In the past few years, thrill-seekers from Hollywood, Silicon Valley and beyond have been travelling to South America to take part in so-called Ayahuasca retreats.
Their goal: to partake in a brewed concoction made from a vine plant Banisteriopsis caapi, traditionally used by indigenous people for sacred religious ceremonies.
Drinkers of Ayahuasca experience short-term hallucinogenic episodes many describe as life-changing.
The active ingredient responsible for these psychedelic visions is a molecule called dimethyltryptamine (DMT).
For the first time, a team led by Michigan Medicine has discovered the widespread presence of naturally-occurring DMT in the mammalian brain. The finding is the first step toward studying DMT— and figuring out its role—within the brains of humans.
“DMT is not just in plants, but also can be detected in mammals,” says Jimo Borjigin, Ph.D., of the Department of Molecular and Integrative Physiology.
Her interest in DMT came about accidentally. Before studying the psychedelic, her research focused on melatonin production in the pineal gland.
In the seventeenth century, the philosopher Rene Descartes claimed that the pineal gland, a small pinecone-shaped organ located deep in the center of the brain, was the seat of the soul.
Since its discovery, the pineal gland, known by some as the third eye, has been shrouded in mystery.
Scientists now know it controls the production of melatonin, playing an important role in modulating circadian rhythms, or the body’s internal clock.
However, an online search for notes to include in a course she was teaching opened Borjigin’s eyes to a thriving community still convinced of the pineal gland’s mystical power.
The core idea seems to come from a documentary featuring the work of researcher Rick Strassman, Ph.D. with the University of New Mexico School of Medicine.
In the mid-1990s, he conducted an experiment in which human subjects were given DMT by IV injection and interviewed after its effects wore off.
In a documentary about the experiment, Strassman claims that he believed the pineal gland makes and secretes DMT.
“I said to myself, ‘wait, I’ve worked on the pineal gland for years and have never heard of this,'” she said.
She contacted Strassman, requesting the source of his statement.
When Strassman admitted that it was just a hypothesis, Borjigin suggested they work together to test it.
“I thought if DMT is an endogenous monoamine, it should be very easy to detect using a fluorescence detector.”
Using a process in which microdialysis tubing is inserted into a rat brain through the pineal gland, the researchers collected a sample that was analyzed for – and confirmed – the presence of DMT. That experiment resulted in a paper published in 2013.
However, Borjigin was not satisfied. Next, she sought to discover how and where DMT was synthesized. Her graduate student, Jon Dean, lead author of the paper, set up an experiment using a process called in situ hybridization, which uses a labeled complementary strand of DNA to localize a specific RNA sequence in a tissue section.
“With this technique, we found brain neurons with the two enzymes required to make DMT,” says Borjigin. And they were not just in the pineal gland.
“They are also found in other parts of the brain, including the neocortex and hippocampus that are important for higher-order brain functions including learning and memory.”
The results are published in the journal Scientific Reports.
Her team’s work has also revealed that the levels of DMT increase in some rats experiencing cardiac arrest.
A paper published in 2018 by researchers in the U.K. purported that DMT simulates the near death experience, wherein people report the sensation of transcending their bodies and entering another realm. Borjigin hopes to probe further to discover the function of naturally occurring levels of DMT in the brain—and what if any role it plays in normal brain functions.
“We don’t know what it’s doing in the brain. All we’re saying is we discovered the neurons that make this chemical in the brain, and they do so at levels similar to other monoamine neurotransmitters.”
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.
e 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 Figure1),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 schizo- or 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 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 in mental 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).
After the discovery of an indole-N-methyl transferase (INMT; Axelrod, 1961) in rat brain, researchers were soon examining whether the conversion of tryptophan (2, Figure Figure2)2) to tryptamine (TA; 3, Figure Figure2)2) could be converted to DMT in the brain and other tissues from several mammalian species.
Numerous studies subsequently demonstrated the biosynthesis of DMT in mammalian tissue preparations in vitro and in vivo (Saavedra and Axelrod, 1972; Saavedra et al., 1973). In 1972, Juan Saavedra and Julius Axelrod reported that intracisternally administered TA was converted to N-methyltryptamine (NMT; 4, Figure Figure2)2) and DMT in the rat, the first demonstration of DMT’s formation by brain tissue in vivo. Using dialyzed, centrifuged whole-brain homogenate supernatant from rats and humans, these same researchers determined that the rate of synthesis of DMT from TA was 350 and 450 pmol/g/hr and 250 and 360 pmol/g/h, using NMT as substrate, in these tissues, respectively. In 1973, Saavedra et al. characterized a nonspecific N-methyltransferase in rat and human brain, reporting a Km for the enzyme of 28 uM for TA as the substrate in rat brain.
The highest enzyme activity in human brain was found in the subcortical layers of the fronto-parietal and temporal lobes and the cortical layers of the frontal parietal lobe. However, an INMT found in rabbit lung was shown to have a much higher Km (270 uM, Thompson and Weinshilboum, 1998; 340 uM, Raisanen and Karkkainen, 1978) than the brain enzyme in rats.
This suggested that INMT may exist in several isoenzyme forms between species and possibly even within the same animal, each having different Km’s and substrate affinities. INMT activity has subsequently been described in a variety of tissues and species.
There have also been several reports of an endogenous inhibitor of INMT in vivo that may help regulate its activity and, thus, DMT biosynthesis (Wyatt et al., 1973a,b; Lin et al., 1974; Narasimhachari et al., 1974; Barker et al., 1981).
he combined data demonstrate that DMT is formed from tryptophan (2, Figure Figure2),2), a common dietary amino acid, via the enzyme aromatic L-amino acid decarboxylase (AADC) formation of TA (3, Figure Figure2)2) and its subsequent N, N-dimethylation.
Both AADC and INMT act on other substrates as well. As a historical and research note regarding DMT, there was initial confusion and misidentification of the products formed when using 5-methyltetrahydrofolate (5-MTHF) as the methyl source in INMT studies due to formation of indole-ethylamine condensation products with formaldehyde (tetrahydro-beta-carbolines) (Barchas et al., 1974; Lin and Narasimhachari, 1974; Rosengarten and Friedhoff, 1976; Barker et al., 1981).
There has also been interest in the role of INMT and DMT biosynthesis in maturation and development. Relatively elevated levels of INMT activity have been found in the placenta from a variety of species, including humans (Thompson et al., 1999).
INMT activity in rabbit lung was reported to be elevated in the fetus and to increase rapidly after birth, peaking at 15 days of age. It then declined to mature levels and remained constant through life (Lin et al., 1974). In this regard, Beaton and Morris (1984) have examined the ontogeny of DMT biosynthesis in the brain of neonatal rats and rats of various ages. Using gas chromatography-mass spectrometry with isotope dilution for their analyses, DMT was detected in the brain of neonatal rats from birth.
DMT levels remained low (1–4 ng/g of whole brain tissue) until days 12 and 17 at which time they increased significantly and then returned to the initial low levels for all subsequent ages. There has yet to be any follow-on research as to the significance of this change in DMT concentrations during rat brain neurodevelopment or correlation with possible changes of INMT activity in other developing tissues, specifically during days 12–17. Nonetheless, these findings correlate well with the Lin et al. (1974) data for INMT changes in rabbits and deserve further inquiry.
There is a significant literature concerning INMT, particularly in peripheral tissues. INMT and its gene have been sequenced (Thompson et al., 1999), commercial antibodies for its detection have been developed and commercial probes exist for monitoring its mRNA and gene expression.
A study using Northern blot detection of the INMT mRNA conducted by Thompson et al. (1999) in the rabbit suggested that INMT was present in significant quantities in the periphery, and particularly the lung, but that it was almost non-existent (low to absent) in the brain.
These data became the foundation for several hypotheses that any neuropharmacological effects of endogenous DMT must lie in its formation in the periphery and its subsequent transport into the brain.
This idea was strengthened by the fact that DMT has been shown to be readily, and perhaps actively, transported into the brain (Cozzi et al., 2009).
However, the data concerning the apparent absence of INMT in brain would appear to be in conflict with the many earlier studies that demonstrated both in vivo and in vitro biosynthesis of DMT in the brain. Indeed, several studies had identified INMT activity or the enzyme itself in the central nervous system (CNS) including the medulla, the amygdala, uncus, and frontal cortex (Morgan and Mandell, 1969), the fronto-parietal and temporal lobes (Saavedra et al., 1973) and, more recently, the anterior horn of the spinal cord as well as the pineal gland (Cozzi et al., 2011).
Thus, in 2011, Cozzi et al. sought to determine why earlier studies (Thompson et al., 1999) had not detected significant INMT in brain using Northern blots despite several reports that brain tissue had been shown to synthesize DMT from TA.
One possibility was that INMT was “expressed in nervous tissue but that in some situations, INMT mRNA is not detectable by Northern analysis (e.g., the INMT gene is inducible, INMT expression is limited to specific brain nuclei, or INMT mRNA in brain is short-lived).” Examining primate nervous system tissues (Rhesus macaque spinal cord, pineal gland, and retina) probed with rabbit polyclonal antibodies to human INMT, all three tissues tested positive.
INMT immunoreactivity in spinal cord was found to be localized in ventral horn motoneurons. The study also showed that INMT response was “robust and punctuate” in the pineal gland.
Further, intense INMT immunoreactivity was detected in retinal ganglion neurons and at synapses in the inner and outer plexiform layers (Cozzi et al., 2011). In 2012, Mavlyutov et al. reported that INMT is also localized in postsynaptic sites of C-terminals of rat motoneurons in close proximity to sigma-1 receptors, which have been linked to control of the activities of ion channels and G-protein-coupled receptors. It was proposed that the close association of INMT and sigma-1 receptors suggests that DMT is synthesized locally to effectively activate sigma-1 in motoneurons. It has been further proposed that DMT is an endogenous sigma-1 receptor regulator (Fontanilla et al., 2009; Su et al., 2009).
Taking these newer data together with historical in vitro and in vivo results regarding INMT enzyme activity in the brain and CNS, it is now clear that the work of Thompson and Weinshilboum (1998) is not the final word on DMT biosynthesis in the brain.
More information:Scientific Reports (2019). DOI: 10.1038/s41598-019-45812-w
Journal information: Scientific Reports
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