The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)

This review (2022) explores the current state of research surrounding 5-MeO-DMT. The authors provide food for thought on its therapeutic potential as well as the commercialization of the substance.

Abstract

“5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring tryptamine that primarily acts as an agonist at the 5-HT1A and 5-HT2A receptors, whereby affinity for the 5-HT1A subtype is highest. Subjective effects following 5-MeO-DMT administration include distortions in auditory and time perception, amplification of emotional states and feelings of ego dissolution that usually are short lasting, depending on the route of administration. Individual dose escalation of 5-MeO-DMT reliably induces a “peak” experience, a state thought to be a core predictor of the therapeutic efficacy of psychedelics. Observational studies and surveys have suggested that single exposure to 5-MeO-DMT can cause rapid and sustained reductions in symptoms of depression, anxiety and stress. 5-MeO-DMT also stimulates neuroendocrine function, immunoregulation and anti-inflammatory processes, which may contribute to changes in mental health outcomes. To date, only one clinical trial has been published on 5-MeO-DMT, demonstrating safety of vaporised dosing up to 18mg. Importantly, the rapid onset and short duration of the 5-MeO-DMT experience may render it more suitable for individual dose finding strategies as compared to longer acting psychedelics. A range of biotech companies have shown an interest in the development of 5-MeO-DMT formulations for a range of medical indications, most notably depression. Commercial development will therefore be the most important resource for bringing 5-MeO-DMT to the clinic. However fundamental research will also be needed to increase understanding of the neurophysical and neural mechanisms that contribute to the potential clinical effects of 5-MeO-DMT and its sustainability and dissemination over time. Such studies are less likely to be conducted as part of drug development programs and are more likely to rely on independent, academic initiatives.”

Authors: Johannes T. Reckweg, Malin V. Uthaug, Atilla Szabó, Alan K. Davis, Rafael Lancelotta, Natasha L. Mason & Johannes G. Ramaekers

Summary

List of abbreviations

5D-ASC; brain-derived neurotrophic factor; CYP2D6; cytochrome P450 2D6; DAMPs; damage-associated molecular patterns; EDI; ego dissolution inventory; IL-6; interleukin-6; LH; luteinizing hormone; MAOI; monoamine oxidase inhibitor; MDD; Mystical Experience Questionnaire.

5-MeO-DMT is a naturally occurring tryptamine that acts as an agonist at the 5-HT1A and 5-HT2A receptors. It causes rapid and sustained reductions in symptoms of depression, anxiety and stress, and may also stimulate neuroendocrine function, immunoregulation and anti-inflammatory processes. Biotech companies are interested in developing 5-MeO-DMT formulations for a range of medical indications, most notably depression. However, fundamental research is also needed to increase understanding of the potential clinical effects of 5-MeO-DMT.

5-MeO-DMT is a naturally occurring tryptamine that can be found in the Amazonian rainforest. It is used in shamanic rituals and healing ceremonies, and as an aphrodisiac in Indian and Mexican cultures. The venom of the Sonoran Desert toad contains 5-MeO-DMT, which is converted to bufotenine through O-methyl transferase. This triggered experimentation with the venom in Western cultures, and its popularity as a psychedelic spread quickly.

It has been speculated that 5-MeO-DMT is also endogenously produced in humans, but other studies have contradicted these findings. Further evidence is needed to support the notion of endogenous production of 5-MeO-DMT and its potential physiological function in humans.

Pharmacology and metabolism

5-MeO-DMT is primarily a non-selective serotonin (5-HT) receptor agonist, with additional binding to the 5-HT-transporter and dopamine receptors or the noradrenergic transporter. It has a 300-1000 fold higher selectivity as compared to the 5-HT2A receptor.

5-HT1A receptors are involved in mood regulation and the control of the autonomic nervous system, whereas 5-HT2A receptors are involved in increased heart rate, vasomotor tone and blood pressure. 5-MeO-DMT induces a signature head twitch response that can be blocked with 5-HT2A receptor antagonists. 5-MeO-DMT is inactivated by MAO-A and CYP2D6 and converted to bufotenine, which binds to 5-HT1A and 5-HT2A receptors. MAOIs can block the biotransformation of 5-MeO-DMT and increase exposure to 5-MeO-DMT leading to enhanced and prolonged behavioral effects or even hyperserotonergic effects.

5-MeO-DMT induces acute subjective effects similar to those of other tryptamine psychedelics such as psilocybin and DMT, including visual, auditory and time perception distortions, emotional experiences and memory impairment. A mystical experience typically involves a sense of oneness with the universe, feelings of reverence, positively valenced feelings such as love or peace, and difficulty putting the experience into words. The 5-MeO-DMT experience contrasts with the DMT experience, which produces vivid and complex visual imagery.

5-MeO-DMT has been reported to cause acute and subacute adverse effects, including flashbacks, reactivations, pressure on the chest or abdomen, loss of body perception, and psychosis, but rarely when used in combination with other tryptamines.

Observational research has demonstrated that 5-MeO-DMT has a rapid onset of subjective effects and lasts for 15-20 minutes. Subjective effects induced by smoked 5-MeO-DMT are characterized by an intense psychedelic experience, with many participants reporting prominent ratings of ego dissolution and oceanic boundlessness. The magnitude of the experience may vary considerably between individuals, and may be caused by different doses administered at ceremonies. Ralph Metzner summarized field and underground reports on the subjective effects of 5-MeO-DMT when administered intranasally. Intranasal administrations are reportedly slower onset and more prolonged than smoking or vaporization.

All formulations of 5-MeO-DMT avoid first pass metabolism, provide high bioavailability and easy control of dose delivery, while smoking produces a fast onset of subjective experiences with high intensity and short duration.

Researchers examined patterns of use, motivations for consumption and subjective experiences associated with 5-MeO-DMT use. They found that most users consumed the drug infrequently, for experiences (ineffability, timelessness, awe/amazement, experience of pure being/awareness).

Prospective observational studies with synthetic 5-MeO-DMT and toad secretion containing 5-MeO-DMT in healthy volunteers have demonstrated immediate and lasting improvements in self-reported ratings of depression, anxiety, stress, mindfulness-related capacities, and satisfaction with life, after a single inhalation of the substance. A follow-up study demonstrated that mindfulness-related capacities were enhanced and feelings of depression were reduced immediately after intake of synthetic 5-MeO-DMT compared to baseline. Seven days post intake, mindfulness-related capacities remained enhanced and feelings of anxiety and stress were significantly reduced compared to baseline.

Observational studies have reported improvements in symptoms of a range of diagnosed psychiatric disorders after ingestion of 5-MeO-DMT, with a notably small proportion reporting a worsening of these conditions. In a separate cross-sectional survey, Davis et al. 2019 demonstrated that people with depression and anxiety reported improvements in their conditions following 5-MeO-DMT use, but only 7 people reported using 5-MeO-DMT specifically to help with their depression or anxiety.

Neurophysiological effects

Initial studies on 5-MeO-DMT in rodents focused on its effect on the release of luteinizing hormone (LH) and prolactin (PRL). The effects of 5-MeO-DMT on PRL release were biphasic, with an initial stimulatory effect followed by an inhibitory effect in the long run. Seeman and Brown compared the neurohormonal effects of 5-MeO-DMT with two other close tryptamine analogs, bufotenin and DMT, and found that 5-MeO-DMT had the most potent pro-secretory effects on PRL levels.

MeO-DMT mediated neuroendocrine response was centrally mediated, and did not involve activation of peripheral 5-HT receptors. The modulatory effect of serotonergic tryptamines on neuroplasticity may provide a general solution to treating all of these related disorders. Serotonergic psychedelics, entactogens and ketamine have been shown to mediate rapid-onset, long-lasting anxiolytic and antidepressant effects in humans following the administration of a single dose or multiple therapeutic doses in randomized, controlled trials.

A recent study found that 5-MeO-DMT modulates several molecular pathways involved in neuroplasticity, and that a single dose of intracranially administered 5-MeO-DMT promoted neuroplasticity in mice. This suggests that 5-MeO-DMT may also have potential neuroplasticity-promoting effects in humans.

To understand the potential effects of 5-MeO-DMT on immune homeostasis, we need to consider two major, downstream effector mechanisms: the influence of 5-MeO-DMT on systemic neuroendocrine regulation and the modulatory effect on immune cells. 5-MeO-DMT has a formidable modulatory capacity in promoting PRL release via central 5-HT receptors, and has been shown to have anti-inflammatory effects in the central nervous system by regulating microglial functions, and has been described as a neuroprotective and neuroplasticity-promoting factor.

MeO-DMT strongly modulates the circulating levels of PRL, which may have anti-inflammatory and immune regulatory properties at both systemic and intracellular levels. However, in the absence of controlled clinical trials using larger patient samples, these findings have to be interpreted with caution. Inflammation is an immediate response to invading microbes or tissue damage mediated by the innate immune system. Pattern recognition receptors (PRRs) detect potentially dangerous, non-self, pathogen-associated molecular patterns (PAMPs).

TLRs, CLRs, NLRs, and other PRRs are activated by microbial ligands, and this leads to the expression of inflammatory cytokines, chemokines, and co-stimulatory molecules, which are critical for the orchestration of both innate and adaptive immune responses. Some PRRs are involved in the constitution and activation of the inflammasome, an important innate immune effector mechanism. Inflammasomes regulate caspase-1 activation and are activated by cytosolic detection of PAMPs and self-derived endogenous damage-associated molecular patterns.

DMT and 5-MeO-DMT have been found to have anti-inflammatory properties, by decreasing the immune tolerance threshold and contributing to the development of long-term adaptive immune responses against self-tissues, such as the brain parenchyma. 5-MeO-DMT and DMT treatment of immune-primed human primary moDCs led to significant inhibition of inflammatory cytokine and chemokine secretion, as well as upregulation of the anti-inflammatory cytokine IL-10. Furthermore, both tryptamines were able to inhibit T helper cell 1 and 17 priming by 5-MeO-DMT and DMT-treated moDCs.

5-MeO-DMT may exert anti-inflammatory and immune effects via systemic neuroendocrine feedback loops, direct inhibition of key inflammatory pathways, and/or upregulation of anti-inflammatory cytokines. These effects may contribute to the long-term beneficial effects of serotonergic tryptamine on the symptoms of depression and anxiety.

5-MeO-DMT may have neuroendocrine, pro-neuroplastic, and anti-inflammatory effects via 5-HT2A, Sig1R, cytokine, and hormone receptors and their associated pathways, which may dampen inflammatory responses, especially in the early-acute phase.

Psychology versus neurophysiology?

Potential mechanisms underlying positive mental health changes induced by psychedelics include both the psychological psychedelic experience and the underlying neurophysiological mechanisms.

A psychedelic-occasioned mystical state of consciousness, or “peak” psychedelic experience, is the primary factor that mediates enduring positive effects in cognition, affect, behavior, and spirituality. The intensity of the acute psychedelic experience is the main predictive factor of a response to a psychedelic in patients with addictive disorder, treatment-resistant depression and obsessive-compulsive disorder. The mechanism triggering a mystical or peak experience leading to a change in downstream behavior and affect is still unclear. However, it can be assumed that lasting changes in the psychological state caused by 5-MeO-DMT coincide with neurobiological changes that occur in parallel through 5-HT1A and 5-HT2A agonism.

The neurophysiological perspective considers psychedelics to promote structural and functional neural plasticity in the brain through 5-HT2A receptor-mediated mechanisms. A nonhallucinogenic analogue of 5-MeO-DMT, termed tabernanthalog, has been shown to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects in rodents. Extra-pharmacological factors such as set and setting can influence the experiential response to a psychedelic. Positive expectations, openness to the psychedelic experience and a trusted, supportive environment are key.

Preoccupation with concerns, rigidity, lack of trust and support increase the chances of an adverse experience with 5-MeO-DMT. Sepeda and colleagues used secondary data from a large survey study to examine whether people who use synthetic 5-MeO-DMT in a structured context have higher ratings of mystical experiences and a lower intensity of challenging experiences compared to people who use synthetic 5-MeO-DMT in a non-structured context. Data suggests that the supportive setting is associated with positive effects of 5-MeO-DMT consumption, and that preparation for the psychedelic experience, including realistic projections of the actual experience with 5-MeO-DMT, psychological support and guidance by trained facilitators, and providing psychological, emotional, and environmental safety, is critical.

The therapeutic potential of 5-MeO-DMT is mainly hypothetical and based on preliminary evidence, which stems from a small number of prospective observational studies and cross-sectional surveys on the naturalistic use of synthetic 5-MeO-DMT and toad secretion containing 5-MeO-DMT in self-selected samples.

Studies have shown that 5-MeO-DMT can improve self-reported feelings of depression, anxiety, stress and satisfaction with life, and can alleviate psychiatric symptom severity in certain clinical populations. This is similar to the results of studies assessing the therapeutic potential of classic psychedelics. After oral ingestion, the psychoactive effects of the classic psychedelics last substantially longer than 4 hours for ayahuasca, 6 hours for psilocybin, and 12 hours for LSD.

As psychedelic-assisted psychotherapy with these substances is costly and time-consuming, 5-MeO-DMT would substantially lower treatment costs. Researchers have conducted two clinical studies with 5-MeO-DMT to assess safety and efficacy in healthy volunteers and patients with treatment resistant depression. The safety data were recently published and show that 5-MeO-DMT produces short-acting, significant increments in the intensity of the psychedelic experience ratings.

At 3 h, 5-MeO-DMT was given on a single day. This suggests that individualized dose escalation may best suit clinical applications that aim to maximize the experience to elicit a strong therapeutic response. The psychedelic experience with 5-MeO-DMT lasts for 15-20 minutes, and cognitive and psychomotor function quickly return to baseline. Additionally, there is little build-up of tolerance to the effects of 5-MeO-DMT, which suggests a less time-intensive procedure for patients as well.

Toad venom contains a range of pharmacological active compounds in addition to 5-MeO-DMT, but it is presently unknown if any of these additional compounds synergistically modulate the effects of 5-MeO-DMT in ways that would be relevant for therapeutic applications. There are ethical and ecological arguments not to pursue clinical development of toad venom, as the toad population may be affected by the increasing demand for 5-MeO-DMT and the invasion of habitat, excessive milking, amphibian trafficking, and black-market.

5-MeO-DMT is a fast-acting tryptamine that induces a psychedelic experience of short duration. It has high binding affinities for the 5-HT1A and 5-HT2A receptors but appears to be more selective for 5-HT1A. Adverse events associated with 5-MeO-DMT are mild and transient and include anxiety, confusion, paranoia, loss of body perception, and flash-backs/reactivations. It is possible that 5-MeO-DMT could be used to treat mental health disorders such as depression, anxiety, PTSD and substance misuse.

Although clinical development of 5-MeO-DMT is in its infancy, GH Research is focusing on developing inhalable and injectable formulations of the substance for psychiatric conditions, and Beckley Psytech is also developing a training program for therapists. Other private companies have also declared their interest in developing 5-MeO-DMT for various indications and in various formulations, including a thermosensitive nasal gel to administer 5-MeO-DMT as an anti-inflammatory. The USONA Institute has published a detailed 5-MeO-DMT synthesis process and guidelines for assessment of the substances’ safety and efficacy.

Clinical studies with 5-MeO-DMT should incorporate different routes of administration, as well as biomarker levels, to determine the pharmacokinetics and pharmacodynamics of 5-MeO-DMT. This will help to optimize clinical treatment modalities in patient populations and to unveil the underlying bio-psychological principles that contribute to healing. Observational research suggests that 5-MeO-DMT exposure can sustain improvements in mental health outcomes for months. A more fundamental, mechanistic understanding of psychological as well as biological processes is currently unknown.

5-MeO-DMT may have potential as a therapeutic agent in mental health treatment, as its rapid onset and short duration may render it more cost-effective as compared to longer acting psychedelics. Biotech companies are interested in developing 5-MeO-DMT formulations and drug development programs, but fundamental research is needed to understand the neurophysical and neural mechanisms that contribute to potential clinical effects.

Conflicts of Interest.

JTR, JGR, MVU, AKD are scientific consultants to GH Research, Entheon, and Tim Ferriss, and are funded by anonymous private donors.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this article. References include Agurell, S., Holmstedt, B., Lindgren, J. E. and Schultes, R. E. (1969), AlvariusPharmaceuticals (2021), Barker, S. A. (2018), Barrett, F. S. and Johnson, M. W. (2015). Psilocybin is used in psychotherapy for alcohol dependence and other disorders. It works by activating the 5HT1A receptor on dendritic cells and by affecting several signal transduction pathways. Prolactin is an inflammatory cytokine that plays a role in autoimmunity. MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder may be effective.

A double-blind comparison of psilocybin and dextromethorphan revealed similarities and differences in subjective experiences. Carhart-Harris, R., Giribaldi, B., Watts, R. et al. (2021) Trial of Psilocybin versus Escitalopram for Depression was conducted. Carhart-Harris, R. L., Nutt, D. J., Roseman, L., Bolstridge, M. et al. (2017) Investigated the role of serotonin and psilocybin in depression and anxiety, and produced the first ever 5-MeO-DMT psychedelic training program. 5-MeO-DMT is associated with healing in a naturalistic group setting. The epidemiology of 5-MeO-DMT use is described, including benefits, consequences, patterns of use, subjective effects, and reasons for consumption.

Ayahuasca may improve depression and anxiety by modifying serum brain-derived neurotrophic factor, and may also have an anti-inflammatory effect. Ayahuasca may also affect the brain’s reward system, and may also affect the activity of certain brain regions. A narrative synthesis of research with 5-MeO-DMT, a psychoactive compound found in mushrooms, has been published. It also reviews the use of psychedelics in the treatment of anxiety associated with a life-threatening disease. Psilocybin decreases depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.

Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. It also has pharmacokinetic and behavioral interactions with monoamine oxidase inhibitors. Incilius alvarius is listed as vulnerable on the IUCN Red List of Threatened Species. Hartogsohn (2016) discusses set and setting, psychedelics and the placebo response, and Henry (1992) discusses the biological basis of the stress response. Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. This results in dendritic retraction in infralimbic cortex and resistance to fear extinction in mice.

The 5-HT1A receptor is involved in Major Depressive Disorder, the Toll-like receptor and RIG-I-like receptor signaling pathways are involved in substance use and psychiatric disorders, and BDNF is a key factor with multipotent impact on brain signaling and synaptic plasticity. Krebs-Thomson, Ruiz, Masten, V., Buell, M. and Geyer, M. A. (2006) examined the roles of 5-HT1A and 5-HT2 receptors in 5-MeO-DMT’s effects on locomotor activity and prepulse inhibition in rats. Kuhn, Vogel, Mailman, Mueller, R. B., Schanberg, S. M. and Breese studied the effects of 5,7-dihydroxytryptamine on prolactin secretion and behavior in rats. Lancelotta, R. L. and Davis, A. K. (2021) Review of fast-acting tryptamines: therapeutic potential, use of benefit enhancement strategies, associations with mystical, challenging, and lasting effects, and review of BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases.

Psychedelic use promotes structural and functional neural plasticity, leads to increased openness, and increases in the experience of ego dissolution, and correlates with serotonin 2A receptor occupancy and plasma psilocin levels. McBride, M. C., McKenna, D. J., Peroutka, S. J., Metzner, R. (2013). Bufotenine: toward an understanding of possible psychoactive mechanisms. Mithoefer, M. C., Grob, C. S., Brewerton, T. D. and others (2016) reviewed novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Most, A. (1984) described the psychedelic toad Bufo alvarius. Narasimhachari, N., Baumann, P., Pak, H. S., Carpenter, W. T., Zocchi, A. F., Hokanson, L., Fujimori, M. and Himwich, H. E. (1974) described the determination of bufotenin and dimethyltryptamine in urine samples from drug-free chronic schizophrenic patients.

Several studies have found that psychedelic therapy for smoking cessation can be effective, and that the subjective effects of psychedelics may not be necessary for their lasting therapeutic effects. Ayahuasca, Dictyoloma incanescens, Piptadenia colubrina, and Mimosa hostilis have been found to have psychedelic effects that modulate the activity and connectivity of the default mode network in the brain. The role of prolactin in central nervous system inflammation is being explored by several researchers. The authors discuss the many different aspects of the topic and provide references for further reading.

Ayahuasca has subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics similar to ayahuasca, but less potent. Psilocybin has rapid and sustained symptom reduction in patients with life-threatening cancer, according to a randomized controlled trial. Psychedelics have been shown to be effective in the treatment of unipolar mood disorders. Ayahuasca, Mucuna pruriens, Bufo alvarius toad, and prolactin are all reported to have a neurochemical interaction in the central nervous system of the rat. Sepeda, N. D., Clifton, J. M., Doyle, L. Y., R., L., RR, G. and A.K., D. 2020.

Sherwood, A. M., Claveau, R., Lancelotta, R., Kaylo, K. W., Lenoch, K., Kargbo, R. B., Davis, A. K., Lancelotta, R., Uthaug, M. V. and Barrow, R. B. (2019) Synthesis and clinical consideration of 5-MeO-DMT. Mucuna species have been found to contain a variety of chemicals that are thought to be involved in the regulation of many different cellular processes, including the immune system. The microbiome and innate immunity, psychedelics as a novel approach to treating autoimmune conditions and indoleamine 2,3 dioxygenase, are discussed.

Ayahuasca, set and setting affect mental health of participants in ayahuasca group retreats. A comparison of reactivation experiences following vaporization and intramuscular injection of synthetic 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is discussed. Ayahuasca has sub-acute and long-term effects on affect, cognitive thinking style, and ego dissolution. Psychedelic drugs have been shown to induce schizophrenia-like psychosis in humans via a serotonin-2 agonist action, and to be necessary for their lasting therapeutic effects. In addition, they have been shown to modulate heart rate dynamics and be adjusted by conditioned and unconditioned fear.