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The Function of Endogenous Dimethyltryptamine in Humans

N,N-Dimethyltryptamine (DMT) is a molecule which belongs to a class of compounds collectively known as methylated indolealkylamines (MIA). DMT can be found in hundreds of different organisms including the human central nervous system, in which case it is considered to be endogenous. The function of endogenous DMT is a subject of tremendous debate. Based on the current research, DMT most likely acts as an agonist at serotonin 5HT2A/5HT2C receptors, as a sigma-1 receptor regulator and as a neurotransmitter at the trace amine (TA) receptors. There is also a good possibility that DMT plays a mechanistic role in psychosis and schizophrenia.

DMT is most widely known as a potent hallucinogen. It was discovered in 1931 when it was first synthesized, but it is also found in various plant sources that were used for shamanistic purposes long before the chemical structure was known. Lesser known is that it can also be found naturally in the human body. [12]. When in this form it is called endogenous DMT. This was a great interest to the scientific community at the time. Unfortunately, the 1960s and 1970s were marred by political fear of hallucinogens due to the counter-culture revolution going on. This prevented much research from being done due to the legal restrictions placed on DMT. However, currently there has been a resurgence of interest by scientists into DMT, and studies are starting to be done once again [8].

The mechanism by which endogenous dimethyltryptamine is produced has been extensively studied. It occurs in a three-step reaction starting from the amino acid, L-tryptophan. Tryptophan first undergoes decarboxylation by the enzyme, aromatic amino acid decarboxylase (AADC). The product of this step is the trace amine, tryptamine (TYP), which acts as a substrate for the next step, which is a methylation reaction using the enzyme, indolethylamine-N-methyltransferase (INMT). This intermediate is N-methyltryptamine (NMT), which acts as the substrate for INMT in the final step. Dimethyltryptamine (DMT) is, of course, the final product of this reaction [11].

Ligand of Trace Amine Receptors and Sigma-1 Receptors
Possibly the most interesting theory about endogenous DMT is the role it appears to have in sensory perception. Research has shown DMT to act as a neurotransmitter of a subclass of trace amine (TA) receptors. It is well established that most hallucinogenic drugs show increased activity at the seratonin 5HT2A receptors [19]. Interstingly, endogenous hallucinogens may not interact with 5HT2A receptors at all [11]. It also seems that 5HT2A agonist activity cannot explain the visual altering effect of hallucinogen use. There is a good likelihood that these effects can be better explained by activity at one of the endogenous hallucinogen trace amine receptors [11]. It is possible that endogenous ligands and endogenous TA receptors play a role in the mediation of CNS perception in humans. Studies have shown that there are several TAAR subtypes that will respond to trace amines other than those considered to be the classical trace amines (p-tyramine, b-phenethylamine, tryptamine and octopamine) so it is very possible that DMT would activate these receptors [11]. Interesting research has been done on insects in which TA do mediate. sensory perception. Although this finding cannot be applied to humans, it certainly does provide support for this theory [11]. It has also been found that alterations in the TAAR gene family are associated with schizophrenia as well as other CNS disorders such as the bipolar disorder. This is due to a specific mutation in the TAAR 6 gene, TRAR 4 which shows a high correlation with delusional and hallucinogenic symptoms such as seen in schizophrenia [11]. Studies on a rat G coupled-protein receptor have found that levels of cAMP are stimulated when exposed to several trace amines, including tryptamine [3]. The sigma-1 receptor has also been found to interact with N-alkylamines such as DMT. Any compound that contains a nitrogen based connected to a long alkyl chain is potentially a good ligand for the sigma-1 receptor, which is a unique intracellular binding site that is not similar to any known mammalian protein [16].

Role of DMT in Schizophrenia
Many researchers have considered the possibility that DMT plays a fundamental part in the etioligy of schizophrenia and other psychotic disorders. Some body fluid studies have shown elevated levels of methylated indolealkylamines in schizophrenic patients, compared with that of normal individuals. It was hypothesized that schizophrenia was caused by some metabolic defect that would allow too much DMT to be produced either by hyperactivity of N-methyltransferase, decreased activity of monoamine oxidase, or a combination of both [4]. In fact, this idea was so popular at one point that it was commonly referred to as the “transmethylation hypothesis [4].” This theory was supported by the hallucinogenic use of Ayahuasca by South American indians. This drink was actually a psychotropic brew of the DMT-containing vine, Psychotria Viridis, and Banisteriopsis Caapsi, a plant containing β carboline monoamine oxidase inhibitors (MAOIs.) Further support for this theory is the fact that unlike other hallucinogens such as lysergic acid diethylamide (LSD), subsequent exposures to DMT will not eventually cause tollerance to develop [6][8]. However, the transmethylation theory was eventually replaced by the dopamine theory of schizophrenia. This theory hypothesizes that excess levels of dopamine are to be blamed. The theory gained support by the success or first generation antipsychotic medications that appeared to work by blocking reuptake of dopamine. Recently the atypical class of antipsychotics has sparked new interest in the transmethylation hypothesis. This is because the mechanism of action for these drugs happens to be the serotonin receptors [3].

In conclusion, endogenous dimethyltryptamine is most importantly a seratonin subsection agonist, a trace amine receptor, and a sigma-1 receptor ligand. There is also a very good likelihood that dimethyltryptamine also plays an important role in schizophrenia, whether it is the direct cause or contributes indirectly. Of course, there are many things that are still unknown about dimethyltryptamine and there will be heated debates on the issue for a long while to come. Hopefully the political climate will allow for ongoing study of this molecule because much more research needs to be done in the future.

1 B. Angrist et al., 2009. Dimethyltryptamine levels in blood of schizophrenic patients and control subjects. DOI
2 B. Borowski et al., 2009. Trace amines: Identification of a family of mammalian G protein-coupled receptors.DOI
3 J. R. Bunzow et al., 2009. Amphetamine, 3,4-Methylenedioxymethamphetamine, Lysergic Acid Diethylamide, and Metabolites of the Catecholamine Neurotransmitters Are Agonists of a Rat Trace Amine Receptor. LINK
4 CIPRIANOLLIVIER, J., and CETKOVICHBAKMAS, M., Schizophr. Res., 1997.Altered consciousness states and endogenous psychoses: a common molecular pathway? DOI
5 N. V. Cozzi . et al., 2009. Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behabior at the serotonin uptake transporter and the vesicle monoamine transporter. DOI
6 Mayfrank, E.G, et al. Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behabior at the serotonin uptake transporter and the vesicle monoamine transporter. 2009. DOI
7 Fontanilla, DLINK., et al. 2009,The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator
8 Mayfrank, E.G., et al.1998. Inhibition of Return in the Human 5HT2A Agonist and NMDA Antagonist Model of Psychosis. DOI
9 D. K. Grandy, 2009. Trace amine-associated receptor 1—Family archetype or iconoclast? DOI
10 J.V. Wallach, 2009.Endogenous hallucinogens as ligands of the trace amine receptors: A possible role in sensory perception. DOI
11 M. S. Jacob and D. E. Presti, Med. Hypotheses, 2005. Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine (DOI:10.1016/j.mehy.2004.11.005).
12 T. Maurice and T. P. Su. 2009. The pharmacology of sigma-1 receptors. (DOI:10.1016/j.pharmthera.2009.07.001).
13 Michael C. H. Oon, Robin M. Murray, Richard Rodnight, Marion P. Murphy and James L. T. Birley, 2009 Factors affecting the urinary excretion of endogenously formed dimethyltryptamine in normal human subjects (DOI:10.1007/BF00426775).
14 Nicholas V. Cozzi, Anupama Gopalakrishnan, Lyndsey L. Anderson, Joel T. Feih, Alexander T. Shulgin, Paul F. Daley and Arnold E. Ruoho, 2009 Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter. (DOI:10.1007/s00702-009-0308-8).
15 A. Pomilio, J. Ethnopharmacol., 1999. Ayahoasca: an experimental psychosis that mirrors the transmethylation hypothesis of schizophrenia (DOI:10.1016/S0378-8741(98)00163-9).
16 S. Ramachandran, U. B. Chu, T. A. Mavlyutov, A. Pal, S. Pyne and A. E. Ruoho, Eur. J. Pharmacol., 2009, 609, 19-26 The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids . (DOI:10.1016/j.ejphar.2009.03.003).
17 H. Rosengarten, J. Psychiatr. Res., 1976, 13, 23 <last_page> 30 Possible source of error in studies of enzymatic formation of dimethyltryptamine. (DOI:10.1016/0022-3956(76)90006-6).
18 Samuel T. Christiana, Robert Harrisona, Elizabeth Quaylea, John Pagela, and John Montia, 2009. The in vitro identification of dimethyltryptamine (DMT) in mammalian brain and its characterization as a possible endogenous neuroregulatory agent. DOI
19 R. Smith, Pharmacology Biochemistry and Behavior, 1998, 61, 323 <last_page> 330 Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors. (DOI:10.1016/S0091-3057(98)00110-5).
20 T. D. Sotnikova, M. G. Caron and R. R. Gainetdinov, Mol. Pharmacol., 2009, 76, 229-235 Trace amine-associated receptors as emerging therapeutic targets. (DOI:10.1124/mol.109.055970).
21 R. STRASSMAN, Behav. Brain Res., 1995, 73, 121 <last_page> 124 Human psychopharmacology of N,N-dimethyltryptamine. (DOI:10.1016/0166-4328(96)00081-2).
22 R. STRASSMAN, C. QUALLS and L. BERG, Biol. Psychiatry, 1996, 39, 784 <last_page> 795 Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans. (DOI:10.1016/0006-3223(95)00200-6).
23 T. -. Su, T. Hayashi and D. B. Vaupel, Science Signaling, 2009, 2, pe12 <last_page> pe12 When the Endogenous Hallucinogenic Trace Amine N,N-Dimethyltryptamine Meets the Sigma-1 Receptor. (DOI:10.1126/scisignal.261pe12).
24 R. Zucchi, G. Chiellini, T. S. Scanlan and D. K. Grandy, Br. J. Pharmacol., 2006, 149, 967-978 Trace amine-associated receptors and their ligands . (DOI:10.1038/sj.bjp.0706948).