A narrative synthesis of research with 5-MeO-DMT

In this review article (2021) researchers combined the evidence from articles about 5-MeO-DMT to enhance our understanding of its potential clinical applications. It was found that although studies in humans are lacking, 5-MeO-DMT has the potential to produce long-term beneficial effects on mental health.

Abstract

“Background: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring, short-acting psychedelic tryptamine, produced by a variety of plant and animal species. Plants containing 5-MeO-DMT have been used throughout history for ritual and spiritual purposes. The aim of this article is to review the available literature about 5-MeO-DMT and inform subsequent clinical development.

Methods: We searched PubMed database for articles about 5-MeO-DMT. Search results were cross-checked against earlier reviews and reference lists were hand searched. Findings were synthesised using a narrative synthesis approach. This review covers the pharmacology, chemistry and metabolism of 5-MeO-DMT, as well epidemiological studies, and reported adverse and beneficial effects.

Results: 5-MeO-DMT is serotonergic agonist, with highest affinity for 5-HT_1A receptors. It was studied in a variety of animal models, but clinical studies with humans are lacking. Epidemiological studies indicate that, like other psychedelics, 5-MeO-DMT induces profound alterations in consciousness (including mystical experiences), with potential beneficial long-term effects on mental health and well-being.

Conclusion: 5-MeO-DMT is a potentially useful addition to the psychedelic pharmacopoeia because of its short duration of action, relative lack of visual effects and putatively higher rates of ego-dissolution and mystical experiences. We conclude that further clinical exploration is warranted, using similar precautions as with other classic psychedelics.”

Authors: Anna O. Ermakova, Fiona Dunbar, James Rucker & Matthew W. Johnson

Notes

As we progress through the psychedelic renaissance, researchers are continuously striving to enhance our understanding of psychedelic substances and the therapeutic potential they may possess. One substance that continues to remain somewhat of a mystery is 5-MeO-DMT. This particular substance is best known for being found in the glandular secretion of the Sonoran Desert Toad as well as a wide variety of plant species. While this particular psychedelic has been used throughout history for ritualistic purposes, modern clinical evidence is only beginning to emerge.

The present study seeks to enhance our understanding of 5-MeO-DMT in order to better inform the clinical development of this substance. To do so, researchers reviewed the current literature available on 5-MeO-DMT. The evidence from the literature was then compiled and analyzed using narrative synthesis, covering aspects of the pharmacology, chemistry and metabolism of 5-MeO-DMT, as well epidemiological studies, and reported adverse and beneficial effects.

The main findings:

• There have been no published clinical trials exploring the effects of 5-MeO-DMT in humans bar one case study investigating the effects of ibogaine and 5-MeO-DMT in a veteran with alcohol use disorder.
• The majority of research on 5-MeO-DMT has been conducted in animal models, establishing effects of the substance on pharmacokinetics, thermoregulation, nociception, heart rate and blood pressure in these models.
• Surveys from recreational users imply that 5-MeO-DMT has rapid anxiolytic and antidepressant effects which are not dissimilar to the findings of early psilocybin and LSD studies.
• Given its short-lasting effects (10-20 minutes) and its ability to induce higher rates of ego-dissolution and mystical experiences, 5-MeO-DMT may be particularly useful psychedelic substance when used in tandem with psychotherapy.

The results of this narrative synthesis indicate that 5-MeO-DMT possess significant therapeutic potential and warrants further clinical investigation. Research is needed to develop the appropriate dose rate in humans and develop the safety profile of 5-MeO-DMT. If these challenges can be overcome, 5-MeO-DMT may be the psychedelic that best fits within the current (or future) medical system.

Summary

Introduction

Psychedelic plants and fungi have been used for centuries for healing and ritual purposes. Research into psychedelics has resumed in the past two decades and early phase clinical trials have been reported in unipolar mood disorders and anxiety, and substance use disorders.

The duration of action of classical psychedelics varies considerably. Short-acting psychedelics may have therapeutic benefit and lower treatment costs if efficacious.

5-MeO-DMT is a short-acting serotonergic psychedelic that was first synthesized in 1936 and later isolated from Dictyoloma incanescens in 1959. It has been found in a large number of plants, including Amanita citrina and Amanita porphyria.

A review of the literature on 5-MeO-DMT found that it is a serotonergic agonist, with highest affinity for 5-HT1A receptors, and induces profound alterations in consciousness (including mystical experiences). It may have beneficial long-term effects on mental health and well-being.

Corresponding author:

5-MeO-DMT has been detected in blood, urine and cerebrospinal fluid in humans, although several studies contradict this finding. Its physiological role is unknown and more research is needed to definitively answer if, when and where 5-MeO-DMT is endogenously produced.

Traditional use

Indigenous peoples of South America have used 5-MeO-DMT containing plants for thousands of years, including the use of cohoba, yopo, and vilca. 5-MeO-DMT is also present in plants that are sometimes used as constituents in ayahuasca.

5-MeO-DMT was included in the Schedule 1 Controlled Substance Act in the United States in 2009 and is a controlled substance in the United Kingdom, Australia, New Zealand and several other countries.

Methods

This review aimed to inform future clinical research on 5-MeO-DMT by identifying relevant articles from PubMed, reviewing the bibliographies from the papers sourced through PubMed, and excluding articles that were not providing novel information about 5-MeO-DMT apart from its use as a 5-HT agonist.

5-MeO-DMT is a non-selective serotonin (5-HT) receptor agonist, with affinity to other receptors and serotonin and norepinephrine transporters. It has no effect on monoamine release nor on noradrenaline or dopamine reuptake.

Receptor binding profiles of 5-MeO-DMT are similar for 5-HT1A and 5-HT2A receptors, but differ for other receptors. Further research is required to resolve the full receptor binding profile of 5-MeO-DMT and understand the functionally selective pharmacology at 5-HT2A and other receptors.

5-MeO-DMT activates phospholipase A2 and phospholipase C signalling pathways, while 5-HT activates -arrestin-2 and protein kinase B. This is likely to be important in understanding the observable effects of exogenous versus endogenous ligands for receptors.

Absorption is rapid and maximal concentration is reached 5-6 min after intraperitoneal injection. The terminal half-life is 12-19 min.

5-MeO-DMT is lipid-soluble and readily crosses the blood – brain barrier. It binds to many different receptors, including 5-HT3, Ca2+ channels, 1, 3, DOR, MOR, KOR, EP3, EP4, GABAA, H2, H3, H4, M1, M2, M3, M4, M5.

5-MeO-DMT is distributed to the cortex, thalamus, hippocampus, basal ganglia, medulla, pons and cerebellum in the rat brain 45 min after IP injection.

Shen et al. (2011) demonstrated that 5-MeO-DMT has non-linear pharmacokinetics for both IP and IV administration, with the additional clearance being dependent on CYP2D6 protein.

When doses of 10 or 20 mg/kg of 5-MeO-DMT are administered to mice, the clearance of 5-MeO-DMT decreases by 50%, indicating that MAOA-mediated metabolism becomes saturated. This is also reflected in the increase in brain concentration of 5-MeO-DMT.

In vivo pharmacology

5-MeO-DMT has been studied in mice, rats, gerbils, hamsters, guinea pigs, rabbits, goldfish, cats, dogs, sheep, pigs and primates.

Behavioural effects

5-MeO-DMT induces a head-twitch in rodents, which is similar to other classic hallucinogens, but is attenuated by selective 5-HT2A receptor antagonists and is absent in 5-HT2A-knockout mice.

5-MeO-DMT reduces locomotor activity, reduces investigatory behaviour and induces forepaw treading, flat-body posture, Straub tail response and hindlimb abduction. These effects are predominantly 5-HT1A mediated, with some contribution of 5-HT2A receptors.

Table 2 shows doses and routes of administration in different species. Note that these ranges are an approximation, depend on particular behaviour/task, and in some species based on only one or two studies and drug administrations.

Neurobiological effects

In a healthy volunteer field study, 5-MeO-DMT suppressed alpha frequencies acutely, followed by a rebound increase in alpha-power 20 min post inhalation.

5-MeO-DMT alters low-frequency oscillations in the medial prefrontal cortex and cortico-thalamic coherence in rats and mice, and decreases blood oxygen level dependent (BOLD) responses in visual cortex (V1) and mPFC. It also prevents anxiety-like behaviour and abnormal neural activity triggered by tinnitus.

5-MeO-DMT increases the number of neuronal progenitor cells in the mouse hippocampus and helps them survive and mature faster.

The effects of 5-MeO-DMT on cat and rat neuron firing in the central and peripheral nervous systems include inhibition of 5-HT neuronal activity and antiepileptic effects. It also increases the excitability of several types of spinal neurons, including motoneurons.

Cardiovascular effects

Psychedelics may increase heart rate and blood pressure via sympathomimetic effects of 5-HT2A receptor agonism, while 5-HT1A agonists decrease heart rate and blood pressure via peripheral vasodilation and vagus nerve stimulation.

5-MeO-DMT, like psilocybin, binds to 5-HT2B receptors. However, no research studies link classic psychedelic use and valvular heart disease.

Thermoregulatory effects

Stimulation of different 5-HT receptors can have opposing effects on thermoregulation, with 5-HT1A receptor agonists causing hypothermia and 5-HT2A receptor agonists causing hyperthermia. The hyperthermic effect may be completely attenuated or even converted into hypothermia by the 5-HT2A antagonist, ketanserin.

Effects on nociception

The analgesic effects of 5-MeO-DMT are non-linear: Nociception is enhanced after very low doses, biphasic at medium doses, and reduced after higher doses of 5-MeO-DMT. 5-MeO-DMT causes increased prolactin levels, dose dependently, in both male and female rats.

5-MeO-DMT can modulate immune responses in human primary immune cell cultures and in two different models, with no impact on antibody production, immune homeostasis interleukins IL-4, IL-5 or T helper 2 cells.

Effects on gene expression

Dakic et al. (2017) identified more than 900 proteins differentially expressed after treatment with 5-MeO-DMT.

Drug interactions

5-MeO-DMT interacts with MAOA inhibitors and shifts 5-MeO-DMT metabolism to alternative pathways such as O-demethylation, extending systemic and central exposure to 5-MeO-DMT. Tetrahydrocannabinol, mitragynine, lithium, haloperidol, benzodiazepines and antidepressants also interact with 5-MeO-DMT.

Acute benzodiazepine treatment potentiates 5-MeO-DMT-induced flat posture and tremor, but attenuates head-twitch and ‘wet-dog shake’ response. Chronic administration of tricyclic antidepressants consistently attenuates 5-MeO-DMT-induced analgesia, head-twitch response, and behaviour response.

Toxicology

5-MeO-DMT can cause ataxia, mydriasis, head nodding, lateral head weaving, tremor, convulsions, shivering, tachycardia and loss of consciousness in high doses.

Tolerance

Tolerance develops to some (but not all) of the behavioural and physiological effects of 5-MeO-DMT in rats, cats and monkeys. Chronic, frequent administration of 5-MeO-DMT diminishes the responsiveness of 5-HT1A receptor-mediated changes in body temperature and corticosterone secretion without altering the responses mediated by 5-HT2 receptors.

Abuse potential and prevalence of use

5-MeO-DMT is not specifically mentioned in the United Nations Office on Drugs and Crime (2020) World Drug Report or the European Monitoring Centre for Drugs Drug Addiction (EMCDDA, 2019) or the Global Drug Survey (GDS, 2020; Global Drug Survey, 2021) surveys.

Epidemiological studies of human recreational/spiritual use

There are no published human clinical trials of 5-MeO-DMT, but there are several epidemiological studies and surveys of recreational/ spiritual/medicinal use. It is used in many different ways, including inhalation, intravenous injection, sublingual or intranasal routes, and oral administration.

5-MeO-DMT has a rapid onset, lasts 15 – 20 min and returns to baseline in 30 min when inhaled. Users report that 5-MeO-DMT elicits more intense effects compared to most other psychedelics, and the absence of visual effects may be due to 5-HT1A receptor action. 5-MeO-DMT users describe content-free experiences, associated with loss of sense of self and bodily awareness, and sensory deprivation. Dose, set and setting have considerable impact on the perceptual and emotional experience.

Retrospective surveys examined 5-MeO-DMT patterns of use, motivations for consumption, subjective effects, potential benefits and consequences associated with use. Most people used it less than 4 times in their life.

In a subsequent survey, more people who took 5-MeO-DMT in a group setting reported improved depression and anxiety, and fewer reported their conditions were unchanged or worsened. Moreover, supportive setting in a group was associated with higher ratings of complete mystical experience.

Several countries where 5-MeO-DMT is unregulated offer retreats and treatment programmes. In one case study, a 31-year-old military veteran with alcohol use disorder reported improvement in mood, cessation of alcohol use and reduced cravings after treatment with 5-MeO-DMT and ibogaine.

Two prospective studies examined the effects of 5-MeO-DMT inhalation and toad secretions on mindfulness and depression. In both studies, ratings of mindfulness and depression decreased immediately after the session and remained so at follow up.

Acute adverse effects of 5-MeO-DMT reported in some studies include fear, sadness, anxiety, confusion, profound experience of one’s own death, crying, paranoia, shaking/trembling, vomiting, nausea, transient headache, pressure or weight in the chest or abdomen and loss of body perception.

A 5-year-old child was hospitalised with profuse salivation and continuous seizures after licking a toad, and a 17-year-old was hospitalised with extreme agitation, hyperthermia, tachycardia and rhabdomyolysis after consuming 5-MeO-DMT and the MAOI harmaline.

There are no reports of deaths related to 5-MeO-DMT from the Office for National Statistics (England and Wales), DAWN 2011 report/2020 preliminary data (Drug Abuse Warning Network), or NPSAD (National Programme on Substance Abuse Deaths).

Discussion

5-MeO-DMT is a naturally occurring tryptamine derivative found in the gland secretions of the Sonoran Desert toad, in a variety of plants, and endogenously in mammals. It has paradoxical effects on pharmacokinetics, thermoregulation, nociception, heart rate and blood pressure.

Data indicates that 5-MeO-DMT should be used with caution in human clinical trials and that concomitant use of MAOIs and lithium should be avoided. Hallucinogen-persisting perception disorder (HPPD) may occur in some people who take psychedelics but have never taken a psychedelic.

The therapeutic potential of 5-MeO-DMT is hypothetical, but intriguing. Its pharmacokinetic and pharmacodynamic properties may confer clinical advantages, such as a short duration of action and absence of visual effects, which might lead to higher rates of mystical experiences.

5-MeO-DMT is a short-lasting psychedelic substance with a unique subjective effect profile. Its high rates of ego-dissolution and mystical experiences make it an intriguing compound to research.

Declaration of conflicting interests

The authors declared conflicts of interest with respect to the research, authorship, and/or publication of this article: A.O.E., J.R., F.D., and M.W.J. provide paid consulting services to Beckley Psytech, M.W.J. is a Professor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine.