Benefits and Challenges of Ultra-Fast, Short-Acting Psychedelics in the Treatment of Depression

5-MeO-DMT and DMT are naturally occurring tryptamines that can be found in a range of Amazonian plant species (19–21). 5-MeO-DMT has also been identified as the primary psychoactive component of the parotoid gland venom of Bufo alvarius, the Sonoran desert toad (22). The psychedelic experience induced by 5-MeO-DMT and DMT is known to differ. DMT has been reported to elicit a dynamic and rich visual experience, sometimes accompanied with sentient encounters or the sense of visiting other worlds (17, 23–26). Subjective experiences with 5-MeO-DMT are often reported to be emotional and devoid of any visuals other than the experience of a “profound white light” (13, 27, 28). Both psychedelics have been associated with a feeling of “ego death” that is characterized by a dissolution of one’s sense of self and, in the case of 5-MeO-DMT, loss of memory (13, 17, 27, 28). Both 5-MeO-DMT and DMT can produce spiritual experiences with altered-self-awareness that are described as overwhelming and profound (13, 23–25, 27, 28).

Both compounds display binding affinities for a wide range of monoamine receptors and transporters, but mostly so for serotonergic receptors. Receptor binding affinities of 5-MeO-DMT and DMT are listed in Table 1 and discussed below. It is suggested that the primary target of psychedelics, including 5-MeO-DMT and DMT, which underlies their psychedelic effect, is the serotonin 5HT_2A receptor (11, 13, 17, 29), but contributory roles of additional receptors, such as 5HT_1A, cannot be excluded (17, 30–32). Receptor binding studies indeed have shown a stronger selectivity of 5-MeO-DMT for the 5HT_1A receptor as compared to the 5HT_2A receptor, suggesting a selectivity ratio that is substantially higher than for DMT and other psychedelics (30, 32–34). Computational docking analysis further confirmed a stronger interaction of 5-MeO-DMT at the 5HT_1A receptor compared to the 5HT_2A receptor (32). The strong affinity of 5-MeO-DMT for 5HT_1A might be very relevant as 5HT_1A agonists have been implicated in the treatment of anxiety and depression (35). The functional relevance of the 5HT_1A receptor for the behavioral effects of 5-MeO-DMT has been suggested in rodent studies which have shown a stronger reduction of drug discrimination effects under 5-MeO-DMT in the presence of a 5HT_1A antagonist as compared to a 5HT_2A antagonist (36–38). Likewise, changes in cortical activity following 5-MeO-DMT in normal and 5HT_2A knock-out mice were reversed by 5HT_1A antagonists (39, 40). Agonism at inhibitory 5HT_1A receptors is often antagonistic to agonism of 5HT_2A receptors which elicit excitatory effects (35, 41, 42). However, the opposite has been shown in that 5HT_1A blockade increased 5-MeO-DMT induced head twitch responses in mice, a preclinical measure of hallucinogenic effects (32). In humans, blockade of the 5HT_1A receptor increased the intensity of the psychedelic experience induced by DMT (23) suggesting a modulatory interplay between the 5HT_1A and 5HT_2A receptors during a psychedelic experience. Yet, the functional and contributory role of the 5HT_1A receptors to the phenomenology of the psychedelic experience as observed with short-acting psychedelics remains poorly understood and needs further exploration. Likewise, the contributory roles of dopaminergic, adrenergic and sigma-1 receptors (30, 33, 43) and possibly trace-amine-associated (TAAR) receptors (44) to the acute psychedelic effects of 5-MeO-DMT and DMT are not clear.

A range of dose-finding studies in healthy volunteers has been conducted to determine safety of 5-MeO-DMT and DMT, often with the aim to determine a dosing regimen for future trials in patient populations. These trials are discussed below and summarized in Table 2. Typically, the route of administration and the dosing regimen employed in these studies has varied. In the case of 5-MeO-DMT most research so far has focused on inhaled (13, 45) and intranasal (46) formulations, but IV formulations are currently under development as well (13). The first study of its kind (45) aimed to assess the impact of a novel vaporized 5-MeO-DMT formulation (GH001) administered via inhalation as single doses of 2, 6, 12, or 18 mg, and in an individualized dose escalation regimen, on the safety, tolerability, and the psychoactive experience in five groups of healthy volunteers. The individualized dosing regimen (IDR) consisted of 6, 12, and 18 mg, where at least one and up to three doses of 5-MeO-DMT interspaced at 3 hours were given on a single day. The decision to move on to the next dose was guided by an evaluation of whether the participant achieved a peak psychedelic experience (i.e., mean subjective ratings of intensity, profoundness and loss of control equal or over 75% on a peak experience scale), at the previously administered dose. If no peak experience was achieved, the next dose was administered, after consultation with and consent from the participant. The aim of the individualized dose escalation was to maximize the intensity of the psychedelic experience across participants, as previous research with other psychedelics has indicated that the stronger the intensity, the better the therapeutic outcome (47, 48). Single doses of 5-MeO-DMT produced instant, short-acting, dose related increases in the intensity of the psychedelic experience ratings that lasted for 15–20 minutes. Up to 50% of the participants in the single dose regimens reported a peak psychedelic experience, whereas that number rose to 100% of the participants that received an individualized dose escalation of 5-MeO-DMT. The duration of the psychedelic experience as estimated by the participants was about 18 minutes. Psychedelic experiences following single, intranasal administrations (range 1–12 mg) of 5-MeO-DMT (BPL-003) appeared instantly and lasted up to 90 minutes (46). The onset, length, and intensity of the experience closely followed plasma concentration time curves of 5-MeO-DMT. Yet, the intensity of the psychedelic experience following a single intranasal dose varied considerably between individuals, as was also shown after inhalation of 5-MeO-DMT (45)

In the case of DMT, most studies have focused on IV-formulations (18, 49–52), the oldest dating back to 30 years ago (24, 53, 54). One study has also focused on inhaled administration (55) and another on the combination of oral DMT and a harmaline MAO inhibitor (56). The duration of the psychedelic experiences varied with the IV infusion rate and between dose formulations. In the case of IV-administration, the rate of infusions varied between 30 seconds and 90 minutes. Short duration infusions of up to 30 or 60 seconds (24, 49, 53, 54) produced a psychedelic experience that lasted up to 30 minutes, while infusion of 11 minutes (50, 51) and 90 minutes (18) extended the experience to 40 and 105 minutes, respectively. Inhalation of two subsequent doses of DMT (55) produced psychedelic effects for up to 20 minutes per dose, whereas 10 intermittent oral doses of DMT combined with a harmaline MAO inhibitor to inhibit degradation of DMT produced psychedelic effects that lasted up to 4–5 hours (56). The total dose of DMT administered in these healthy volunteer studies has also varied considerably because of differences in route and rate of administration as is shown in Table 2.

Adverse events following acute administrations of 5-MeO-DMT and DMT in clinical trials were generally mild and resolved spontaneously (18, 24, 25, 45, 49–51, 53, 54, 57, 58). Both compounds produced transient increments in blood pressure and heart rate during the psychedelic experience. The most frequently reported adverse events included anxiety, nausea and headache. Subacute effects of 5-MeO-DMT, occurring in the days following dosing, included flashbacks or reactivations, i.e., brief (in the order of seconds) and benign sensory re-experiences of 5-MeO-DMT (45, 59). Reactivations following 5-MeO-DMT have also been reported in non-clinical settings (60–62). These studies mostly suggest a neutral or positive valence of this phenomenon (61, 62) and a lower prevalence after intramuscular as compared to inhaled use (60). The mechanism underlying sub-acute reactivations is unknown. It has been speculated that reactivations could reflect temporary epileptoform activity related to the distinct selectivity of 5-MeO-DMT for the 5HT_1A receptor (63). However, current data suggest a beneficial role of 5HT_1A stimulation in most preclinical epilepsy models (64) and patients with temporal lobe epilepsy (64–67). Preclinical work in cats showed that 5-MeO-DMT significantly suppressed photically induced myoclonus, suggesting antiepileptic properties (68). It might be the case however that the phenomenon of reactivations is more typical for 5-MeO-DMT than for other psychedelics.

Although psychedelic experiences as such are typically not reported as adverse events in clinical trials it should be noted that both 5-MeO-DMT and DMT can produce intense negative emotions or adverse physical effects as part of the experience (13, 26, 29, 69). Intense psychedelic experiences always carry the risk of producing psychological distress, although these are also often reported to be cathartic (70). This appears to be the case for psychedelics in general, in that intense psychedelic experiences, even when negative, are associated with enduring increases in well-being (71) or a reduction in psychopathology (48). It is noteworthy in this regard that individuals that were exposed to an intense psychedelic experience with 5-MeO-DMT or DMT in clinical trials scored relatively low on the challenging experience questionnaire (45, 56, 59). Psychological experiences with 5-MeO-DMT and DMT are however difficult to predict, as with any psychedelic, and rare psychotic reactions can occur (72–74). The risk of psychosis or negative experiences should be reduced with psychiatric screening and the exclusion of patients with a predisposition towards psychotic illnesses from clinical treatment with psychedelics, by careful preparation and anticipation of the psychedelic experience, and by establishing trust and rapport between the session monitor and study participants in a safe environment (75).

Preliminary indications for the therapeutic potential of 5-MeO-DMT and DMT mostly come from prospective observational studies on the naturalistic use of smoked 5-MeO-DMT (synthetic or toad venom) and DMT containing brews such as ayahuasca. These studies demonstrated immediate (within 24 hours) and lasting improvements (i.e., up to 4 weeks) relative to baseline, in self-reported ratings of depression, anxiety, stress, mindfulness-related capacities, and satisfaction with life, after a single administration of the substance in healthy volunteers (21, 76–81) and depressed patients (82). Naturalistic studies also come with notable limitations, such as the lack of dose information, lack of control groups, and high drop-out rates. Yet, persisting improvements in mood and attitude towards life have also been observed in healthy volunteers at 1 and 4 months after participation in a placebo-controlled trial with intermittent intranasal dosing of DMT (100 mg) combined with harmine (56). Likewise, a placebo-controlled, prospective study in healthy volunteers reported improvements in ratings of depression at 1–2 weeks following IV DMT doses (7–20 mg) (83).

To date, a limited number of early clinical trials have assessed the potential for antidepressant efficacy of 5-MeO-DMT and DMT in small samples of depressed patient populations. These are discussed below and summarized in Table 3. The first placebo controlled trial was conducted in 29 patients suffering from treatment resistant depression (TRD) and demonstrated the clinical utility of ayahuasca to rapidly decrease symptoms of depression by more than 50% at 1 and 7 days after treatment (84) as rated with the Hamilton Depression Rating Scale (HAM-D). On day 7, 43% of the patients were in remission. It should be noted however that therapeutic indications observed for ayahuasca brews do not exclusively generalize to DMT. Ayahuasca brews also contain β-carboline alkaloids such as harmine, harmaline, and tetrahydroharmine (85). The latter are monoamine oxidase inhibitors (MAOI) allowing DMT to reach the central nervous system for a prolonged period of time (86) and that have an accepted clinical utility as antidepressants by themselves (87, 88).

The first exploratory study (49) to assess the therapeutic potential of DMT in patients (N=7) with major depression disorder (MDD), reported a significant mean decrement (−4.5 HAM-D score) in symptoms as compared to baseline, the day after an IV DMT administration of 0.3 mg/kg (about 21 mg for a person of 70 kg). The antidepressant effect was relatively small, only a 19% symptom reduction from baseline, possibly because the doses were relatively low. A larger antidepressant effect was reported in a Brazilian trial in which patients suffering from TRD (N=6) where treated with two subsequent doses of inhaled DMT (15 mg and 60 mg) (89). Response rates (i.e., a reduction of 50% or more from baseline) at 1 and 7 days after treatment were 83.33% as assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS). At 1 month after treatment the response rate was 66.67%. Remission rates at 7 days and at 1 month after treatment were 66.67% and 50% respectively. None of these studies provided pharmacokinetics of DMT, which makes it difficult to compare the bioavailability of IV and inhaled formulations. Subjective ratings of the psychedelic experiences in both DMT studies suggest however that the intensity was higher after the inhaled dose formulation (84.15%) as compared to the IV formulation (55.83%) as assessed on visual analogue scales.

Potent and rapid antidepressant effects of a vaporized 5-MeO-DMT formulation (GH001) were demonstrated in a clinical phase 1/2 trial involving 16 patients with treatment resistant depression (59). The trial investigated two single dose levels (12 and 18 mg) of 5-MeO-DMT and an individualized dosing regimen with up to three increasing doses (6, 12, and 18 mg) of 5-MeO-DMT within a single day, with a primary endpoint of efficacy in the IDR group, as assessed by the proportion of patients in remission (i.e., MADRS ≤10) 7 days after treatment. The proportion of patients in remission at day 7 were 50% and 25% in the 12 mg and 18 mg groups respectively, and 87.5% in the IDR group. In this group, seven out of eight patients achieved a peak experience, six after the second administration (6 mg and 12 mg doses), and one after the third administration (6 mg, 12 mg, and 18 mg doses). All remissions were observed from day 1, and 60% of remissions were already observed 2 hours after treatment. The subjective, mean intensity of the psychedelic effect in the IDR group was around 90% as assessed with a peak experience scale.

Clinical studies in depressed patients thus have suggested that 5-MeO-DMT and DMT induce a therapeutic response within 24 hours that persists for at least 1 week (59) and 1 month (89) respectively. It is unknown at present how long the therapeutic effects of 5-MeO-DMT and DMT will last. It is to be expected that therapeutic efficacy of ultra-fast, short-acting psychedelics will not last forever, and that patient relapse rates will start to increase over weeks and months, just as has been previously observed after treatments with traditional antidepressants (90), ketamine (91), psilocybin (6), and ECT (92). Future trials with 5-MeO-DMT and DMT should therefore be designed to treat depressed patients over longer time intervals of 6–12 months, to establish the duration of the therapeutic response, and to probe the feasibility and efficacy of treatment re-dosing in case of patient relapse. Such studies can provide insights into how to prolong and extend the rapid acting benefits of ultra-fast, short-acting psychedelics in the treatment of depression.

A principal advantage of ultra-fast, short acting psychedelics is that they allow for repeated dosing in a single session in order to achieve dose optimization for individual patients in a clinical setting. Individualized dosing regimens might allow for a reduction in inter-individual variations in subjective (93, 94) and therapeutic responses (47, 95) to a psychedelic that have been observed after a fixed dose. Inter-individual variations in the response to a psychedelic might result from biological variations in 5HT_2A receptor binding (96), drug metabolism (97), as well as from variations in subjective expectations (98, 99). Yet, the intensity and quality of the psychedelic experience may be relevant, because positive associations between the intensity of psychedelic experiences and therapeutic effects in patients with depression have been reported in a range of clinical trials (47, 48, 84, 95, 100, 101), though not all (9).

These data therefore suggest that individualized dose escalation of ultra-fast, short acting psychedelics may be best suited for clinical applications that aim to maximize the psychedelic experience to elicit a strong therapeutic response. So far, individualized dose escalation regimens have only been considered as part of treatment protocols for 5-MeO-DMT. In these protocols, successive, dose escalation steps were offered to healthy volunteers and patients with treatment resistant depression with the aim to increase dosing up until an individual achieved a maximal “peak” psychedelic experience (45, 59). In healthy volunteers, individualized dose escalations of a vaporized formulation of 5-MeO-DMT (GH001) consistently produced peak psychedelic experiences while the intensity of the subjective response to a single dose administration was more variable (45). Similar associations between dose regimens of 5-MeO-DMT (GH001) and the intensity of the psychedelic experience have been reported in patients with treatment resistant depression (59). More importantly, a larger fraction (87.5%) of patients that received an individualized dose escalation of vaporized 5-MeO-DMT to elicit a peak experience achieved remission as compared to the fraction of patients (25%–50%) who achieved remission after a single dose (59). These data support the notion that intensity of the psychedelic experience is predictive of the therapeutic response and can be employed as a subjective marker to guide individualized dosing regimens.

Two DMT trials in depressed patient populations also employed dose escalations that were either spaced 48 hours (49) or 90 minutes (89) apart. Dose escalations were fixed and did not allow for flexible, personalized treatment. In the first study (49), dose escalation only generated a moderate intensity of the psychedelic experience, possibly because the doses were relatively low and widely spaced apart. Yet, response (83.33%) and remission (66.67%) rates in the second study (89) at 7 days after dosing were not so much different from response (100%) and remission (87.5%) rates observed with IDR treatments with 5-MeO-DMT at 7 days after dosing (59). Likewise, as previously indicated, the mean intensity of the psychedelic experience achieved in both studies appears similar. This suggests that fixed incremental dose regimen might also beneficially affect treatment outcome. The gradual transition from low to high doses in dose escalation regimens possibly enables patients to mitigate their fear and increase their confidence to proceed to the next dose level, and thereby provide a smoother entry into a full dose psychedelic experience. The importance of a positive mindset for the quality of a psychedelic experience has been well documented and might add to the antidepressant effects of psychedelics (99, 102). Large patient studies that allow comparisons between single and incremental dose regimens and assess mindset and quality of the psychedelic experience at each dose step will be needed to disentangle potential pharmacological and non-pharmacological aspects of dose escalation regimens.

Tolerance and sensitization are neuroadaptive processes characterized by a rapid decrease and increase respectively in responsiveness after repeated exposure to a given drug. Rapid tolerance (also called tachyphylaxis) to the autonomic and psychological effects of a psychedelic has been shown to occur in humans after a few moderate daily doses of LSD, but sensitivity to LSD also quickly reversed after 1 or 2 days of discontinuation (103). Tolerance and cross-tolerance have also been demonstrated with other classical psychedelics such as psilocybin and mescaline in animal models of psychedelic action (104), and several studies have shown that rapid tolerance to psychedelics correlates with downregulation of 5HT_2A receptors (11) or glutamate binding sites (105). However, tolerance to the behavioral effects of DMT appears less pronounced in humans. The intensity of the subjective psychedelic experience of intravenous 0.3 mg/kg DMT in healthy volunteers did not change over four successive administrations on a single day, whereas physiological reactivity decreased (53). An indication of moderate acute tolerance was observed in a study with continuous DMT administration in healthy volunteers, where subjective effects of DMT remained stable during 90 minutes of infusion, despite increasing plasma concentration (18). In animals, chronic administration of 5-MeO-DMT (2 mg/kg i.p., every 30 minutes for 4 hours) produced a rapid tolerance to the behavioral effects of the drug and reduced the duration of the effect from 14.9 minutes to 1.2 minutes (106). Tolerance, however, totally disappeared within 4 hours following termination of 5-MeO-DMT treatment (106). In humans, 12 mg and 18 mg of 5-MeO-DMT preceded by 6 mg or by 6 mg and 12 mg, respectively (all interspaced at 3 hours), consistently produced more intense psychedelic peak experiences as compared to single doses of 12 mg and 18 mg (45, 59). These differences may simply be accounted for by inter-individual variations in reactivity to 5-MeO-DMT but may also hint in the direction of increased sensitization. The latter may arise from experience learning and decreased anxiety after exposure to the first dose of 5-MeO-DMT and increased “openness” for a subsequent dose. In theory, sensitization may also result from 5HT_2A receptor upregulation, but no study so far has evaluated 5HT_2A receptor density in humans after exposure to repeated doses of 5-MeO-DMT. Sensitization to the psychedelic action of 5-MeO-DMT was demonstrated however in mice (i.e., enhanced head-twitch responses) with prior exposure to electroconvulsive shocks that caused 5HT_2A receptor upregulation (107). Overall, human studies designed to assess tolerance and sensitization following closely interspaced doses of 5-MeO-DMT and DMT are scarce and need further investigation, but the clinical data so far seems to suggest that a solid psychedelic response can be maintained or achieved following close repetitions of ultra-fast, short-acting psychedelics.

Several neurobiological and psychological mechanisms have been implicated in the antidepressant response to treatments with classic psychedelics that are also relevant to 5-MeO-DMT and DMT.

Neuroimaging studies in major depressive disorder have revealed distinct pattern of hyperconnectivity and hypoconnectivity within the default mode network (DMN) and the frontal parietal network (FPN) respectively, as well as compromised cross-network connectivity of the salience network (SN) (108–110). A recent psilocybin trial in patients with major depression demonstrated post-treatment symptom relief to be associated with increased functional connectivity between these networks as defined by diminished network modularity (101). Studies in healthy volunteers also demonstrated a global increase in cross-network connectivity after treatment with classic psychedelics (111), including ayahuasca (112) and DMT (58). Ayahuasca increased DMN-SN connectivity and within network connectivity at 24 hours after dosing, while DMT acutely increased global functional connectivity (58). These data suggest that psychedelics may exert some of their antidepressant effects by increasing cross-connectivity of brain networks that are deficient in major depression. Whether specific actions of 5-MeO-DMT and DMT on brain function differ from long-acting psychedelics, however, is difficult to determine given that direct comparator studies are lacking.

Other mechanisms of action that have been implicated to contribute to the antidepressant response of psychedelics include the enduring increases in neuroplasticity (113) and immunomodulation (114) that can be observed post-treatment. A large number of reports suggest that decreased neuroplasticity, and neural atrophy in the hippocampus and the prefrontal cortex (PFC) play an essential role in the general pathophysiology of depression (115–118) and that structural repair can be stimulated with compounds that promote structural and functional neural plasticity (115, 119, 120). The neuroplasticity-promoting effects of several serotonergic psychedelics, including 5-MeO-DMT and DMT, have been reported in vitro (121, 122). In vivo, single dose injections of 5-MeO-DMT rapidly increased the proliferation of neural progenitors and their dendritic complexity in the dentate gyrus of mice (123). Likewise, activation of the innate immune system, as indicated by elevated blood levels of pro-inflammatory cytokines and acute phase proteins, is associated with major depressive disorder (124). In vivo studies have demonstrated that 5-MeO-DMT and DMT inhibit the production of pro-inflammatory cytokines (i.e., IL-1 beta, IL-6, TNF-alpha, and the chemokine IL-8), while increasing the secretion of the anti-inflammatory cytokine IL-10 (125). Anti-inflammatory action of 5-MeO-DMT was also shown in humans as indicated by a rapid decrease in salivary IL-6 levels after a single dose (78). In TRD patients, reductions in MADRS rating following treatment with ayahuasca were associated with increased levels of a potential marker of neuroplasticity, i.e., brain-derived neurotropic factor (BDNF) (126), and reductions in an inflammatory marker, i.e., C-reactive protein (127). Yet, definitive evidence supporting the contribution of increased neuroplasticity and immunomodulation to the antidepressant response induced by ultra-fast, short-acting psychedelics is currently lacking and should come from future clinical trials.

The antidepressant response to 5-MeO-DMT and DMT might however also be psychologically driven. Psychedelic experiences with 5-MeO-DMT and DMT, depending on the dose and formulation, have been reported to be very intense (18, 25, 45, 58, 59), potentially inducing an “ontological shock” that may lead to radical shifts in self-perception and increased psychological flexibility when coping with day-to-day stressors (79, 80). Psychedelic alterations in consciousness are characterized by a perturbation of self-referential processing, giving rise to subjective states where self-other boundaries disappear (128, 129). Anecdotal as well as clinical reports have suggested that the experience of intense subjective psychedelic effects can facilitate psychological shifts and insights in behavioral patterns and it has been argued that these are fundamentally important to an enduring therapeutic response with a psychedelic (130–132). Others have argued that psychedelic experiences are just epiphenomena of underlying neurobiological mechanisms that are truly driving the therapeutic response (133). Both perspectives are not necessarily mutually exclusive when explaining the therapeutic effects of 5-MeO-DMT and DMT.

Advanced results from clinical trials of psilocybin for depression suggest that regulatory approval of psychedelic therapy is within reach, which is why questions on the societal impact of psychedelics as they are scaled up to clinical practice have started to be raised. While economic analyses of cost-effectiveness and cost-benefits of psychedelic treatment versus traditional antidepressant treatment are lagging behind (134), high costs of current treatment models with psilocybin (6–10) that involve the presence of multiple therapists during lengthy dosing sessions and integrated (psycho)therapy (see Table 3 for a prototype example of a psilocybin treatment model), are anticipated to impede their accessibility. This has fueled a fundamental discussion on the need to combine psychedelic treatment with integrated therapy as their interactive contribution to the therapeutic outcome is primarily hypothesized (135, 136), but has not been rigorously tested (137). Inclusion of assisted therapy in clinical trials with psychedelics furthermore provides a challenging mixture for regulatory bodies that are traditionally asked to review efficacy of drugs rather than psychotherapy (138). It has been suggested therefore that psychological support during psychedelic treatment should primarily focus on safety rather than efficacy (139).

Challenges of scaling psychedelic treatment for clinical practice will also affect potential treatment programs with 5-MeO-DMT and DMT. Early patient studies, as shown in Table 3, have explored the option to deliver psychedelic treatment in the absence of specialized therapists or therapy, but in the presence of standard medical care and psychological support to provide guidance and safety during psychedelic treatment. In DMT studies, preparation and integration/debriefing sessions were reported to be an explicit part of the treatment protocol (49, 89), but without much specification and without a need for therapists integrated into the trial. In patient studies with ayahuasca (84) and 5-MeO-DMT (59), no preparation or integration sessions were scheduled, but medical and psychological support was present during treatments and provided on an as needed basis. Psychedelic treatment models that do not capitalize on integrative therapy as part of the psychedelic experience might be easier and less costly to implement in clinical settings, provided that antidepressant efficacy is maintained. Yet, even treatment models that focus on safety and care should incorporate directions on how to create a trusted environment in which patients feel safeguarded and prepared for an experience with 5-MeO-DMT and DMT. Standardization is recommended for such guidelines.

Short-acting formulations of psychedelics may also reduce the time and effort that both patients and staff must invest in treatments, which might be preferable over long-acting formulations. Even with short-acting formulations, total treatment duration might still be considerable depending on a number of parameters such as rate of IV infusion, the presence of MAO inhibitors, or the number of administrations. As can be observed in Tables 2 and 3, IV infusion rates that have been explored varied from 60 seconds to 90 minutes, with psychedelic experiences lasting between 15 and 105 minutes. Intranasal DMT experiences even extended to 4–5 hours when combined with harmaline. While inhaled formulations of DMT and 5-MeO-DMT always produced short lasting experiences, the total treatment duration could still last somewhere between 3 and 9 hours depending on the number of dose increments and the duration of dosing intervals. It is to be expected that some parameters of 5-MeO-DMT and DMT treatment regimens will be adapted in future drug development trials in order to find the optimal balance between treatment delivery and efficacy. Such insights will contribute to future consensus on definitional terms of short-acting formulations and their applications.

Although findings from early trials with 5-MeO-DMT and DMT in the treatment of depression are encouraging, there are also a number of limitations, the most important ones being the small sample size and the open label design of most studies. Studies with a small sample size are prone to overestimation of treatment effect sizes, particularly in the absence of a proper control group. Open-label trials with psychedelics might be particularly sensitive to extra-pharmacological factors such as expectancy effects that are known to moderate treatment responses (140). Patients who apply for participation in trials with psychedelics may enter with high treatment expectations that have been shaped and hyped though many media channels over recent years. Such expectations might drive strong placebo or nocebo effects that can add to or bias the actual treatment effects (99, 102, 140). That is, clinical trial participants who realize that they are in the active treatment group may show a strong clinical response because of increased expectations, whereas those who find out that they are in the placebo group may feel worse because of decreased expectations. Future trials with 5-MeO-DMT and DMT will therefore need to include large patient samples and add placebo and active control groups to control for non-pharmacological confounders and to properly mask allocation to psychedelic treatments. The latter is an acknowledged challenge for any trial with psychedelics given that these produce unique psychedelic experiences that can be easily recognized (140). Unfortunately, active treatment controls which can fully blind allocation to a psychedelic arm in a clinical trial are presently not available, which leaves the alternative design aimed at showing a dose dependent response, as a second best to control for positive expectations. In addition, nocebo effects can be minimized by offering patients in the placebo group the perspective of entering an open-label extension with the psychedelic treatment, after completion of the double-blind phase of the trial.

There are also unexplored grounds. Current trials with psychedelics have primarily focused on the onset and duration of a treatment response after one or two dosing days, without paying attention to strategies to sustain or reintroduce a treatment response in case patients relapse. Unlike clinical trials with classical antidepressants where a demonstration of sustained treatment efficacy over a couple of weeks was sufficient to assume a closed-loop treatment model based on daily dosing, clinical trials with single dose administrations of psychedelics have provided open-loop models in which continuation of treatment efficacy is not accounted for. Future trials with psychedelics, including 5-MeO-DMT and DMT, would therefore have to incorporate strategies aimed at continuation of the antidepressant response to provide a closed-loop model of psychedelic treatment. Such strategies could for example include re-dosing sessions for patients who relapse in order to assess whether renewed exposure to the psychedelic treatment produces a similar antidepressant response as observed after first exposure. Alternative to re-dosing, other approaches may be explored to sustain the antidepressant response, such as concurrent treatment with traditional antidepressants, neurostimulation, and/or cognitive training programs which potentially may leverage enduring and adaptive learning and coping behavior during critical, post-treatment windows of neuroplasticity (141).

In sum, clinical studies on 5-MeO-DMT and DMT have highlighted a number of potential benefits in the treatment of depression as well as challenges for future clinical implementations, as listed in Table 4. Ultra-fast, short-acting psychedelics may acquire a unique position amongst the medical armamentarium of antidepressants; one that capitalizes on instant and durable relief, with only brief interventions. Acceptance of ultra-fast, short-acting psychedelics by regulatory authorities will depend on future clinical trials with a focus on replication, duration, and maintenance of antidepressant efficacy in large patient samples.