Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine

This early review (2005) suggests that the effects of exogenous DMT may be due at least in part to activity at the trace amine receptor.

Abstract

“The presence of the potent hallucinogenic psychoactive chemical N,N-dimethyltryptamine (DMT) in the human body has puzzled scientists for decades. Endogenous DMT was investigated in the 1960s and 1970s and it was proposed that DMT was involved in psychosis and schizophrenia. This hypothesis developed from comparisons of the blood and urine of schizophrenic and control subjects. However, much of this research proved inconclusive and conventional thinking has since held that trace levels of DMT, and other endogenous psychoactive tryptamines, are insignificant metabolic byproducts. The recent discovery of a G-protein-coupled, human trace amine receptor has triggered a reappraisal of the role of compounds present in limited concentrations in biological systems. Interestingly enough, DMT and other psychoactive tryptamine hallucinogens elicit a robust response at the trace amine receptor. While it is currently accepted that serotonin 5-HT2A receptors play a pivotal role in the activity of hallucinogenic/psychedelic compounds, we propose that the effects induced by exogenous DMT administration, especially at low doses, are due in part to activity at the trace amine receptor. Furthermore, we suggest that endogenous DMT interacts with the TA receptor to produce a calm and relaxed mental state, which may suppress, rather than promote, symptoms of psychosis. This hypothesis may help explain the inconsistency in the early analysis of endogenous DMT in humans. Finally, we propose that amphetamine action at the TA receptor may contribute to the calming effects of amphetamine and related drugs, especially at low doses.”

Authors: Michael S. Jacob & David E. Presti

Summary

Introduction

DMT was first synthesized in 1931 and identified in the 1950s as one of the active compounds in a potent psychoactive snuff prepared from the seeds of the Amazonian plant Anadenanthera peregrina. It has since been described in hundreds of organisms, including fungi, marine sponges, tunicates, frogs, legumes, and grasses.

Despite its ubiquitous presence throughout the plant and animal kingdoms and even in the human body, DMT was classified as a Schedule One controlled substance by the US government in 1970. This classification has significantly impeded scientific research pertaining to DMT.

After the discovery of endogenous DMT in humans, psychiatric researchers suggested that excess DMT biosynthesis may promote psychotic symptoms. More recent studies have shown that endogenous DMT may act as a neurotransmitter in the TA system, alleviating rather than promoting psychotic symptoms.

Endogenous human DMT and schizophrenia: the early research

In 1952, Osmond and Smythies suggested that a disorder in metabolism might produce a psychotomimetic substance and prompt schizophrenic symptoms. Later, Axelrod demonstrated that mammalian tissue could produce DMT, and Brune and Himwich suggested that methylated tryptamines might act as an endogenous trigger for psychoses. After Franzen and Gross’ discovery, researchers found an increase in the urinary excretion of DMT in schizophrenic patients, but concluded that DMT did not play a causal role in schizophrenia.

Several challenges have prevented a more precise examination of the role of endogenous DMT in general. This paper will address the first two issues in light of recent discoveries.

DMT biogenesis: new research

The biochemistry of DMT production in vitro was studied significantly in the 1970s. It was noted that the human AADC gene can undergo alternative splicing, fashioning two different isoforms, one of which catalyzes the decarboxylation of 5-hydroxytryptophan and LL -DOPA, and the other of which was unable to decarboxylate either.

The pathway shown in Fig. 1 concludes with two successive methylation reactions, with N-methyltryptamine being the lowest affinity substrate for indolethylamine-N-methyltransferase (INMT), followed by TYP.

A contemporary investigation of INMT has provided a more detailed analysis of INMT, but does not provide a complete story. The authors place much weight on the significance of observed Km values for recombinant human INMT and do not take into account several additional genetic and enzymatic concerns.

Although years of research have shown that high Km values are significant in biological systems, the meaning of these values is still open to interpretation. Thus, we advise against placing undue emphasis on numerical values of Km when interpreting in vitro activity.

The absence of constitutively produced INMT transcripts in the brain does not mean that they are never produced. Stress responses can trigger INMT transcription, and DMT can cross the blood brain barrier.

DMT: physiology and psychological effects

A double-blind, placebo-controlled study of DMT in humans was conducted in 1994. Subjects reported increases in blood pressure, heart rate, pupil diameter, and rectal temperature, as well as increased blood concentrations of b-endorphin, corticotrophin, cortisol, prolactin, and growth hormone.

Strassman’s studies provide an excellent methodology for future research with psychoactive tryptamines, although most of the psychedelic doses may be too high to be of relevance in understanding endogenous DMT activity.

DMT does not appear to lead to tolerance in mammals, which provides additional evidence that endogenous DMT may play a physiological role.

DMT: a neurotransmitter in the trace amine pathway?

DMT plays a physiological role via what neurochemical pathway? Although serotonin 5-HT2A receptors are thought to play a major role, the complex effects of these chemicals on mental state are largely not understood.

DMT has shown high affinity for synaptosomal membranes and involvement in active transport processes indicative of a reuptake mechanism. Tyramine is the proposed endogenous ligand for the TA1 receptor, and DMT’s activity at this receptor is almost equal to that of tyramine. Researchers speculated that a DMT receptor was present on rat synaptosomal membranes in the late 1970s, and that DMT is actively transported into rat nerve cells.

DMT likely exerts much of its potent hallucinogenic response via the 5-HT system, but endogenous DMT would interact at TA receptors, especially given its presence at very low (nanomolar) concentrations. Low dose administration is more likely to provide a window into DMT’s role during endogenous production.

Low doses of DMT may elicit a calm and relaxed mental state due to agonism at trace amine receptors, rather than the 5-HT system. The enteric nervous system may also play a role in the regulation of emotion.

Recent studies have uncovered several potential links between the TA system and schizophrenia, including increased AADC activity and decreased MAO activity in schizophrenic patients, as well as evidence for an AADC isoform with unique affinity for substrates other than 5-hydroxytryptophan.

DMT: an endogenous anxiolytic?

DMT may have affinity for the TA system, which is connected to the emotional centers of the body and shows possible connections to many psychiatric conditions. This may explain why DMT is present in the fluid of schizophrenic patients, and why smoking tobacco leads to decreased MAO activity.

Amphetamine, methamphetamine, and MDMA have significant efficacy at the trace amine receptor and produce calming effects in humans, especially at low doses.

The dopamine hypothesis of schizophrenia still remains dominant today, but it is increasingly believed that abnormalities in other neurotransmitter systems may also contribute to this condition. It may be valuable to examine the concentrations of DMT and its metabolites in human urine and blood.

Conclusions

We have reviewed the current research on INMT and AADC activity, and have proposed a role for DMT in the trace amine system. This hypothesis could explain why DMT is so powerful at low doses.

The brain is extraordinarily complex and interconnected, and every possibility discovered which allows for additional regulation at the molecular level is exploited in the nervous system.