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.
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.
Papers cited by this study that are also in Blossom
Barker, S. · Frontiers in Neuroscience (2018)
Barrett, F. S., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2015)
Barsuglia, J. P., Davis, A. K., Palmer, R. et al. · Frontiers in Psychology (2018)
Belser, A. B., Agin-Liebes, G. I., Swift, T. C. et al. · Journal of Humanistic Psychology (2017)
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring tryptamine found in various plants and in the parotoid gland secretion of the Sonoran Desert toad (Incilius alvarius). The Introduction summarises ethnobotanical reports and biochemical traces that have prompted interest in 5-MeO-DMT, while noting that strong evidence for longstanding indigenous use is limited. The compound has been detected alongside other indole alkaloids such as DMT in plant materials, and its presence in toad venom has driven recreational and experimental use in Western contexts. The authors also review suggestions, and conflicting data, about possible endogenous production of 5-MeO-DMT in mammals and humans, concluding that further evidence is needed to support any physiological role. This paper sets out to survey the clinical pharmacology, subjective effects, neurophysiological actions, and potential therapeutic applications of 5-MeO-DMT, drawing on receptor binding and preclinical studies, observational and survey data, and the limited clinical research to date. The review aims to identify mechanistic pathways (serotonergic, neuroendocrine, immunological, and neuroplasticity-related) that could plausibly underlie reported mental health effects and to highlight gaps that need addressing before clinical development can proceed safely and effectively.
The extracted text does not present a dedicated Methods section or a clear description of a formal search strategy, inclusion/exclusion criteria, or systematic review procedures. From the prose it is evident that the paper is a narrative review synthesising multiple types of evidence: in vitro receptor binding studies, animal experiments, observational and web-based surveys, prospective naturalistic studies in healthy volunteers, and early-phase clinical trials and registrations. The authors integrate findings from molecular pharmacology (receptor affinity and metabolism), preclinical behavioural and neuroendocrine experiments in rodents, cross-sectional and prospective human surveys (including a web-based survey of N=515), small prospective observational cohorts (examples reported with n=42 and n=11), and registered but early-stage clinical trials. Because explicit methods for literature identification and quality appraisal are not reported in the extracted text, readers should understand this as a narrative synthesis rather than a systematic review or meta-analysis.
Pharmacology and metabolism: Two receptor binding studies using human cloned receptors reported that 5-MeO-DMT is a non-selective serotonin receptor agonist with highest affinity for the 5-HT1A receptor (reported Kd/affinity ~1.9–3 nM). The compound shows roughly 300–1000 fold greater selectivity for 5-HT1A over 5-HT2A, which contrasts with many classic psychedelics whose experiential effects are primarily attributed to 5-HT2A activation. Additional, lower-affinity interactions with the serotonin transporter and dopamine or noradrenergic transporters were noted. Metabolically, 5-MeO-DMT is primarily inactivated by monoamine oxidase A (MAO-A) via oxidative deamination and is O-demethylated by CYP2D6 to produce bufotenine, an active metabolite with higher affinity for 5-HT2A and substantial 5-HT1A affinity. Concurrent MAOI use can block deamination, increasing exposure and prolonging effects, with potential for exaggerated serotonergic outcomes. Subjective effects, routes and temporal profile: Human reports and observational research indicate that 5-MeO-DMT produces perceptual distortions (visual, auditory, time), amplified emotions, intense mystical/"peak" experiences and feelings of ego-dissolution. Smoked or vapourised administrations produce an extremely rapid onset (peaks within seconds) and a short duration of effects typically lasting about 15–20 minutes. Intramuscular (IM) injection has been reported to onset over 1–6 minutes and last up to 60 minutes, yielding a slower and often milder subjective course; intranasal administration reportedly onsets in 5–7 minutes and can last 45–60 minutes. The magnitude of the experience varies substantially between individuals; approximately 20–30% of ceremonial participants report low-to-medium psychedelic intensity, which may reflect dose, inhalation technique, or preparation variability. Acute adverse reactions reported across studies include fear, anxiety, nausea, vomiting, headache, trembling, confusion and transient loss of body perception. Short-lived reactivations or "flashbacks" (sensory disturbances or brief re-experiencings) have been described during the week following exposure, generally experienced as neutral or positive in large samples; rare cases of psychosis have been reported, sometimes in conjunction with other tryptamines. Observational and early clinical outcomes: A web-based survey of N=515 reported infrequent lifetime use (typically less than once a year) and predominantly spiritual motivations; 90% of respondents endorsed moderate-to-strong mystical-type experiences and few reported craving or substantial legal, medical or psychiatric problems. Two prospective naturalistic studies described rapid improvements in self-reported depression, anxiety, stress and mindfulness-related capacities after a single inhalation of toad venom or synthetic 5-MeO-DMT. In one study (n=42) reductions in depression, anxiety and stress and increases in mindfulness and life satisfaction were reported at 24 hours and, for some measures, up to 4 weeks post intake; higher acute ego-dissolution correlated with larger improvements. A smaller follow-up (N=11) found immediate decreases in depression and sustained increases in mindfulness at 7 days, with anxiety and stress significantly reduced at that time point. Cross-sectional surveys of respondents with diagnosed psychiatric disorders reported high proportions reporting improvement after 5-MeO-DMT: PTSD 79%, depression 77%, anxiety 69%, substance use problems 63% and obsessive–compulsive disorder 53%, with only 2–10% reporting worsening. In a separate sample of people with depression (n=149) and anxiety (n=173), around 80% reported improvement after group use of 5-MeO-DMT; few reported worsening. Neurophysiological effects: Early rodent work showed marked effects on pituitary prolactin (PRL) release: robust acute increases in PRL followed by a longer-term inhibitory phase, interpreted as centrally mediated and involving serotonergic mechanisms and subsequent dopaminergic modulation. Comparative work indicated stronger PRL effects for 5-MeO-DMT than for bufotenine or DMT, partly reflecting in vivo stability and blood–brain barrier transport differences. The review situates 5-MeO-DMT within a broader literature linking serotonergic psychedelics to promotion of neuroplasticity, noting Brain-derived neurotrophic factor (BDNF) as a key mediator: single-dose effects on serum BDNF have been observed with other psychedelics (LSD, ayahuasca), implying a plausible pathway for antidepressant-like actions. Immune and inflammatory regulation are proposed to occur via two main downstream mechanisms: neuroendocrine modulation (for example via PRL) and direct effects on immune cells and intracellular pathways mediated by 5-HT2A and sigma-1 receptor (Sig1R) signalling. Toad venom versus synthetic 5-MeO-DMT: Bufo alvarius secretion contains a complex mixture of pharmacologically active compounds (bufagins, catecholamines, bufotenine and other sterols). The authors note that clinical improvements reported in users of toad venom and synthetic 5-MeO-DMT have been similar, suggesting 5-MeO-DMT is the principal active therapeutic ingredient, but they emphasise that the variable and complex composition of venom complicates development and raises ethical and ecological concerns about toad extraction. Emerging clinical development and safety signals: Reckweg and colleagues and other groups have registered early clinical studies of inhalable and intranasal formulations; two clinical studies on inhalable formulations were reported as completed and safety data have been published. Early clinical observations suggest cognitive and psychomotor function return to baseline quickly after the short-lived psychoactive period and adverse events are generally mild and transient, although details of trial designs and outcomes are limited in the extracted text.
Reckweg and colleagues interpret the assembled literature as providing a signal that 5-MeO-DMT may have therapeutic utility in mental health, principally because it can reliably induce intense "peak" or mystical experiences that observational and prospective studies have associated with rapid improvements in measures of depression, anxiety, stress and wellbeing. They highlight a mechanistic plurality: psychological effects (the intensity of acute subjective experience as a predictor of outcome), neuroplastic and neurotrophic effects (BDNF-related pathways), neuroendocrine modulation (notably biphasic prolactin effects), and immunoregulatory actions mediated via 5-HT2A and Sig1R as plausible contributors to therapeutic outcomes. The authors position 5-MeO-DMT as potentially advantageous compared with longer-acting psychedelics because of its rapid onset and short duration, which could lower treatment time and cost and allow for practical dose-escalation strategies when a first exposure fails to elicit a peak experience. They also note translational research avenues, including comparisons with non-hallucinogenic analogues derived from 5-MeO-DMT chemistry (for example tabernanthalog) that produced pro-plasticity and anti-addictive effects in rodents, raising the possibility of separating psychoplastogenic benefits from subjective effects. Key limitations and uncertainties acknowledged include the predominance of observational, survey-based and small naturalistic cohorts rather than large, controlled clinical trials; heterogeneity in dosing, route, and context in field reports; variable composition of toad venom; incomplete understanding of the relative contributions of 5-HT1A versus 5-HT2A signalling to subjective and therapeutic effects; and insufficient evidence for endogenous production or physiological roles of 5-MeO-DMT in humans. The authors call for both commercially funded clinical development to bring standardised formulations into trials and independent academic research to probe basic neurophysiological mechanisms, emphasising that fundamental studies are less likely to be covered within industry programmes. They also reiterate ethical and ecological concerns about relying on toad venom as a source and prefer synthetic formulations for drug development. Overall, the discussion frames 5-MeO-DMT as an intriguing short-acting psychedelic with preliminary human and preclinical signals warranting further controlled investigation, while cautioning that robust mechanistic and clinical evidence is still required before clinical adoption.
Introduction 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring tryptamine that can be found in seeds, bark and leaves of a number of plants in the Amazonian rainforest. Small amounts of 5-MeO-DMT have been traced in seeds of the Virola and Anandenantera peregrine (i.e. yopo, cohobo, rapé) and in while barks or leaves of plants such as Dictyoloma incanescens. Typically such plant materials also contain other indole alkaloids such as N,N-dimethyltryptamine (DMT). 5-MeO-DMT is an entheogen of which indigenous use for shamanic purposes, tribal ceremonies and healing rituals in South America and the Caribbean has been suggested, but strong evidence is lacking. There are also reports of the use of Mucana pruriens seeds that contain small amounts of indole alkaloids including 5-MeO-DMT, as an aphrodisiac in Indian and Mexican cultures. 5-MeO-DMT has also been identifiedas the primary psychoactive component of the parotoid gland venom of Bufo alvarius (Incilius alvarius), the Sonoran Desert toad, where it accounts for about 20-30% of its dry weight. The venom of the Bufo alvarius also contains bufotenine) from which 5-MeO-DMT is converted through O-methyl transferase). The first published analysis of the venom of Bufo alvarius appeared in the nineteen-sixties, which may have triggered experimentation with the toad's venom in Western cultures. In 1984, an underground pamphlet (see Figure) titled 'Bufo Alvarius, the Psychedelic Toad of the Sonoran Desert'appeared. It was seemingly the first guide for collecting, drying and smoking the venom of the Sonoran Desert toad. It created an opportunity for researchers and psychonauts, and its popularity as a psychedelic spread quickly. It has been speculated that 5-MeO-DMT might also be endogenously produced in humans because its derivative bufotenine (5-OH-DMT) and its structural analog N,Ndimethyltryptamine (DMT) have been detected in urine, blood, and cerebrospinal fluid. Other studies have contradicted these findings however) while a pooled analysis indicated that such markers were only present in limited fractions of study participants. One study also showed the presence of indoleamine precursors of 5-MeO-DMT in the pineal gland in rats, while in vitro work on human pineal extract suggested that 5-MeO-DMT can be synthesized through further methylation of the precursor 5-methoxytryptamine (5-MeOT) or bufotenine. Further evidence to support the notion of endogenous production of 5-MeO-DMT and its potential physiological function in humans is needed.
Two receptor binding studies based on human cloned receptors mutually revealed that 5-MeO-DMT is primarily a non-selective serotonin (5-HT) receptor agonist, while additional binding to the 5-HT-transporter and dopamine receptorsor the noradrenergic transporter) may contribute to its action. Both studies converged on the finding that 5-MeO-DMT has the highest binding affinity for the 5-HT1A receptor (i.e. 1.9-3 nM) and a 300-1000 fold higher selectivity as compared to the 5-HT2A receptor. This is noteworthy, as for most psychedelics the functional and experiential effects in humans appear to be mediated primarily via activation of the serotonergic 5-HT2A receptor. 5-HT1A receptors have been implicated in mood regulationand the control of the autonomic nervous system. Specific stimulation of 5-HT1A receptors produces sympathoinhibition and decrease blood pressure and heart rate, whereas ligation of 5-HT2A receptors produce sympathomimetic effects such as increased heart rate, vasomotor tone and blood pressure. Preclinical studies showed that some 5-MeO-DMT induced behaviors such as decreased locomotor activity, investigatory behavior and disturbed thalamo-cortical oscillations are selective to 5-HT1A receptor activation as these can be attenuated by a selective 5-HT1A antagonist but not by the 5-HT2A antagonist. Other autonomous effects of 5-MeO-DMT such as hyperthermia can be attenuated both by 5-HT1A and 5-HT2A receptor antagonists. 5-MeO-DMT induces a signature head twitch response in animals that is common to all psychedelics and that can only be blocked with 5-HT2A antagonists. Other behavioral effects of 5-MeO-DMT in preclinical studies, including locomotor activity and exploration, sensorimotor gating, and those associated with 5HT behavioral syndrome, appear to be primarily modulated by 5-HT1A , although 5-HT2A activation is involved involved. 5-MeO-DMT is primarily inactivated through a deamination pathway mediated by monoamine oxidase A (MAO-A), and it is O-demethylated by cytochrome P450 2D6 (CYP2D6) enzyme to produce an active metabolite, bufotenine). The latter binds with higher affinity to the 5-HT2A receptor than 5-MeO-DMT) and also displays high affinity for the 5-HT1A receptor. Concurrent use of 5-MeO-DMT with drugs or plants containing a MAO inhibitor (MAOI) can block its biotransformation and increase exposure to 5-MeO-DMT leading to enhanced and prolonged behavioral effects or even to hyperserotonergic effects. A summary of the biotransformation of 5-MeO-DMT and bufotenine and their affinity for 5-HT1A and 5-HT2A receptors is given in Figure.
Effects following administration of 5-MeO-DMT are similar to those of other tryptamine psychedelics such as psilocybin and DMT and are known to include a diverse set of acute subjective effects including visual, auditory and time perception distortions, emotional experiences and memory impairment. 5-MeO-DMT is known to induce intense mystical-type or 'peak' experiences, as well as feelings of ego dissolution. Components of a mystical experience typically involve an authoritative sense of unity or connectedness accompanied by feelings of reverence, positively valenced feelings such as love or peace, alterations to the sense of both time and space, and difficulty with putting the experience into words. Reports of ego-dissolution are often described as a sense of oneness with the universe or the experience of relaxed boundaries between the self and the world. The 5-MeO-DMT experience contrasts with the DMT experience, as the latter is known to produce particularly vivid and complex visual imagery rather than marked egodissolution. Inhalation of smoked or vaporised secretion from the Incilius alvarius toad (50 mg of bufotoxin, estimated 5-MeO-DMT content 5-7 mg) has been found to occasion mystical experiences of similar in intensity to high-dose psilocybin, another psychedelic tryptamine popularly found in "magic mushrooms", but with a much shorter duration of action. Acute adverse effects include fear, sadness, anxiety, confusion, fatigue, crying, paranoia, trembling, vomiting, nausea, headache, pressure on the chest or abdomen and loss of body perception) Subacute effects include flashbacks, i.e. short re-experiencing of some of the subjective 5-MeO-DMT effects and reactivations, i.e. brief (in order of seconds) sensory disturbances such as flashes of light. Reactivations have been reported during the week after 5-MeO-DMT exposure, and may occur more frequently after vaporization as compared to intramuscular administration. Of particular importance, the reactivation phenomenon has been reported primarily as a positive or neutral experience from large samples of recreational and ceremonial users. Rare cases of psychosis have also been reported), sometimes when used in combination with other tryptamines. 5-MeO-DMT is orally inactiveas it is rapidly metabolized by monoamine oxidase enzymes in the gut and liver. Therefore, 5-MeO-DMT is usually administered parenterally through smoking or inhalation of vapor or less commonly via intravenous, intramuscular, rectal, sublingual or intranasal applications. Smoking and vaporization are the most popular routes of administration because these are relatively easy and accessible and well documented in unofficial user guides. Observational research has demonstrated that smoking/inhalation of 5-MeO-DMT vapor causes a very rapid onset of subjective effects, reaching peak effects in a matter of seconds) and lasting for 15-20 minutes. In observational studies, 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, experiences characterized by disruption of self-world boundaries, and feelings of unity with others' and one's surroundings. The magnitude of the experience however may vary considerably between individuals, as about 20-30% of participants in 5-MeO-DMT ceremonies reported a low to medium psychedelic experience. This variability in psychedelic experience may have been caused by differences in doses administered at ceremonies, inhalation techniques, and the actual concentration of 5-MeO-DMT used by different facilitators. Conversely, intramuscular injection (IM) has been reported to produce a slower onset of subjective effects, beginning between 1 and 6 minutes after injection, and lasting for up to 60 minutes. Subjective reports suggest that subjective experiences after IM administration are more gentle, more gradual and less intense as compared to vaporized 5-MeO-DMT, and produces less reactivations, which are flash-memories of the 5-MeO-DMT experiences that can occur infrequently during 1-2 weeks after an experience with 5-MeO-DMT. In his book "The Toad and The Jaguar", Ralph Metzner summarized field and underground reports on the subjective effects of 5-MeO-DMT when administered intranasally. Intranasal administrations of 5-MeO-DMT purportedly induce a slower onset (i.e., 5-7 minutes) of subjective effects due to delayed absorption of the material through the mucus membrane. Dissociative effects of intranasal administrations are reportedly less pronounced, but more prolonged (i.e. 45-60 minutes) as compared to smoking or vaporization. Snuffing synthetic 5-MeO-DMT into the nasal passage was associated with mild and transient burning sensations, while snuffing of toad secretion, was noted to be toxic and quite unpleasant. Conceptually, all formulations (smoked, vaped, IM, intranasal, intravenous) allow for a high bioavailability of 5-MeO-DMT because they avoid first pass metabolism, with intravenous formulations providing maximal (100%) bioavailability. IM, intravenous, intranasal and vaped administration offer easy control of dose delivery as compared to smoking. IM and intranasal administration of 5-MeO-DMT produce a relatively gentle experience with a slow onset and longer duration, while smoked and vaporized administration provide fast onset of subjective experiences with high intensity and short duration. At present, biopharmaceutical companies with an interest in 5-MeO-DMT are exploring and developing vaporized, intranasal, IM and intravenous formulations for delivering 5-MeO-DMT (see Table).
Patterns of use, motivations for consumption and subjective experiences associated with 5-MeO-DMT use have been examined using a web-based retrospective survey (N=515) by Davis and colleagues. Findings revealed that respondents consumed 5-MeO-DMT infrequently, less than once a year, and less than four times in a lifetime, mainly for spiritual exploration. The majority (90%) reported moderate-to-strong mystical-type experiences (ineffability, timelessness, awe/amazement, experience of pure being/awareness), and relatively fewer (37%) experienced challenging experiences. Less than half (39 %) reported repeated consumption during the same session, and very few reported drug craving/desire (8%), or legal (1%), medical (1%), or psychiatric (1%) problems related to use. Prospective observational studies on the naturalistic use of 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, mindfulnessrelated capacities, and satisfaction with life, after a single inhalation of the substance. In the first prospective study with 5-MeO-DMT,) demonstrated that, compared to baseline, participants (n=42) reported reductions of depression, anxiety, and stress, as well as increases in mindfulness-related capacities and satisfaction with life, 24 hours post intake of toad venom containing 5-MeO-DMT. Such improvements in mood, mindfulness-related capacities, and life satisfaction were found to persist up to 4 weeks after intake. It was further found that participants who experienced higher levels of ego dissolution reported higher levels of satisfaction with life, and lower levels of depression and stress 24 hours after the drug experience. A follow-up study by the same group) demonstrated that mindfulness-related capacities were enhanced, and feelings of depression were reduced immediately after intake of synthetic 5-MeO-DMT compared to baseline (N=11). Seven days post intake, mindfulness-related capacities remained enhanced and feelings of anxiety and stress were significantly reduced compared to baseline). Again, it was found that the more of an acute experience of ego dissolution, the more of a decrease in feelings of depression, anxiety, and stress, and the more of an increase in mindfulness-related capacities, both directly after the session and at the 7-day follow up. Taken together, results from these two prospective studies demonstrate fast-acting, and in some cases immediate, improvements in mood in selfreported healthy volunteers, who ingested the substance in a naturalistic environment. Importantly, these studies also suggest a relationship between the strength of the acute psychedelic experience and the magnitude of persisting mood changes. Further observational studies have reported reductions in symptomology of a range of different diagnosed psychiatric disorders after ingestion of 5-MeO-DMT.) employed a cross-sectional survey to characterize patterns of use, and assess potential risks and benefits associated with 5-MeO-DMT use. Of the respondents that indicated to have been diagnosed with a psychiatric disorder, marked improvements were reported in the following conditions: PTSD (79%), depression (77%), anxiety (69%), substance use problems (63%), and obsessive compulsive disorder (53%), with a notably small proportion (2-10%) reporting a worsening of these conditions. In a separate cross-sectional survey, the same group) demonstrated similar reports of improvements in depression and anxiety conditions amongst respondents following 5-MeO-DMT use in a group setting. Namely, authors demonstrated that of those with depression (n=149), 80% reported an improvement in their conditions following 5-MeO-DMT use, whereas 17% reported no change in depression, and 3% reported a worsening of their depression. In those who had anxiety (n=173), 79% reported an improvement in their condition following 5-MeO-DMT use, whereas 19% reported no change in anxiety, and 2% reported a worsening of their anxiety. Similarly to the observational studies in healthy participants, Davis and colleaguesfound that the stronger the mystical experience, and the higher the ratings of spiritual significance and personal meaning of the acute 5-MeO-DMT experience, the higher the reported improvements in depression and anxiety. The authors further noted that out of the entire sample, only 7 individuals reported using 5-MeO-DMT specifically to help with their depression or anxiety, highlighting that the reported improvements of most respondents were unintended.
The full spectrum of the potential (neuro)physiological effects of 5-MeO-DMT in mammals is yet to be understood. Here, we will mainly focus on two, therapeutically relevant physiological domains: the neuroendocrine and immunological effects of this indolealkylamine hallucinogen. We will first discuss the possible neuroendocrine effects of 5-MeO-DMT on mammalian physiology. Then we will focus on the consequences of its administration in inflammatory regulation and immune functions in preclinical and observational studies.
Initial studies in the late 70's and early 80's focused on the effect of 5-MeO-DMT on luteinizing hormone (LH) and prolactin (PRL) release by the pituitary gland in rodent models). These early studies mapped the in vivo effects of 5-MeO-DMT administration on the level of neuroendocrine factors involved in the regulation of hormonal cycles, metabolism, and systemic immune functions. While 5-MeO-DMT did not affect LH and estrogen levels, it strongly promoted the release of PRL in rats. The onset of this stimulatory effect on PRL response was slow and gradual, possibly due to the sensitization of pituitary-related serotonergic mechanisms. Later, a biphasic effect of 5-MeO-DMT on PRL secretion was described that involved the originally observed, initial, secretion-stimulating effect followed by an inhibitory effect on PRL release in the long run. The initial pro-secretory effects of 5-MeO-DMT was hypothesized to be due to its ability to activate postsynaptic 5-HT receptors. On the other hand, the subsequent inhibitory effect on PRL-secretion was found to be based on increased functional activity of tuberoinfundibular dopamine neurons. Furthermore, Seeman and Brown) also compared the neurohormonal effects of 5-MeO-DMT with two other, close tryptamine analogs, bufotenin and DMT. They found that the most potent pro-secretory effects on PRL levels were observed in case of 5-MeO-DMT administration, followed by bufotenin, and finally by DMT. This latter phenomenon was, at least partly, due to the different in vivo stability of these tryptamines, as well as individual characteristics related to their intraparenchymal transport via the blood-brain barrier. Another important message of these early animal studies was that the observed, 5-MeO-DMT-mediated neuroendocrine response was centrally mediated, and did not involve activation of peripheral 5-HT receptors. An important aspect of the possible therapeutic use of serotonergic tryptamines is their modulatory effect on neuroplasticity. Neuropsychiatric diseases, such as major depressive disorder (MDD), anxiety, PTSD, or addiction have high comorbidityand share common underlying neural principles. A plethora of previous reports suggest that decreased neuroplasticity, and neural atrophy in the prefrontal cortex (PFC) play an essential role in the general pathophysiology of these disorders. These disruptive structural changes in the PFC could be rectified by compounds that can promote structural and functional neural plasticity. In essence, such compounds would provide a general solution to treating all of these related disorders. Serotonergic psychedelics, entactogens One of the key neuroplasticity-modulating neuroendocrine factors is Brain-derived neurotrophic factor (BDNF). BDNF is a crucial neurotrophin that is involved in both the maintenance of brain homeostasis and in multiple neuropathologies. Multiple evidence suggests that psychedelics and related compounds could prove useful in the effective modulation of BDNF/neurotrophin levels, and thus in the alleviation of the physiological, behavioral, and cognitive symptoms of several neurodegenerative disorders. A single, low dose of LSD was shown to acutely increase BDNF levels in healthy volunteers. Likewise, a doubleblind randomized placebo-controlled ayahuasca clinical trial reported the modulation of BDNF in patients with MDD. The authors reported significant modulation of serum BDNF by a single dose of ayahuasca, which suggests a link between the previously observed antidepressant
To understand the potential effects of 5-MeO-DMT on immune homeostasis, we need to consider two major, downstream effector mechanisms that may alter the inflammatory/immune status of the organism as a consequence of indolealkylamine administration. These two proposed major mechanisms are i) the influence of 5-MeO-DMT on systemic neuroendocrine regulation; and ii) its modulatory effect on immune cells, and on inflammatory and immunerelated intracellular pathways via 5-HT2A and Sig1R. In the following, we will discuss these two effector mechanisms in detail by reviewing the available literature to date. As discussed above, 5-MeO-DMT has a formidable modulatory capacity in promoting PRL release via central 5-HT receptors. This effect appears to be biphasic in rodent models with increased serum PRL levels in early-acute phase, and gradually decreased levels in the long run. PRL is involved in multiple physiological processes including the regulation of metabolism, cellular growth and apoptosis, as well as immune functions. Initially, PRL was considered to be an immunostimulatory factor with potential deleterious effects in autoinflammatory and autoimmune pathologies, as hyperprolactinemia was a signature biomarker in different autoimmune diseases). In the last decade however, this common view has been challenged by findings demonstrating that PRL has no effect on the symptom development and severity of experimental autoimmune encephalomyelitis, a standard animal model for multiple sclerosis, and can even be protective in rheumatoid arthritis. Moreover, recent Core to the psychological perspective is the notion that 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). This notion is also shared by patients treated with psychedelics, who acknowledge the importance of acute subjective effects in therapeutic outcomes as documented in qualitative interviews. A recent review of twenty studies assessing the clinical response to psychedelics in patients with addictive disorder, treatment-resistant depression and obsessive-compulsive disorder provided further support and concluded that the main predictive factor of a response to a psychedelic is the intensity of the acute psychedelic experience). This conclusion also seems in line with results from the 2 observational studies on 5-MeO-DMT Likewise, anti-inflammatory and immune effects as observed with 5-MeO-DMT) and other psychedelicsor increased expression of neurotrophic factors may contribute to the therapeutic effect of psychedelics as well. The neurophysiological perspective attaches more value to the quality of psychedelics to promote structural and functional neural plasticity in the brain through 5-HT2A receptormediated mechanisms) and considers psychedelic induced mystical experiences as biomarker of 5-HT2A receptor stimulation. It has been postulated that such neurobiological, or "psychoplastogenic", effects can be decoupled from the subjective effects of psychedelics through chemical design without losing therapeutic potential. It is interesting in the present context that an engineered prototype of such a nonhallucinogenic psychedelic is an analogue of 5-MeO-DMT, termed tabernanthalog. Tabernanthalog promoted structural neural plasticity, reduced alcohol-and heroin-seeking behaviour, and produced antidepressant-like effects in rodents, suggesting that it might be effective at treating a range of neuropsychiatric diseases and addiction. Future comparisons of the therapeutic effects of 5-MeO-DMT and tabernathalog in clinical studies will therefore be of particular interest when evaluating the ). As such, it is likely that psychedelic-assisted psychotherapy with these substances will be costly and time-consuming for both the patient and the practitioners. Here, a short-acting psychedelic such as 5-MeO-DMT would substantially lower treatment costs, resulting in a more financially accessible treatment option. As previously reviewed, the psychoactive effects of inhaled 5-MeO-DMT are immediate, reaching peak effects in a of seconds, and lasting up to 20 minutes. The preliminary therapeutic evidence, as well as the potential pharmacological advantages of 5-MeO-DMT versus other classical psychedelics, has proven intriguing to researchers and pharmaceutical companies alike, fueling a growing number of clinical trials which are currently in various stages of development (Table). At present, two clinical studies have been registered at ClinicalTrials.gov with the aim to establish safety of inhalable and intranasal formulations of 5-MeO-DMT in healthy volunteers. The inhalable formulation has also been administered to patients with treatment resistant depression in order to assess safety and efficacy. Both studies with the inhalable formulation have been completed and the safety data as collected in healthy volunteers were recently published). This On average, the duration of the psychedelic experience with 5-MeO-DMT was estimated to last for 15-20 minutes. After the psychoactive effects have worn off, both cognitive and psychomotor function also quickly return to baseline. Likewise, vital signs at 1 and 3 h after administration were not affected and adverse events were generally mild and resolved spontaneously. As well as attesting to the clinical cost-effectiveness of such a short-lasting psychedelic experience, the rapid dissolution of drug-induced cognitive and psychomotor dysfunction also suggests the safety of 5-MeO-DMT in relation to day-to-day operations requiring skilled performance, suggesting a less time-intensive procedure for patients as well. As such, the ability of 5-MeO-DMT to induce "peak" effects of similar intensity to highdose psilocybin, but in such a short amount of time, is a facet of the 5-MeO-DMT experience that is of particular therapeutic interest. Additionally, as demonstrated in Reckweg and colleagues, if a peak experience is not achieved upon first administration, a dose-escalation scheme can be safely employed in order to reliably induce such an experience. Thus there seems to be very little build-up of tolerance to the effects of 5-MeO-DMT, which is in contrast to other psychedelic substances.
The main difference between toad venom of the Bufo alvarius and synthetic 5-MeO-DMT is that the former contains a range of pharmacological active compounds in addition to 5-MeO-DMT. These include cardioactive agents such as bufagins (i.e. bufandienolides), catecholamines, such as epinephrine and norepinephrine, indolealkylamines, such as bufothionine, serotonin, cinobufotenine, bufotenine and dehydrobufotenine, and non-cardiac sterols, such as cholesterol, provitamin D, gamma sitosterol and ergosterol. 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. Although research into 'entourage' effects of toad venom would be of fundamental scientific interest, it is likely that the pharmacological constellation of toad venom is too complex and variable to be seriously considered as a target product for clinical drug development. Moreover, mental health improvements that have been associated with 5-MeO-DMT were similar for users of toad venom and synthetic versions of 5-MeO-DMT which suggest that 5-MeO-DMT is the primary compound with therapeutic potential. There are also ethical and ecological arguments not to pursue clinical development of In such a scenario, neurophysiological and psychological considerations of mental health changes observed after psychedelics do not have to be mutually exclusive and can offer complementary perspectives. In sum, clinical research on the therapeutic potential of 5-MeO-DMT seems justified as preclinical, observational and survey data provide a signal of its potential utility in mental health treatment. The rapid onset and short duration of the 5-MeO-DMT experience may render it more cost-effective as compared to longer acting psychedelics. A range of biotech companies have shown a particular interest in the production of 5-MeO-DMT formulations and drug development programs that can launch these formulations into clinical applications. Commercial development will therefore be the most important resource for bringing 5-MeO-DMT to the clinic in the near future. It should be noted however that fundamental research will be needed in addition in order to create understanding of the neurophysical and neural mechanisms that contribute to potential clinical effects of 5-MeO-DM. Such studies are less likely to be conducted as part of drug development programs and will depend more on independent, academic initiatives. --Human subjects --Involves human subjects: If yes: Informed consent & ethics approval achieved: => if yes, please ensure that the info "Informed consent was achieved for all subjects, and the experiments were approved by the local ethics committee." is included in the Methods. ARRIVE guidelines have been followed: No => if it is a Review or Editorial, skip complete sentence => if No, include a statement in the "Conflict of interest disclosure" section: "ARRIVE guidelines were not followed for the following reason: Not applicable " (edit phrasing to form a complete sentence as necessary). => if Yes, insert in the "Conflict of interest disclosure" section: "All experiments were conducted in compliance with the ARRIVE guidelines." unless it is a Review or Editorial
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