This theory-building paper (2009) proposes that endogenous hallucinogen trace amine receptors (not serotonin 2A receptors) mediate the visual altering effects of psychedelics.
Abstract
“While the endogenous hallucinogens, N,N-dimethyltryptamine, 5-hydroxy-N,N-dimethyl-tryptamine and 5-methoxy-N,N-dimethyltryptamine, have been acknowledged as naturally occurring components of the mammalian body for decades, their biological function remains as elusive now as it was at the time of their discovery. The recent discovery of the trace amine associated receptors and the activity of DMT and other hallucinogenic compounds at these receptor sites leads to the hypothesis that the endogenous hallucinogens act as neurotransmitters of a subclass of these trace amine receptors. Additionally, while activity at the serotonin 5-HT2A receptor has been proposed as being responsible for the hallucinogenic affects of administered hallucinogens, in their natural setting the 5-HT2A receptor may not interact with the endogenous hallucinogens at all. Additionally 5-HT2A agonist activity is unable to account for the visual altering effects of many of the administered hallucinogens; these effects may be mediated by one of the endogenous hallucinogen trace amine receptors rather than the serotonin 5-HT2A receptor. Therefore, activity at the trace amine receptors, in addition to serotonin receptors, may play a large role in the sensory altering effects of administered hallucinogens and the trace amine receptors along with their endogenous hallucinogen ligands may serve an endogenous role in mediating sensory perception in the mammalian central nervous system. Thus the theory proposed states that these compounds act as true endogenous hallucinogenic transmitters acting in regions of the central nervous system involved in sensory perception.”
Authors: Jason V. Wallach
Summary
Introduction
DMT, bufotenine and 5-methoxy-DMT are naturally occurring components of human blood, brain and cerebral spinal fluid. They may act as formal neurotransmitters of the central nervous system and exert a signaling function in regions of the CNS involved in sensory perception.
In vitro studies have shown that several TAAR subtypes respond to trace amines other than the classical trace amines, suggesting that there may be additional endogenous ligands for these receptors. Additionally, the TAARs may play a role in numerous neural processes, including sensory perception.
Legal restrictions placed on hallucinogens have severely limited their availability for scientific research. Hopefully, an understanding of the activity of these compounds within the CNS will lead to novel treatments for psychological disorders.
DMT endogenous role as a neurotransmitter
Jacob and Presti have proposed an anxiolytic role for endogenous DMT based on the belief that low dose administrations are comparable in concentration and biological action to endogenous DMT. However, if DMT is indeed a neurotransmitter of the TAARs and not a hormone, low dose administrations would still act as an agonist at 5-HT receptors.
Neurotransmitters act on a sub-population of possible receptors in a localized manner, whereas hormones act indiscriminately on all sites they are capable of binding to. Neurotransmitters are released from the presynaptic terminal and then quickly removed from the synapse clearing the way for new chemical information. Both morphine and codeine have been shown to be constituents of the CNS, but their concentrations are very small. They probably do have a dramatic effect at their synaptic site of release.
Serotonin response; anxiolytic role reconsidered
DMT is known to have activity at 5-HT1 and 5-HT3 receptors, and since this effect is observed at low levels of administered DMT, it seems more probable that the endogenous hallucinogens act as true endogenous hallucinogens.
The true biological role of the endogenous hallucinogens
Researchers have been puzzled over the role of endogenous hallucinogens in altered states of consciousness for over 50 years. I propose that the role of endogenous hallucinogens in ordinary sensory perception allows them to precipitate in altered states of consciousness as well.
TA vs. 5-HT2A
Many studies have focused on DMT and other indole and phenethylamine hallucinogens as partial agonists of serotonin receptors, but 5-HT activity may not be involved with the action of the endogenous hallucinogens at all.
Human studies using psilocybin and the 5-HT2A antagonists ketanserin and risperidone showed that these antagonists decrease all subjective effects of psilocybin, including the visionary restructialization effects (VR). This indicates that the 5-HT2A antagonists may also be exerting an antagonistic effect on the TAARs. Future projects should evaluate the selectivity of these antagonists for TAAR sites, as well as their subjective effects, and include hallucinogen affinity for TAAR sites in addition to 5-HT sites.
5-HT2A activation alone is unable to account for the visual phenomenon common of the classical indoleamine and phenethylamine hallucinogens. The subjective effects of MDMA, 5-MeO-DMT and DET are solely emotional and virtually devoid of the visual phenomenon common of other hallucinogens.
5-MeO-DMT has a higher affinity for 5-HT2A than DMT and produces a smaller cAMP response at TAAR1 than DMT.
5-MeO-DMT is likely to act as a ligand for a specific TAAR not involved in visual perception, but rather in some other sensory modality or neural process. This will allow us to assign dose dependent subjective effects to specific receptors.
5-HT1A agonism unable to account for lack of visual effect of 5-MeO-DMT
DMT is one of the strongest visual hallucinogens known, but 5-MeO-DMT has significantly less affinity for the 5-HT2A receptor than 5-MeO-DMT does. This may explain why 5-MeO-DMT has less visual activity than 5-MeO-DMT, but the 5-HT1A theory may also be correct. The hallucinogen S (+) alpha-methyltryptamine (AMT) has greater 5-HT2A affinity than DMT and significantly less 5-HT1A activity than DMT, thus having minimal visual effects.
MDMA has been shown to bind to TAAR1 in mice, yet it lacks significant VR activity. TAAR1 may not be one of the endogenous hallucinogen receptors, although it may still prove to play a role in the behavioral effects of administered hallucinogens.
Conclusions
Endogenous hallucinogens are likely to act as transmitters of the CNS and are associated with ASC. Antagonists of the TAARs may represent novel pharmacological targets for treatment of psychotic disorders.
Endogenous hallucinogens are a completely novel area of study that will lead to valuable treatments for psychological disorders as well as a general advancement in our understanding of sensory perception.