J.V. Wallach - Endogenous hallucinogens as ligands of the trace amine receptors: A possible role in sensory perception
(Medical Hypotheses, Volume 72, Issue 1, Pages 91-94)
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 involvedin sensory perception.
Genetic studies have associated alterations in the TAAR gene family with schizophrenia [7–9] and other CNS disorders such as bipolar disorder [8]. Additionally it has been shown that a specific mutation in the TAAR6, previously TAAR4, gene TRAR4 has been correlated most significantly with the delusional and hallucinogenic symptoms of schizophrenia [7]. This implicates TRAR4 as being expressed in neural regions involved in sensory perception. Therefore, it is not surprising that TAAR6 is found in several key sensory processing brain regions including the amygdala, the hippocampus and the frontal cortex [9]. As TAAR6’s endogenous ligand is unknown, it may be one of the endogenous hallucinogens.
5-HT1A agonism unable to account for lack of visual effect of 5-MeO-DMT:
While DMT is one of the strongest visual hallucinogens known it has significantly less affinity (IC50 value) for the 5-HT2A receptor than 5-MeO-DMT does, 75 ± 16 nM and 14 ± 1 nM, respectively [22]. Therefore, if 5-HT2A activity is correlated with the visual effects of hallucinogens, 5-MeO-DMT should have strong visual activity. One theory proposed to account for 5-MeO-DMT’s lack of visual activity is the theory that agonist activity at 5-HT1A opposes the subjective effects of 5-HT2A activation [12], as 5-MeODMT shows greater affinity for 5-HT1A than DMT, 6.5 ± 1.5 nM and 170 ± 35 nM, respectively [22]. 5-HT1A and 5-HT2A activation has been discovered to mediate opposing responses on membrane excitability in the CNS of rats [30]. Strassman showed that pretreatment with the 5-HT1A antagonist pindolol significantly increased the reported psychological response to DMT [12]. One experiment that would clarify if 5-HT1A inhibits the visual activity induced by 5-HT2A activity would be pindolol pretreatment followed by 5-MeO-DMT administration. If the subjects then report the presence of visual activity, the 5-HT1A theory may then be correct, although we must account for the possibility that in addition
to dampening the 5-HT2A mediated activity, 5-HT1A may also opposes activity mediated by the TAAR sites. One thing that counters
the 5-HT1A theory is that the hallucinogen S (+) alpha-methyltryptamine (AMT) has greater 5-HT2A affinity (46 ± 6 nM) [22] than DMT and significantly less 5-HT1A activity (1900 ± 375 nM) [22] than DMT. While not formally evaluated by any hallucinogen rating scales, racemic AMT has been reported to have minimal visual effects by several subjects [26]. Thus if 5-HT1A and 5-HT2A agonist activity were all that was pertinent for visual activity, AMT would be one of the most potent visual hallucinogens known. Clearly 5- HT activity alone cannot account for the reported subjective effects of hallucinogenic compounds, specifically the visual activity.
Mitä muutakaan matkat on ku visuaalisia!
