N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen : Past, Present, and Future Research to Determine Its Role and Function

Steven A. Barker

Frontiers in Neuroscience, 2018, 12, 536.

doi: 10.3389/fnins.2018.00536

 

This report provides a historical overview of research concerning the endogenous hallucinogen N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the “natural” role of an endogenous hallucinogen from the effects observed from peripheral administration are also emphasized.

Keywords : N, N-dimethyltryptamine, hallucinogen, psychedelic, neurotransmitter, brain

 

INTRODUCTION

Despite their presence in the human pharmacopeia for millennia, we have yet to resolve the biochemical mechanisms by which the hallucinogens (psychedelics) so dramatically alter perception and consciousness. It is the only class of compounds that efficiently and specifically does so. For that matter, we do not fully understand the biochemistry of perception itself or how we live such a vivid and complex internal life in the absence of external stimulation.We do not understand the basic biochemical mechanisms of some of our most common experiences, such as the many human aspects of creativity, imagination or dream states. This is also true for extraordinary states of consciousness such as “visions” or spontaneous hallucinations or phenomena such as near-death experiences (NDE). And it is troubling that we have not sufficiently turned the scientific method on these latter subjects despite the profound role they have played in the evolution of our science, philosophy, psychology and culture.

The experiences derived from the administration of hallucinogens are often compared to dream states. However, the experience of administered hallucinogenic substances is far more intense, robust and overwhelming than the subtlety of mere dreams. By comparison, the natural biochemical processes for our related “hallucinatory” experiences are obviously far more highly regulated, occurring as an orchestrated and inherent function of the “normal” brain. Nonetheless, it is conceivable that attaining an explanation for these related natural human phenomena may lie in resolving the biochemical mechanisms involved in the more dramatic pharmacology of hallucinogens, recognizing that the complexities and intensity of the “administered” experience are, essentially, an overdose relative to corresponding natural regulatory controls. Given their status as “psychedelics” (mind-manifesting substances), increased study of the hallucinogens, particularly with advanced brain imaging and molecular biology approaches, may provide a better understanding of the “common” biochemistry that creates mind.

Perhaps the science behind the discovery of endogenous opioids offers us a corollary. We came to better understand the common human experience of pain through examining the pharmacology of administered opiates and the subsequent discovery of endogenous opioid ligands, receptors and pathways that are predominantly responsible for and regulate the experience and perception of pain. Such may also be the case for understanding perception and consciousness.With the discovery of the endogenous hallucinogen N, N-dimethyltryptamine (DMT, 1, Figure 1), perhaps, as with the endogenous opioids, we have a similar opportunity to understand perception and consciousness. Recent research has stimulated a renewed interest in further study of this compound as a neuro-regulatory substance and, thus, a potential neuro-pharmacological target. Taking results from these and more classical studies of DMT biochemistry and pharmacology together, this report examines some of the past and current data in the field and proposes several new directions and experiments to ascertain the role of endogenous DMT.

A BRIEF HISTORY OF DMT

In terms of Western culture, DMT was first synthesized by a Canadian chemist, Richard Manske, in 1931 (Manske, 1931) but was, at the time, not assessed for human pharmacological effects. In 1946 the microbiologist Oswaldo Gonçalves de Lima discovered DMT’s natural occurrence in plants (Goncalves de Lima, 1946). DMT’s hallucinogenic properties were not discovered until 1956 when Stephen Szara, a pioneering Hungarian chemist and psychiatrist, extracted DMT from the Mimosa hostilis plant and administered the extract to himself intramuscularly (Szára, 1956). This sequence of events formed the link between modern science and the historical use of many DMT-containing plants as a cultural and religious ritual sacrament (McKenna et al., 1998), their effect on the psyche and the chemical structure of N, N-dimethyltryptamine.

The discovery of a number of hallucinogens in the 1950’s and observations of their effects on perception, affect and behavior prompted hypotheses that the syndrome known as schizophrenia might be caused by an error in metabolism that produced such hallucinogens in the human brain, forming a schizoor psycho-toxin (Osmond and Smythies, 1952). The presence of endogenous hallucinogenic compounds, related mainly to those resembling dopamine (mescaline) or serotonin (DMT), were subsequently sought. Although several interesting new FIGURE 1 | Structure of N, N-dimethyltryptamine (DMT, 1). compounds were found, the only known hallucinogens isolated were those derived from tryptophan (DMT, and 5-methoxy- DMT). Data were subsequently developed illustrating pathways for their endogenous synthesis in mammalian species, including humans. Over 60 studies were eventually undertaken in an attempt to correlate the presence or concentration of these compounds in blood and/or urine with a particular psychiatric diagnosis (for a review see Barker et al., 2012). However, there has yet to be any clear-cut or repeatable correlation of the presence or level of DMT in peripheral body fluids with any psychiatric diagnosis. Nonetheless, the discovery of endogenous hallucinogens and the possibilities rendered in various hypotheses surrounding their role and function inmental illness, normal and “extraordinary” brain function spurred further research into the mechanisms for their biosynthesis, metabolism and mode of action as well as for their known and profound effects on consciousness (Mishor et al., 2011; Araújo et al., 2015).

(…)

N_N-Dimethyltryptamine_DMT_an_Endogenous_Hallucino