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

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 the safety of vaporized dosing up to 18 mg. Importantly, the rapid onset and short duration of the 5-MeO-DMT experience may render it more suitable for individual dose-finding strategies compared with longer-acting psychedelics. A range of biotech companies has 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 neurophysiological 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.

Keywords: 5-MeO-DMT; clinical development; mental health; neuroinflammation.

FIGURE 1

Depictions of the bufo alvarius toad, the structure of 5‐MeO‐DMT, and the cover of the pamphlet “Bufo alvarius: the psychedelic toad of the Sonoran desert” (Most, 1984), the first guide for collecting, drying, and smoking the toad venom

FIGURE 2

Biotransformation of 5‐MeO‐DMT and its metabolite bufotenine and their mean binding affinities (Ki) for 5‐HT1A (Hamon et al., ; Halberstadt et al., 2012) and 5‐HT2A receptors (Halberstadt et al., ; McKenna & Peroutka, 1989)

FIGURE 3

The putative physiological effects of 5‐MeO‐DMT administration on the neuroendocrine and immune systems. (a) The systemic physiological effects of 5‐MeO‐DMT may include direct modulation of prolactin secretion via central hypothalamic serotonin receptors. This can result in systemic anti‐inflammatory and immunomodulatory effects through prolactin receptor‐expressing immune cell types. (b) Serotonin 1A and 2A (5‐HT1a/2a), Toll‐like (TLR), and inflammatory cytokine receptors (e.g., IL‐1β receptor, IL1‐R) are expressed on the cell surface, while sigma‐1 receptors (Sig1R) are localized intracellularly mainly at the mitochondrion‐associated endoplasmic reticulum interface. TLRs and other pattern recognition receptors recognize various sets of pathogenic structures and transduce signals through the NF‐κB/IRF pathways (e.g., IRF3). IL1‐R is specifically modulated by inflammatory cytokines of the IL‐1 family (e.g., IL‐1β). The activation of TLRs/IL1‐Rs results in down‐stream signaling through the MyD88 adaptor proteins. This receptor–adaptor interaction leads to the activation of the essential coadaptors IRAK1/4 and TRAF6 and leads to the subsequent phosphorylation of several effector pathways/regulators, such as IRF3 or NF‐κB (via NEMO/IKKα/IKKβ). These transcription factors then translocate to the nucleus regulating the expression of type I IFN, chemokine, and inflammatory cytokine genes, such as IFNβ, IL‐1β, IL‐6, IL‐8, IL‐18, and TNF‐α. 5‐MeO‐DMT may interfere with these pathways via down‐stream signals from 5‐HT1a, 5‐HT2a, and Sig1R. The activation and assembly of the inflammasome complex by PAMPs/DAMPs lead to the recruitment and activation of caspase‐1, and the subsequent cleavage of pro‐IL‐1β and IL‐18 to the biologically active, released form (IL‐1β and IL‐18). 5‐MeO‐DMT may also inhibit this process through an unknown mechanism(s). (c) 5‐MeO‐DMT can also directly modulate the production of anti‐inflammatory cytokines, such as IL‐10 and TGF‐β, by 5‐HT1a/2a and/or Sig1R expressing immune cell types thereby inhibiting local and systemic inflammatory processes. Abbreviations: 5‐HT: serotonin; IL: interleukin; TNF: tumor necrosis factor; CRP: C‐reactive protein; MyD88: Myeloid differentiation primary response 88 adaptor protein; IRAK: Interleukin‐1 receptor‐associated kinase; TNF receptor‐associated factor 6 adaptor protein; IRF: Interferon regulatory factor; NF‐κB: Nuclear factor kappa‐light‐chain‐enhancer of activated B cells transcription factor; NEMO: NF‐kappa‐B essential modulator; IKKs: inhibitory‐κB kinases; IFN: interferon; TGF‐β: Transforming growth factor‐beta; Red T‐arrows represent inhibitory effects. Created with BioRender.com