Psychedelic drugs such as mescaline, psilocybin, and lysergic acid diethylamide (LSD) were extensively used in psychiatry before they were placed in Schedule I of the United Nations Convention on Psychotropic Substances in 1971. After decades of suspension, there is now a major revival of human psychedelic research driven by modern brain imaging studies and clinical trials providing safety and efficacy data for the use of psychedelics in the treatment of mental disorders (Carhart-Harris and Goodwin, 2017; Reiche et al., 2018; Carhart-Harris et al., 2021).

5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a naturally-occurring tryptamine with high potency, ultra-rapid onset, and short duration of psychedelic effects (Shulgin and Shulgin, 1997). 5-MeO-DMT is predominantly found with other psychoactive molecules in the toxic secretion of the Bufo alvarius toad, also called the Sonoran Desert toad or Colorado River toad, but also in certain plants, such as Dictyoloma incanescens (Pachter et al., 1959). 5-MeO-DMT was first synthesized in 1936 (Hoshino and Shimodaira, 1936) and while it has a similar molecular structure as the classic psychedelics N,N-Dimethyltryptamine (DMT) and psilocybin, its pharmacological activity might be distinct. 5-MeO-DMT works mainly as a selective serotonin receptor agonist at the 5-HT_1A and 5-HT_2A receptors, whereby functional dominance of the 5-HT1A subtype has been suggested (Spencer et al., 1987; Winter et al., 2000; Krebs-Thomson et al., 2006; Shen et al., 2010), while DMT and psilocybin (i.e. psilocin) are overall less selective (Ray, 2010) with some data indicating a functional dominance of the 5-HT2A subtype (Vollenweider et al., 1998; Barker, 2018; Madsen et al., 2019).

5-MeO-DMT from natural or synthetic sources has a history of naturalistic use in spiritual or self-exploratory contexts (Weil and Davis, 1994; Davis et al., 2018), and its particular potency and ability to induce so called peak experiences (PE) or mystical experiences has been highlighted (Ott, 1999; Barsuglia et al., 2018). 5-MeO-DMT-related PEs have been described to encompass the experience of “ego dissolution” and an overwhelming sense of “oneness” or “unity” that can elicit an emotional change in perspective (Davis et al., 2018; Uthaug et al., 2019). The occurrence of PEs has been shown to be correlated with therapeutic effects in many of the prior studies with other psychedelic agents, including tryptamines (Garcia-Romeu et al., 2014; Johnson et al., 2014; Bogenschutz et al., 2015; Griffiths et al., 2016; Ross et al., 2016; Roseman et al., 2018). Observational studies on the naturalistic use of 5-MeO-DMT and toad venom containing 5-MeO-DMT have reported that the intensity of the experience is associated with improvements in subjective measures of satisfaction with life and reduction of psychological distress in participants without an underlying mental health condition (Uthaug et al., 2019; Uthaug et al., 2020) and an anonymous web-based survey has reported that the intensity of mystical experiences and higher ratings of spiritual significance and personal meaning is associated with self-reported improvements of self-reported depression and anxiety (Davis et al., 2019). However, it is currently still unknown whether 5-MeO-DMT actually has therapeutic effects in mental disorders, and which dose range of 5-MeO-DMT is needed to potentially elicit a therapeutic response.

This is the first formal prospective clinical study to investigate the safety profile of 5-MeO-DMT and its dose-related effects on states of consciousness. Most available information on 5-MeO-DMT is derived from retrospective surveys or internet fora such as Erowid (erowid.org) or observational studies (Uthaug et al., 2019; Uthaug et al., 2020), but since those reports describe the use of material of largely unknown quantity, quality, and purity, which is often naturally-sourced, and with likely highly variable administration methods and bioavailability, no firm conclusions can be drawn from those studies, including on dose-response effects on states of consciousness and dose-related safety aspects. What has been suggested, however, is that 5-MeO-DMT is non-addictive, and with a low potential for abuse (Davis et al., 2018). Also, the onset of psychoactive effects after inhalation was shown to occur within 1–50 s (Uthaug et al., 2019), with an overall duration of effects of up to about 30 min (Davis et al., 2018). In contrast to other psychedelic substances, there seems to be very little build-up of tolerance to the effects of 5-MeO-DMT (Schlemmer et al., 1977; Strassman and Qualls, 1994; Strassman et al., 1996).

The current study (GH001-HV-101) primarily aimed to investigate safety and tolerability and the psychoactive effects of a novel vaporized 5-MeO-DMT formulation (GH001) in healthy volunteers in a controlled clinical setting. Further aims were to assess the impact of 5-MeO-DMT on cognitive functioning, mood, and well-being. The study evaluated single, ascending doses of 2, 6, 12, and 18 mg 5-MeO-DMT administered via inhalation as well as individualized dose escalation (IDE) of 5-MeO-DMT at doses ranging from 6 to 18 mg. The overall aim of the study was to determine the dosing regimen of 5-MeO-DMT that would achieve a peak experience in healthy volunteers. That aim is relevant for future dose selection in clinical populations, because strong associations between psychedelic peak experiences and therapeutic effects have been reported for other tryptamines (Garcia-Romeu et al., 2014; Johnson et al., 2014; Bogenschutz et al., 2015; Griffiths et al., 2016; Ross et al., 2016; Roseman et al., 2018). Higher doses were contemplated to occasion stronger psychoactive effects, with the IDE contemplated to elicit the strongest effects and having the highest potential to cause a peak experience. Due to the short-lived nature of psychoactive effects, no clinically-relevant change in scores on cognitive measures were expected.

The main aim of the current study was to assess the safety and tolerability of a novel vaporized 5-MeO-DMT formulation (GH001) administered via inhalation as single doses and in an individualized dose escalation and to identify the dosing regimen of 5-MeO-DMT that would elicit a peak experience as assessed with a novel PES scale. In addition, the current study aimed to qualify and quantify the altered state of consciousness as a function of the 5-MeO-DMT dose with validated questionnaires such as the EDI, 5D-ASC, MEQ, and CEQ. Measures of cognitive function, mood and well-being were taken at baseline, at 2 h, and at 7 days after dosing to monitor acute and subacute effects of 5-MeO-DMT on the affective and cognitive state. Higher doses of 5-MeO-DMT produced significant increments in the mean intensity of the psychedelic experience as compared to the lowest 2 mg dose on all questionnaires, except the CEQ. Prominent effects were observed following single doses of 6, 12, and 18 mg, while most peak experiences were observed following individualized dose escalation of 5-MeO-DMT doses. Measures of cognition, mood, and well-being were not affected by 5-MeO-DMT. Vital signs at 1 and 3 h after administration were not affected and adverse events were generally mild and spontaneously resolving. It should be noted that Phase 1 studies are exploratory by nature and that current findings need replication in future studies with larger samples sizes.

Overall, 5-MeO-DMT elicited a substantial psychedelic experience as retrospectively assessed with all questionnaires, except the CEQ. All doses elicited significantly higher PES and MEQ ratings as compared to the lowest dose of 2 mg. In total, eight participants reported a peak experience (i.e., PES rating ≥75%): one participant at the 6 mg dose, two participants at the 12 mg dose, one participant at the 18 mg dose, and all four participants in the individualized dose escalation group. EDI and 5D-ASC ratings generally differed from the lowest 2 mg dose after IDE. Our data suggest that the 5-MeO-DMT dose needed to achieve a peak experience largely varies between individuals. Variability was prominent in the single dose conditions but also in the IDE dose condition. During the latter, peak experiences were achieved in all participants but at different individual doses [after a single dose of 6 mg (N = 1), after inhalation of 6 and 12 mg (N = 2) and after inhalation of 6, 12, and 18 mg (N = 1)]. This suggests that individualized dose escalation of 5-MeO-DMT adequately administered via inhalation is an efficient way to tailor the individual doses needed to reach a peak experience. High inter-individual variability of psychoactive effects after 5-MeO-DMT administration was also described in an observational study (Uthaug et al., 2020), were it was noted that the magnitude of the psychedelic experience was not significantly correlated to the total dose of 5-MeO-DMT that participants received (individual doses ranging from 3 to 24 mg, total dose of up to 4 administrations ranging from 17 to 61 mg). Of note, in our study, peak experiences with 5-MeO-DMT were not considered as challenging by participants as evidenced by very low CEQ and Anxious Ego Dissolution ratings. This suggests that 5-MeO-DMT administered as the inhaled GH001 formulation caused little distress.

The current study was the first to employ the PES, which was developed to provide a quick, accurate and easy to use scale for monitoring the magnitude of psychoactive effects after administration of 5-MeO-DMT. The scale focuses on three dimensions of a psychedelic experience, i.e., intensity, loss of control, and profoundness (Barrett et al., 2015; Nour et al., 2016). As such, the scale integrates central aspects of the MEQ (i.e., profoundness, intensity) as well as the EDI and 5D-ASC (i.e., loss of control/ego dissolution and intensity). Despite its brevity, it appeared to be a relevant indicator of the occurrence of peak experiences in eight individuals that were not always recognized in ratings of the more complex MEQ, EDI, and 5D-ASC scales. For example, in the present study, only three individuals achieved a rating >60% across all subscores of the MEQ (i.e., MEQ rating >3), which is the MEQ threshold for a mystical experience (Barrett et al., 2015; Barsuglia et al., 2018). Likewise, only 4 individuals achieved EDI ratings and oceanic boundlessness ratings above 60% of the total score. The MEQ, EDI and 5D-ASC scales capture many aspects of a psychedelic experience that seem not to be typical for the intense, short-lasting psychoactive effects of 5-MeO-DMT when used in the clinical setting, and those scores may be more appropriate in the spiritual or self-exploratory contexts of naturalistic use. For example, among visitors of a psychospiritual retreat program in Mexico (Barsuglia et al., 2018) who received 50 mg of toad venom containing 5-MeO-DMT, over 75% had “a complete mystical experience” (≥60% on all MEQ subscales). The PES however appears to offer a selective and distinct addition to existing questionnaires for use in the clinical setting that can rapidly capture the occurrence of a peak experience. However, further validation of the PES and its performance relative to other scales is required.

As expected, 5-MeO-DMT formulated as GH001 did not elicit any short-term or long-term changes in memory, attention, and cognitive function. Even 2 hours after the administrations, participants did not perform significantly better or worse compared to baseline or 1 week after administration. These results are in line with the notion that psychoactive effects of 5-MeO-DMT are short-lasting and that cognitive and psychomotor functions quickly return to baseline after administration. These findings further attest to the safety profile of pharmaceutical grade 5-MeO-DMT if adequately administered in a controlled setting and suggest the safety of 5-MeO-DMT in relation to day-to-day operations requiring skilled performance. These findings are also in line with the level of 5-MeO-DMT concentrations in blood that were low already 1 h after administration and were barely measurable at 3 h after administration, even after the individualized dose escalation. This suggests that 5-MeO-DMT is rapidly metabolized and eliminated from the body without causing any relevant accumulation after successive doses. A lack of accumulation has previously been reported for DMT by (Strassman et al., 1996) who found no significant residual build-up of DMT over the course of four consecutive intravenous administrations, 30 min apart. This rapid elimination has also been shown for 5-MeO-DMT in mice and rats (Shen et al., 2010). It should be noted however that the present study provides limited information on the progression of 5-MeO-DMT concentration over time and that dedicated studies are needed to establish a full pharmacokinetic profile of 5-MeO-DMT.

Contrary to previous reports from surveys and observational studies (Davis et al., 2019; Uthaug et al., 2019; Uthaug et al., 2020), no improvement in measures of mood and wellbeing after the administration of 5-MeO-DMT was found; however, such improvements would also not have been expected as the present study selected healthy volunteers with minimal BPRS ratings at baseline. Many participants in the survey (Davis et al., 2019) self-reported having been diagnosed with depression (41%) or anxiety (48%) and most self-reported that these conditions were improved following 5-MeO-DMT use. Likewise, many participants in observational studies (Uthaug et al., 2019; Uthaug et al., 2020) reported psychological self-exploration and problem-solving as their main motives for using 5-MeO-DMT. The absence of change in mental health outcomes of participants in the present study therefore does not contradict with previous reports.

The present study provides relevant information on the dose range and regimen of the inhaled GH001 formulation of 5-MeO-DMT that can be expected to elicit a psychedelic peak experience. Previous research with other psychoactive tryptamines has repeatedly demonstrated that the magnitude of a psychedelic experience is a strong predictor of a positive therapeutic response in patients suffering from depression (Roseman et al., 2018; Palhano-Fontes et al., 2019; Romeo et al., 2021). This may be the case for 5-MeO-DMT as well, although a confirmation needs to be obtained from prospective studies in populations with clinical psychopathology. A Phase I/II study is ongoing with the inhaled GH001 formulation of 5-MeO-DMT in patients with Treatment-Resistant Depression (GH001-TRD-102; NCT04698603). This study aims to investigate safety, tolerability, and anti-depressive therapeutic effects of treatment with 5-MeO-DMT.

In conclusion, single doses of 6, 12, and 18 mg of the inhaled GH001 formulation of 5-MeO-DMT were able to induce a peak experience in a minority of healthy participants. An individualized dose escalation regimen produced a peak experience in every participant. Individualized dose escalation of 5-MeO-DMT dosing may be preferable for clinical applications that aim to maximize the short-term psychoactive effects to elicit a strong therapeutic response.