Author: Gary Jackson

The brain on DMT: mapping the psychedelic drug’s effects

In 1972, Juan Saavedra and Julius Axelrod reported that intracisternally administered TA was converted to N-methyltryptamine (NMT; 4, Figure 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.

Drug Discovery

Unlike other classic psychedelics, such as LSD or psilocybin, DMT’s effects on the brain are relatively brief, lasting a matter of minutes, rather than hours. DMT can produce intense and immersive altered states of consciousness, with the experience characterised by vivid and bizarre visions, a sense of ‘visiting’ alternative realities or dimensions, and similarities with near death experiences. But exactly how the compound alters brain function to account for such effects has been unclear. It is evident that we have too long ignored the field of hallucinogen research, in all of its potential aspects. This is especially true if continuing research demonstrates a clear role for one of its more prominent members, DMT, as an endogenous regulator of brain function.

  1. Evidence shows that a key enzyme for DMT synthesis, called indole-ethylamine-methyltransferase (INMT), has been detected in the human cerebral cortex and pineal gland.
  2. Molecular biological studies of DMT’s effects on these receptors and DMT’s effects on their up-or-down regulation will also prove informative.
  3. After the scans, the participants were handed questionnaires, which were designed to evaluate the subjective effects they had experienced.
  4. It is not unreasonable to question whether measurement of DMT and its metabolites, and thus the role and function of endogenous DMT, can be understood by simply trying to measure these compounds in the periphery.
  5. Participants reported a lifetime use of 8.9%, with 4.3% reporting use during the last year.

DMT breaks down the brain’s segregated networks of activity

The subjective effects of DMT from ayahuasca administration (0.6–0.85 mg/kg DMT; Riba et al., 2003) usually appear within 60 min, peak at 90 min and can last for approximately 4 h (Cakic et al., 2010). The prolongation of effect is attributed to the MAOI effects of the constituent harmala alkaloids. Riba et al. (2015) have also reported the effects of oral and vaporized DMT alone. This study also showed that smoked DMT caused a shift from the MAO-dependent route to the less active CYP-dependent route for DMT metabolism. Commonly used doses for vaporized or inhaled free-base DMT are 40–50 mg, although a dose may be as much as 100 mg (Shulgin and Shulgin, 1997). It is of interest to note that intranasal free-base DMT is inactive (0.07–0.28 mg/kg; Turner and Merlis, 1959) as is DMT administered rectally (De Smet, 1983).

Future DMT administration studies

Because it can change heart rate, perceptions, and emotional states, it may also change the way drugs that affect these functions work. DMT is a hallucinogenic tryptamine drug that occurs naturally in various plants, such as Psychotria viridis or Chacruna. Some people call it the “spirit molecule” due to the intense psychedelic experience. Like other hallucinogenic drugs, DMT may cause persistent psychosis and hallucinogen-persisting perception disorder (HPPD). HPPD is more commonly known as “flashbacks.” Both are rare and may be more likely to occur in people with preexisting mental health conditions. That’s why we’re committed to providing unbiased, evidence-based information about drugs, including harm-reduction strategies, regardless of legal status.Learn more about the principles of harm reduction.

These phenomena, termed ‘network disintegration and desegregation’ and increased ‘global functional connectivity’, align with previous studies with other psychedelics. The changes to activity were most prominent in brain areas linked with ‘higher level’, human-specific functions, such as imagination. A new study has unveiled how psychedelics achieve their perception-altering effects in the human brain. The research used a powerful combination of brain analysis techniques to provide the clearest picture yet of how the short-acting, but powerful psychedelic DMT (dimethyltryptamine) affects brain activity. The researchers found that DMT triggered changes within and between different brain regions.

ACTIONS

The data derived from the areas of research addressed above will no doubt suggest several possible new avenues for additional future research on DMT. In order to advance, however, regulatory blockades to hallucinogen research must be removed. Progress in hallucinogen research in these areas has been slowed due to over-regulation. For at least the last 50 years, research on DMT and other hallucinogens has been impeded in the United States by passage of the Congressional Amendment of 1965 and the Controlled Substances Act of 1970 by the United States Congress that classified DMT and other major hallucinogens as Schedule-I substances.

In addition, it has been suggested that adequate expression of placental INMT may be necessary for pregnancy success (Nuno-Ayala et al., 2012). However, DMT has been shown to interact with a variety of ionotropic and metabotropic receptors. While the subjective behavioral effects of exogenously administered DMT appear to be primarily acting via 5-HT2A receptors, the interaction of other receptors, such as other serotonergic and glutaminergic receptors, may also play a synergistic and confounding role. Indeed, the activation of frontocortical glutamate receptors, secondary to serotonin 5-HT2A receptor-mediated glutamate release, appears to be a controlling mechanism of serotonergic hallucinogens (dos Santos et al., 2016a,b). However, although this type of receptor research is quite mature, these findings have yet to define and accurately correlate what makes a compound hallucinogenic vs. compounds that have similar binding characteristics that are not hallucinogenic. Clearly, we are missing some pieces to the hallucinogen receptor/mode-of-action puzzle.

Mapping of these receptors in brain tissues, with a determination of the nature and degree of colocalization of DMT’s enzymes for synthesis in mind, will also add impetus to the growing recognition of DMT’s possible “normal” functions in brain. This understanding may also lead to new therapeutic applications for regulating and altering endogenous DMT levels and function, providing new avenues for understanding hallucinogen pharmacology and their possible therapeutic use. The data further suggest there may well remain a “hallucinogen” receptor or receptor complex that has yet to be discovered. A more integrative mechanism to explain hallucinogenic activity, as suggested by Urban et al. (2007); Ray (2010); Halberstadt and Geyer (2011); and Carhart-Harris and Nutt (2017), is also intriguing and requires further inquiry. The data to be derived in such imaging studies are highly dependent on the instrumentation and methods used and the interpretation of the data can often be somewhat subjective.

DMT was administered at doses of 0.05, 0.1, 0.2, and 0.4 mg/kg to 11 experienced hallucinogen users. The results of these studies showed peak DMT blood levels and subjective effects were attained within 2 min after drug administration and were negligible at 30 min. DMT was also shown to dose-dependently elevate blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of β-endorphin, corticotropin and cortisol. The lowest dose that produced statistically significant effects relative to placebo and that was also hallucinogenic was 0.2 mg/kg (Strassman, 1991, 1996). Studies examining non-serotonergic receptors for DMT, such as TAAR and sigma-1, have begun to bear useful and insightful evidence for the possible “normal” roles of endogenous DMT and should be extended and expanded. Molecular biological studies of DMT’s effects on these receptors and DMT’s effects on their up-or-down regulation will also prove informative.