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when administered to humans, and these used to measure the degree of occupation of the
compounds activate the sigma-1 receptor. It receptor by DMT) demonstrated that less than
was later shown in clinical trials that the hal- 50% of sigma-1 receptors are occupied by 50
lucinogenic effects of the benzomorphans are mM DMT [10].
prevented by naloxone [36,37], which blocks Based on the above evidence, it is likely that
opiate receptors but not sigma-1 receptors. the concentration of DMT required to induce
Thus, it is currently accepted [38] that the effects via the sigma-1 receptor would produce
hallucinogenic effects of the benzomorphans extremely high levels of 5-HT2A receptor occu-
are mediated by the kappa-opioid receptor— pation. It is well-established that the 5-HT2A
the same receptor that is responsible for the receptor is responsible for mediating the effects
effects of the hallucinogen salvinorin A from of psilocybin and other hallucinogens [6]; thus,
the plant Salvia divinorum. Thus, there is very in all probability the hallucinogenic effects of
little evidence linking the sigma-1 receptor to DMT are mediated by the 5-HT2A receptor
Further studies are hallucinogenic effects. In fact, many drugs that
activate the sigma-1 receptor, such as cocaine
and not by the sigma-1 receptor. There is, how-
ever, one possible linkage between 5-HT2A
necessary to determine and certain steroid hormones, are not halluci-
nogenic.
receptors and sigma-1 receptors. One effect of
5-HT2A receptor activation is the production
One area that needs to be investigated is of inositol-1,4,5-triphosphate within neurons,
whether the interaction whether administration of DMT actually re- which leads to elevated intracellular levels of
sults in brain concentrations that are sufficient calcium. The sigma-1 receptor has been shown
with sigma-1 receptors to activate the sigma-1 receptor. The reported to associate with the receptor for inositol-1,4,5-
disassociation constant of DMT for the sigma-1 triphosphate and regulate calcium signaling
contributes to or modifies receptor (14.75 mM, see [10]) is several-fold [40]. It is thus theoretically possible that the
higher than the plasma concentrations of DMT 5-HT2A-mediated effects of DMT could be
the psychoactive effects that occur after intravenous administration of modulated by the action of the drug at sigma-1
a high dose of the drug to humans (0.17–1.08 receptors. Further studies are necessary to de-
of DMT. mM, see [3]). By contrast, the affinity of DMT
for 5-HT2A receptors in the human cortex is
termine whether the interaction with sigma-1
receptors contributes to or modifies the psycho-
reportedly 462 nM [39], which matches up active effects of DMT. In conclusion, although it
very closely with the plasma concentrations of would be very interesting to find that a hallu-
DMT reported by Strassman and Qualls [3]. cinogen such as DMT acts as a neuromodulator,
It should be noted that there is some evidence given the available evidence it seems unlikely
that DMT may actively accumulate in the brain that DMT is an endogenous signaling molecule
[26-28], making it possible that the concentra- in the human brain. Furthermore, there is little
tion of DMT in the brain may be higher than evidence to support the hypothesis that the
the plasma concentration. Nevertheless, even if sigma-1 receptor is responsible for mediating
DMT brain levels are several-fold higher than the hallucinogenic effects of DMT. •
plasma concentrations, it is still not clear that
the concentration of DMT in the brain would References for this article on pages 72-73.
be high enough to produce substantial activa-
tion of sigma-1 receptors. A photolabeling pro-
tection study of the sigma-1 receptor (a method