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This study investigated possible interactions between alcohol and hallucinogens in 11 lysergic acid diethylamide
"LSD# and:or psilocybin users through retrospective structured interviews[ Of those who had used LSD with alcohol\
75=6 per cent reported a complete blockade of subjective alcohol e}ects\ while the remaining cases reported a
diminished response[ In addition\ 59 per cent of respondents who had used alcohol and psilocybin together reported
a partial antagonism of subjective alcohol e}ects[ T!test analyses revealed that LSD|s antagonism of alcohol e}ects
were signi_cantly greater than those associated with psilocybin[ It is proposed that LSD|s e}ect on alcohol intoxication
may involve interactions with various serotonergic and:or dopaminergic receptor systems[ Copyright Þ 1999 John
Wiley + Sons\ Ltd[
KEY WORDS * lysergic acid diethylamide^ alcohol^ psilocybin^ hallucinogens^ serotonin^ dopamine
Copyright Þ 1999 John Wiley + Sons\ Ltd[ Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
ALCOHOLÐHALLUCINOGEN INTERACTIONS 450
Table 0[ Subjective e}ects associated with concurrent use of alcohol and hallucinogens
Id Age Sex Estimated Estimated Concurrent use of Concurrent use of alcohol and
lifetime lifetime alcohol and LSD psilocybin
use of LSD use of psilocybin
Subjective Subjective Subjective Subjective
alcohol LSD alcohol psilocybin
e}ects e}ects e}ects e}ects
e}ect is signi_cantly greater than that associated to H\ LSDÐalcohol interactions work two ways[
with psilocybin t"01# 4=630\ p ³ 9=990[ {The _rst example would be if I were to use LSD
and then drink\ I wouldn|t feel any of the e}ects of
alcohol until after the e}ects of the LSD had worn
REPRESENTATIVE SUBJECTIVE REPORTS o} [ [ [ and if I were to take LSD once I was already
subjectively feeling drunk\ the alcohol e}ects would
LSDÐalcohol interactions go away after taking the LSD[|
G\ a 14!year!old male\ reported extensive experi! T\ a 13!year!old male\ reported using LSD on
ence with LSD\ using it on 59Ð89 separate 14 occasions[ T reported that there were several
occasions[ Typically\ G can begin to discern the occasions where he consumed an intoxicating dose
e}ects of alcohol after four drinks and it takes of alcohol "more than six drinks# while under the
approximately seven or eight drinks for G to in~uence of LSD[ According to T\ {You can|t get
become signi_cantly intoxicated[ According to G\ drunk when you are on LSD [ [ [ One time I drank
{When I was on LSD I found that no matter what about 07 beers\ a half bottle of Bailey|s and a
quantity of alcohol I consumed on the high\ I did Mickey of vodka on two hits of acid and I didn|t
not notice any of the e}ects of the alcohol|[ G feel anything from the booze [ [ [ it was just a normal
recalled one speci_c occasion when he drank LSD high[|
approximately 01 beers over the course of an eve!
ning after ingesting LSD] {[ [ [ at that point\ I didn|t
notice the e}ects of the alcohol at all[ I was not PsilocybinÐalcohol interactions
drunk\ nothing[ I just felt a little bloated[| B\ a 15!year!old male\ has used psilocybic mush!
H\ a 16!year!old female\ reported extensive rooms on 19 separate occasions[ When using alco!
experience with LSD\ using it on between 59 and hol concurrently with psilocybic mushrooms\ B
64 separate occasions[ She reported using an intoxi! claims that {I could feel a combination of both[ It is
cating dose of alcohol "more than seven drinks# in not like LSD where the alcohol e}ects are blocked[
combination with LSD {several| times[ According Sometimes one would be stronger than the other\
Copyright Þ 1999 John Wiley + Sons\ Ltd[ Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
451 S[ P[ BARRETT ET AL[
but that would just depend on how much I took of partially diminished alcohol e}ects\ a full 39 per
each|[ cent of psilocybin users failed to report any anta!
L\ a 14!year!old male\ has used psilocybic mush! gonizing e}ect[ Because very little is known about
rooms on 49 separate occasions[ According to L\ the pharmacological actions of psilocybin\ and the
when using psilocybin with a normally intoxicating precise nature of the interaction between psilocybin
dose of alcohol "more than four drinks#\ {[ [ [ it pro! and alcohol was not clearly revealed by the present
duces a more mellow buzz[ The alcohol e}ect was data\ the remainder of the discussion will focus
deadened|[ When asked to compare this experience primarily on _ndings concerning the concurrent
with that of LSD\ {I could feel the alcohol more for administration of LSD and alcohol[
sure on mushrooms|[ Prior to commencing a discussion of hypo!
V\ a 17!year!old male\ reported 49 previous uses thesized means by which LSD could attenuate sub!
of psilocybic mushrooms\ including several jective alcohol e}ects\ it would seem appropriate to
occasions where he consumed a normally intoxi! address some possible limitations of the present
cating dose of alcohol "more than six drinks#[ study[ The _rst issue concerns whether or not study
According to V\ when using alcohol and psilocybic participants could reliably recount their experiences
mushrooms together] {You can tell that you|ve with the concurrent use of alcohol and hal!
drunk alcohol when on mushrooms\ but there lucinogenic drugs[ There are several indications
would be less of an e}ect [ [ [ you could feel it more that memory is not signi_cantly impaired by the
than when on LSD|[ administration of hallucinogens[ For example\
there are numerous reports that LSD experiences
can be accurately and vividly recalled "e[g[
DISCUSSION Hofmann\ 0879^ Abraham et al[\ 0885# suggesting
The present data indicate that the subjective that LSD intoxication has a negligible impact on
response to ethanol is strongly attenuated by the memory storage and retrieval[ The accuracy of rec!
administration of LSD[ Of the 04 LSD users who ollections reported by subjects in the present study
reported concurrent use of alcohol\ 02 reported a is further supported by the fact that most of these
complete blockade of alcohol|s subjective e}ects\ participants had extensive past hallucinogenic use
while the remaining two cases reported experi! and reported having used hallucinogens and alco!
encing a virtual elimination of subjective alcohol hol in combination on several occasions[ Thus\ par!
e}ects when the drug was combined with LSD[ The ticipants| responses to questions concerning
_nding that LSD|s antagonism of alcohol|s e}ects alcoholÐhallucinogen interaction e}ects were based
reportedly occurred irrespective of whether the sub! on numerous experiences rather than a single event
ject had consumed LSD prior to drinking or the and compared to their own extensive experience
LSD was ingested when already intoxicated further with hallucinogenic drugs alone or in combination[
supports the conjecture that LSD|s e}ect on the A second consideration concerns whether par!
subjective response to alcohol may be due to a direct ticipants| recollections of alcohol e}ects were sim!
pharmacological interaction[ In contrast to LSD\ ply overwhelmed by the hallucinogenic properties
the use of psilocybic mushrooms failed to fully anta! of LSD and:or psilocybin[ The observation that
gonize the subjective e}ects of alcohol[ Although participants were able to reliably distinguish
nine of the 04 psilocybin users reported a dimin! between LSD and psilocybin in terms of each drug|s
ished response to alcohol\ no participants reported e}ect on the subjective alcohol experience when
that the administration of psilocybin completely taken concurrently argues against this possibility[
blocked the subjective e}ects of alcohol[ Of the In addition\ participants were highly consistent in
remaining six participants\ _ve reported that psi! their reporting concerning both the nature and
locybin had no impact on their subjective response strength of alcoholÐdrug interactions\ despite their
to alcohol\ while the _nal subject stated that psi! di}erential drug histories and being blind to the
locybin actually enhanced the subjective e}ects of study|s hypotheses[ Finally\ the amount of alcohol
alcohol "i[e[ caused an increase in the subjective reportedly consumed by some participants while
sense of intoxication#[ Thus\ although some par! under the in~uence of LSD argues against the possi!
ticipants reported a tendency for psilocybin to bility that alcohol e}ects were simply overwhelmed
weaken the subjective e}ects of alcohol\ this e}ect by hallucinogen intoxication[ For example\ par!
was not as pronounced as that associated with LSD^ ticipant M described an occasion on which he had
while 099 per cent of LSD users reported at least 13 drinks following the use of LSD and T recalled
Copyright Þ 1999 John Wiley + Sons\ Ltd[ Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
ALCOHOLÐHALLUCINOGEN INTERACTIONS 452
drinking 07 beers\ a half bottle of liqueur and 02 interferes with alcohol|s discriminative stimulus
ounces of vodka while in a state of LSD intoxi! properties "Maurel et al[\ 0887#[ In their review
cation[ article\ Kostowski and Bienkowski "0888# refer to
While both the consistency and magnitude of such _ndings\ and conclude that serotonergic
reports of LSD|s e}ect on alcohol intoxication neurotransmission plays a key role in the formation
attest to its reliability\ it is important to note that of the ethanol cue\ and that this cue is primarily
in any retrospective study certain issues of potential mediated through 4!HT0B and 4!HT1C receptors[
bias may arise[ Because subjects were not randomly Unfortunately\ the precise nature of LSD|s
selected it remains possible that their experiences action at 4!HT0B remains unknown "Peroutka\
are not characteristic of all hallucinogenic drug 0883#[ The present discussion will therefore focus
users[ However\ this possibility was minimized by on the actions of LSD at 4!HT1C receptors[ LSD
the fact that participants were recruited from four displays partial agonist e}ects at 4!HT1C receptor
di}erent {communities| of drug users through snow! sites "Glennon\ 0889^ Fiorella et al[\ 0884^ Egan et
ball sampling[ It should also be noted that several al[\ 0887#[ Thus\ although LSD displays high a.n!
additional steps were taken to avoid possible inter! ity\ its agonist actions at 4!HT1C are of low e.cacy[
viewer bias[ First\ questions used for queries about Because LSD is a partial agonist at 4!HT1C recep!
potential drug interactions were standardized and tors\ the precise nature of its e}ect at these sites will
neutrally worded[ Second\ three di}erent inter! depend on available 4!HT concentrations and on
viewers were used and all interviews were blindly the presence of other 4!HT agonists and:or antag!
rated[ Finally\ raters were instructed to eliminate onists "Glennon\ 0889^ see also Bonson et al[\ 0885#[
cases were interviewer bias was present[ At low 4!HT concentrations and:or in the absence
The present data are consistent with the notion of another agonist\ LSD behaves as a low!e.cacy 4!
that there is a direct\ pharmacological interaction HT1C agonist\ achieving approximately 29 per cent
between LSD and alcohol[ Although the current maximal excitation "Marek and Aghajanian\ 0885^
methodology did not directly examine either of Egan et al[\ 0887#[ In the presence of a high e.cacy
these drugs| pharmacological e}ects\ LSD is known agonist "i[e[ at higher 4!HT concentrations#\ LSD
to act at various serotonergic and dopaminergic exerts its own maximal e}ect while suppressing the
receptor types "e[g[ Peroutka\ 0883^ Watts et al[\ receptor|s responsiveness to the other agonist\
0884# implicated in ethanol reinforcement "e[g[ thereby blocking the other agonist from achieving
Koob et al[\ 0887# and discriminative stimulus "e[g[ maximal excitation[ Under such conditions\ LSD
Kostowski and Bienkowski\ 0888#[ This raises the may thus appear to function as an antagonist[
possibility that LSD|s e}ect on the subjective LSD|s partial agonist actions are consistent with
response to alcohol may involve an action at one the hypothesis that LSD may prevent the level of
or more of these systems[ 4!HT1C excitation required for the alcohol cue to
LSD exerts e}ects at several 4!HT receptor sub! be subjectively experienced\ and this mechanism
types\ displaying a.nity for 4!HT0A\ 4!HT0B\ 4! may underlie the _ndings of the present study[
HT0D\ 4!HT0E\ 4!HT1A\ 4!HT1C\ 4!HT4A\ 4!HT4B\ 4! The hypothesis that LSD attenuates the ethanol
HT5\ and 4!HT6 "Peroutka\ 0883^ Bonson et al[\ cue in humans through such serotonergic mech!
0885#[ With respect to LSD|s multiple 4!HT anisms is consistent with the present observation
actions\ activity at 4!HT1C and:or 4!HT0B receptors that this e}ect was diminished or absent following
would seem to represent the best candidates for the administration of psilocybin[ Although LSD
LSD|s attenuation of subjective alcohol e}ects\ as and psilocybin are considered similar in terms of
these are the only 4!HT receptor subtypes that have subjective e}ects\ they di}er with regard to ser!
been directly implicated in the formation of the otonergic pharmacological properties[ For exam!
ethanol cue "Maurel et al[\ 0887^ Wilson et al[\ 0887^ ple\ LSD is known to bind to various 4!HT sites
Kostowski and Bienkowski\ 0888#[ Mixed 4! with a greater a.nity than psilocybin "Glennon
HT0B:1C receptor agonists completely generalize to et al[\ 0874^ McKenna et al[\ 0889#[ Furthermore\
the ethanol cue in rats "Kostowski and Bienkowski\ psilocybin is currently believed to act as a full agon!
0888^ Maurel et al[\ 0887^ Szeliga and Grant\ 0887#\ ist at 4!HT1 receptors "Vollenweider et al[\ 0887#\
and are known to produce ethanol!like responses whereas LSD acts as a partial agonist at these sites[
in humans "Kostowski and Bienkowski\ 0888#[ Evi! If\ as hypothesized\ LSD exerts an e}ect on the
dence also suggests that the blockade of 4!HT0B alcohol cue via suppression of the requisite 4!HT1
and 4!HT1C receptors\ alone or in combination\ response\ then one might expect psilocybin to fail
Copyright Þ 1999 John Wiley + Sons\ Ltd[ Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
453 S[ P[ BARRETT ET AL[
to fully attenuate the subjective e}ects of alcohol[ or alcohol[ Indeed\ without a fuller characterization
Aside from its actions at 4HT receptors\ LSD of each of these drugs| e}ects\ interpretation of the
has also been demonstrated to exert partial agonist present results must remain largely speculative[
e}ects at dopamine D0 "Watts et al[\ 0884# and Despite the fact that the present analysis is unable
D1 "Giacomelli et al[\ 0887# receptors[ Midbrain to fully elucidate the mechanisms governing alco!
dopaminergic activity is thought to be critical for holÐhallucinogen interactions\ the present _ndings
the reinforcement of ethanol administration "e[g[ are highly relevant for several reasons[ First\ this
Koob et al[\ 0887#[ Although DA transmission is is\ to the best of the authors| knowledge\ the _rst
implicated in ethanol reinforcement\ there is cur! documentation of a recreational drug eliminating
rently only limited evidence to suggest that DA subjective alcohol e}ects in humans[ Further explo!
transmission substantially contributes to ethanol|s ration of the interaction between LSD and alcohol
subjective e}ects[ Blocking DA neurotransmission revealed by the present _ndings may ultimately
with preferential DA receptor antagonists does not enhance our understanding of the mechanisms that
appear to a}ect either the discriminative stimulus mediate the subjective e}ects of ethanol[ Second\
e}ects of alcohol in rats "Kostowski and Bien! evidence suggests that alcohol is often co!admin!
kowski\ 0888# or the subjective e}ects of alcohol in istered with hallucinogenic drugs "Martin et al[\
humans "Litten\ 0885#[ Although dopamine antag! 0885#[ Given the amounts of alcohol reportedly
onists fail to signi_cantly alter subjective ethanol consumed by some participants in the present study
e}ects\ there is nevertheless some indication that while under the in~uence of LSD and the illustrated
dopamine agonists may attenuate aspects of the potential for LSD to attenuate alcohol e}ects\ this
ethanol cue[ For example\ amphetamine\ a potent practice may pose signi_cant health risks[ Third\
DA receptor agonist\ has been reported to anta! this analysis demonstrates that\ despite the fact that
gonize ethanol e}ects in rats "Schechter\ 0863# and similarity between LSD and psilocybin has been
cocaine administration has been shown to attenuate assumed by some researchers "e[g[ Strassman\
the sedative e}ects of alcohol in humans "e[g[ Foltin 0881#\ there is likely some discordance in the phar!
et al[\ 0882#[ Such evidence suggests that LSD|s macological e}ects of these two hallucinogens[
blockade of subjective alcohol e}ects may relate to Finally\ this study illustrates a distinctive and e}ec!
its agonist activity at DA receptors[ Unlike LSD\ tive approach for delineating drugÐalcohol inter!
psilocybin does not display an a.nity for DA recep! actions in humans[
tors\ although there is some evidence that it may
increase DA transmission indirectly through ser!
otonergic mechanisms "e[g[ Vollenweider et al[\
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Copyright Þ 1999 John Wiley + Sons\ Ltd[ Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#
ALCOHOLÐHALLUCINOGEN INTERACTIONS 454
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Copyright Þ 1999 John Wiley + Sons\ Ltd[ Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 448Ð454 "1999#