944 and delica , at i•ulant a ,
1 9 5 4 inclua i ve , vho aadatlve a , heroin ,
r eg iaterad vith othe r op iata a , co-
Select ive Serv ice caine , tranqu l l i aera ,
upon age 18 inhalanu
Carpente r , Cohort-aequentlal a) 12 yean 1979 ongoing 14 tele 1 year a ) l , l50 NOt On-a ite s Alcohol , c lgaret tea ,
Leater , dea lgn-aan.s b ) 15 yea n phone l yeara b) 4 50 ye t COII -pereanal inter aar l j uana , a.pheta
Pand l na , and IIAIIp lea of New Jeney c) 18 yean 8 ona i te unt il aqe c) 450 pleted vi-• alnea , barb ituratea ,
Labouv le edole-nta-- 24 1 6 d) 150 -Hlf-acblin1- LSD, other payche
a) 9 cohor ta born year a atered queat 1on de l i c a , heroin , other
1967-75 after age na 1rea narcot lca , tranqu 1 -
b) l cohorta born 24 -behavioral teata l i ae r a , quaaludea ,
1964-66 -blood aa.ple ccca lne , inhalanta ,
c ) l cohorta born -paycholoq lcal pep, uoyl and butyl
1961-63 teat n i t rate a , over -the
d) 3 control g roupa -..d lcal ex- counte r paychothera
at T4 peutlc a , caffe i ne
Te lephone
contact s
-.a jor l i fe event a
-alcohol and druq
ta k i ng oute011e a
E l l iott National Youth 11-17 yeara 1976 1980 5 1 year 1 , 725 T2- 1655 Pe r eanal at ruc Tobacco , bee r ,wine ,
Survey-Nat ional Tl-1626 tured inter l iquor , aa r l j uana ,
probabi l i ty ault 1- T4 -1 543 vi-• ha lluc inoqena , co
ataqe cluater aa.ple T5-1494 ca i ne , he roin,
o f dvelUnga aed ical and non
aed lcal uae of
a.phe taainea , bar
b i tur ate s ....
Q)
w
Jeaeor , Young adult follow- Gradea 1969 198 1! 6 1 year 432 NOt yet Tl-T4 --Self -ad Beer , w ine , hard
Jeaaor , and up. H igh achoo l 7-9 1 year coapleted alni atered quea l iquor , aa r i j uana ,
Donovan aaaple--randoa aa.ple 1 year Uonna lrea in LSD, aaphetaal ne a ,
of atudenta froa 7 yean achoo l ( h igh cocaine ,
g radea 7-9 of l 2 yeara achoo l aa.ple ) heroi n , tranqu i-
j unior high achool a in ... u g roupa 11aer a , barbitu
i n a ...u city (collaqe �UJ�ple ) rate a , aorpb i ne
in the Rocky
Mounta ina, alaoat
all of Ang lo-
Aaler ican , aiddle
c laaa bac kground
Collaqe aa.ple- Collaqe 1970 19n! 6 1 year 205 not yet '1'5 , T6-Mu lt
randoa aa.ple of f reahaan 1 year coapleted fol low-upa 1 aaUed
f reahaan claaa arta 1 year Hlf-adainia tered
and ac ience 6 yeara quea tionna i rea
unive r a i ty atudenta 2 yea r a
in a ... 11 Rocky
Mountain c i t y
Character istics of Long i tud inal Studies of Drug Use in Normal Populations Listed by Completion Status ,
Type of Sample , Age o f Respondents , and Year of First Contact .
PrlnClrpal Popula tion Grade/A;• at Year of Year of Total Interval S i aa of She of Methode of Da ta Druga Inqu ired About
I nveat igato r a Cbaractar i a t ica Tl of Sa.pla Fi r at Laat Nullbe r Between Saaple Tl Matched Collect ion �
co
Elig i ble for contact Contact of Contacta Elig i ble Panel ..
Panel Contact a for Pane l
Johnaton Mon i tOr ift9 tba Grade 1 2 1975- Oft90lft9 11 for aaeh 1 year 2 , 4 00 NOt yet Tl--Se lf-adainia Alcoho l , c igarettea,
and Bac�n FUture--cohort •• ongoin<J cohor t for each ( target ea.plated tered queation .. r i juana , a.pheta
quantial dedgn. coho rt for each na i rea i n claaa •1ne a , barbi turatea ,
Sueeeaaive nation (2 yr a cohor t , roau T2, adult LSD, other payche
a l ly rapra ..ntat ive for each 1 , 200 for fol low-upa - de l ica, heroin , othe r
cohorta of high cohort each co Ma i led queat ion nareot ica , t r anqu i
achoo l .. niora f ra. 1/2 hort l/2 na i rea l i &er a , quaaludea ,
1 1 5 publ ic and 1 5 aa.pla) aa.ple ) coca ine , inhalanta ,
p r ivate h igh achoo l a 1 PCP , .-y l a nd butyl
repeated annua lly , nitratea , over -the
entire aanior claa .. a counte r paychothe ra
in aehool a w i t h 300 peut ica , caffeine
aenior a , and aub
aa.plea ( N-300 ) i n
larger aehoo l a
K andel Mul t i atage randa. Gr ada a 1971 198 � 3 6 .antha a) 1 , 321 1 , 081 Tl , T2--Salf-a.S.in- Cigarette a , beer or
aaapla of adola8Centa 10-11 9 yaara b) 330 244 l aterad quaat ion- wine , hard liquor .
enrolled in New York nai raa in claaa- .. r i j uana , haah i ah ,
public aeeonda r y roa.a .. thedr ine , LSD ,
schoo l .. leeted other payehedelic a ,
f r- 18 achoo l a Tl--Mult follow cocaine , heroin ,
a ) regular atudanta up- -Hou sehold other narcot ics , in
b) ab .. ntaaa intarviwa halanta , cough syrup ,
at i•u lant a , aedat ivea
and tr anqu i l i zers
(� ical and non
� ical u .. )
Kaplan Seventh g rade Grade 7 1971 1981- 4 1 yea r 9 , 30 0 Not yet Tl-T3--Se lf- Ma r i j uana/haah i ah ,
atudenta e n rolled i n 1982 1 year ca.pleted adaini atered ba r b iturate a , inha-
18 of 36 j u n ior h igh 9-11 yea ra queationna i r e a lanta , hal luc inogena ,
echoo l a of t ha aJIPhe t-ine a ,
Houaton Independent T4 --Adu1t fol- tr anqu i l i zers ,
Schoo l Distr ict lovup--House- heroin , othe r na r -
ho l d interv i-a cot ica , quaalude a ,
coca ine
Lauer and Al l atudenta in 2 7-12 1980 19 8 4 5 1 year 2 , 194 Not yet Se l f-adainiaterad C igare t te a , chewinq
Akera j un ior h igh achoo l a , ccmplet- queat ionna irea in tobacco , anu f f ,
1 aanior h igh echoo l ad claaaroo. c igar s/pipe
in ... 11 IONA c i ty
Sal iva teat
Schlegel Randoal •aiiPle of 9 -12 1974 U8ill 7 4 110ntha 1 , 781 91 8 (Tl-T4 ) Sel f-ad- saer , w i ne , l iquor ,
atudenta in 2 echoo l 4 110ntha •iniaterad quae- c igarette a , aJIPheta-
boarda ( urban , rural) 4 IIOfttha Uonna l rea i n •inea , barbiturate a ,
in aouthe rn Onta r io 1 year claaaroo.. .. r i j uana , ha llucino-
2 yeara (T5-T7 ) Ma i led gena , t ranqu i l i ze r s ,
2 year• sel f-adaini atered he roin , g lue
que at ionnai rea
S. ith Students and foraer Grade a 1969 1981 4-6 1 year 1 , 93 5 No t yet Tl-'!'5--Self-ad- Cigarette a , bear ,
atudenta in • iddla- 8-10 1 year �leted •iniatered quea- w i ne , l iquor , .. r i-
c laaa preda.inant- 1 year Uonna i r e a , pee r j uana , haah i ah , upe ,
ly wh ite schoo l 1 year ratinga of per - dooma , tr ipping
d i at r ict i n the 8 yaa ra .ana l i ty , echool atu f f , cocaine ,
g reater Boston area recorda he roin and other
op iatea , d rug ator e
....
'!'6--Adult fol- �icine , an i f f ing (D
l_..up - Ma i led atuff , ca.bi nat ion VI
questionna i re• drug a
Append ix
D
PARAQUAT ISSUE
186
18 7
188
REFEREICES