In healthy volunteers, intravenous DMT produced significant reductions in depressive symptoms one to two weeks after administration in both placebo-controlled and prospective samples, with trait neuroticism reduced only in the placebo-controlled group and symptom change correlated with the intensity of acute "oceanic boundlessness" peak experiences. The authors suggest IV DMT’s short, controllable action may alleviate depressive symptomatology via induced peak experiences and warrants further clinical investigation.
Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybin’s acute effects (4–6 h) may have pragmatic and cost-effectiveness limitations. Here, we explored the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT), a closely related, but faster-acting psychedelic intervention, on mental health outcomes in healthy volunteers. Data is reported from two separate analyses: (1) A comparison of mental health-related variables 1 week after 7, 14, 18, and 20 mg of IV DMT versus IV saline placebo (n = 13) and, (2) A prospective dataset assessing effects before versus 2 weeks after 20 mg of IV DMT (n = 17). Mental health outcomes included measures of depression severity (QIDS-SR16), trait anxiety (STAI-T), Neuroticism (NEO-FFI), wellbeing (WHO-5), meaning in life (MLQ), optimism (LOT-R), and gratitude (GQ-6). In both the prospective and placebo-controlled datasets, significant improvements in scores of depression were found 1–2 weeks after DMT administration. Significant reductions in trait Neuroticism were only found for the placebo-controlled sample. Finally, changes in depression and trait anxiety correlated with acute peak experiences (assessed via ‘Oceanic Boundlessness’). While the use of two separate cohorts in pooled analysis limits the generalizability of these correlational findings, these results suggest that DMT may reduce depressive symptomatology by inducing peak experiences. The short half-life of IV DMT and its potential for flexible dosing via controlled infusions makes it an appealing candidate for psychedelic medicine. Further research in clinical samples is needed to corroborate the therapeutic potential of DMT.
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Earlier research has established that classic serotonergic psychedelics can improve a range of mental health outcomes, with most clinical work to date focusing on psilocybin, LSD and ayahuasca. N,N-Dimethyltryptamine (DMT) differs from these compounds in producing an especially intense but very short-lived acute experience when administered intravenously or smoked, and prior human work on DMT monotherapy is limited to very small samples or studies in which DMT is a component of ayahuasca. These features—short duration, distinctive phenomenology and limited human monotherapy data—mean that the therapeutic potential and mechanisms of IV DMT remain uncertain. Timmermann and colleagues set out to examine whether IV DMT alters negative psychological factors implicated in psychiatric disorders (depressive symptomatology, trait anxiety, and trait Neuroticism) and positive psychological factors (well-being, optimism, nature-relatedness, gratitude and meaning in life) in psychedelic‑experienced healthy volunteers. The paper reports two related datasets: a small single‑blind, placebo‑controlled study with fixed-order placebo then DMT, and a larger prospective dataset in which participants received DMT as part of an EEG–fMRI protocol. The investigators also tested whether the quality of the acute experience—measured as Oceanic Boundlessness—was associated with subsequent changes in depression and anxiety.
Two separate experimental datasets were collected from psychedelic‑experienced healthy volunteers recruited by word‑of‑mouth. Screening included physical tests, a psychiatric interview (including the MINI), and medical examination; main exclusions were psychedelic naivety, current or past psychiatric illness, family history of psychosis, excessive alcohol use, needle phobia or significant medical conditions. Across both studies 30 participants received IV DMT fumarate, but details of dropouts and sample sizes for specific analyses vary across the extracted text. The placebo‑controlled study was single‑blind with 13 volunteers (6 female, 7 male; mean age 34.76). Placebo (IV saline) was always administered in the first session and DMT in the second, with sessions separated by 7 days. As part of dose finding, four DMT doses were used (7, 14, 18 and 20 mg) delivered as a bolus IV injection (2 ml over 30 s, flushed with saline). Subjective DMT effects lasted on average 17 min with peak effects at 2–3 min. Mental health questionnaires were completed at baseline (one day before placebo), 1 week after placebo (5–7 days) and 1 week after DMT (6–9 days). Doses were collapsed for analysis due to sample size and plasma variability. The prospective EEG–fMRI study initially recruited 25 participants who underwent four dosing sessions across two days (two doses per day) in a pseudo‑balanced order; sessions were separated by approximately 2 weeks and two sessions on a day were separated by about 4 h. IV DMT (5 ml bolus over 30 s, flushed) and saline placebo (5 ml) were administered while participants wore an EEG cap inside an MRI scanner. Questionnaires for mental health outcomes were completed at baseline (one day prior to the first dosing session) and 2 weeks after the first dosing session (12–15 days). Because participants received both DMT and placebo during the same study visit, no placebo follow‑up measurement was obtainable in this cohort; the main comparisons therefore contrasted baseline versus 2‑week post‑DMT scores. Some participants dropped out or were excluded for motion or non‑attendance. Primary psychometric outcomes were QIDS‑SR16 for depressive symptoms, STAI‑T for trait anxiety and the Neuroticism scale of the NEO‑FFI. Secondary outcomes included WHO‑5 (well‑being), LOT‑R (optimism), GQ‑6 (gratitude) and the Meaning in Life Questionnaire. Acute effects were assessed with the 5D‑ASC and the Oceanic Boundlessness (OBN) dimension was used for hypothesis‑driven correlations with later changes in depression and anxiety. Statistical analyses were performed separately for each dataset: paired t‑tests (or Wilcoxon where data were non‑normal) compared post‑DMT versus placebo (placebo‑controlled) or post‑DMT versus baseline (prospective). To reduce floor/ceiling effects in healthy volunteers, participants scoring minimum/maximum values at placebo/baseline were excluded from certain comparisons; the extracted text indicates two exclusions from the placebo sample and three from the prospective sample for QIDS analyses. For primary outcomes no multiple comparisons correction was applied; Bonferroni correction was used for the secondary non‑clinical measures. Correlational analyses between OBN and change scores pooled participants from both studies to increase power, with one‑tailed significance thresholds specified for these hypothesis‑driven tests.
Primary outcome — depressive symptoms: In the placebo‑controlled sample, scores on the QIDS‑SR16 were significantly reduced 1 week after DMT compared with 1 week after placebo (reported statistic z[10] = -2.06, p = 0.027 two‑tailed, r = 0.67). There was no significant change between baseline and 1 week after placebo (z[10] = -0.29, p = 0.77). In the prospective sample, depressive symptoms were also reduced 2 weeks after DMT compared with baseline (t[13] = -3.24, p = 0.0065, d = 1.37). The extracted text does not give a fully consistent account of final analysed Ns across all tests; degrees of freedom are reported for the statistics above. Trait anxiety and Neuroticism: Trait anxiety did not reach statistical significance in either dataset, though medium effect sizes were reported. In the placebo‑controlled sample the comparison of 1 week post‑DMT versus 1 week post‑placebo yielded t[12] = 1.61, p = 0.13, d = 0.45; in the prospective sample the comparison of 2 weeks post‑DMT versus baseline yielded t[16] = -1.58, p = 0.13, d = 0.55. For Neuroticism, the placebo‑controlled sample showed a significant reduction after DMT versus placebo (t[12] = -2.60, p = 0.02, d = 0.72), but the prospective sample did not show a significant change (t[16] = -1.48, p = 0.16, d = 0.57). No significant differences were observed for placebo versus baseline in the placebo‑controlled dataset for these traits. Acute experience and associations with outcomes: Compared with placebo, DMT produced significantly higher scores on several 5D‑ASC dimensions including Oceanic Boundlessness (OBN), Dread of Ego‑Dissolution, Visual Restructuralization and Auditory Alterations (all p < 0.001), while Vigilance Reduction did not differ. Pooled correlational analyses across both studies found that higher OBN scores were associated with larger reductions in depression (r = -0.40, p = 0.026, one‑tailed) and trait anxiety (r = -0.38, p = 0.020, one‑tailed) assessed 1–2 weeks post‑DMT minus baseline. The investigators emphasise that pooling the datasets increases power but introduces heterogeneity due to differing doses and procedures. Positive psychological factors: Increases in nature‑relatedness and gratitude were observed when comparing DMT against baseline, but these effects did not survive correction for multiple comparisons. No significant changes were reported for well‑being (WHO‑5), optimism (LOT‑R) or meaning in life (MLQ) after correction. Other operational details: the acute subjective effects lasted on average 17 min with peak effects at 2–3 min post‑injection, and doses were collapsed in analyses due to small samples and plasma variability.
Timmermann and colleagues interpret their findings as tentative evidence that a single IV DMT administration can reduce depressive symptomatology in psychedelic‑experienced healthy volunteers, since reductions in QIDS‑SR16 scores were observed in both a small single‑blind placebo‑controlled study and a prospective sample. They further note a reduction in trait Neuroticism in the placebo‑controlled sample, and an association between the intensity of acute 'Oceanic Boundlessness' experiences and subsequent decreases in depression and trait anxiety, consistent with prior work implicating peak‑type experiences in therapeutic change with psychedelics. The investigators caution that several factors limit the generalisability and magnitude of the observed effects. Different doses used in the placebo‑controlled arm and methodological differences across studies introduce variability, and pooling datasets for correlational analyses reduces homogeneity. The prospective EEG–fMRI study design meant no placebo follow‑up was available, and both studies were conducted in neuroscience rather than therapeutic contexts (e.g. participants in scanners), which may blunt positive outcomes compared with therapeutic settings. The sample consisted of psychedelic‑experienced healthy volunteers rather than clinical populations; this carries potential ceiling/floor effects and led the team to exclude participants with extreme baseline scores for some analyses. The authors highlight that DMT's short duration and intensely unusual phenomenology might both constrain and shape therapeutic utility: brief exposures may be advantageous for scalability and flexible dosing but may also limit the time available for psychological insight unless infusion methods are adjusted or integration is strengthened. Neurobiological mechanisms are discussed briefly: like other classical psychedelics, DMT is primarily a 5‑HT2A agonist and may facilitate therapeutic effects by promoting cortical plasticity that allows revision of entrenched cognitive and behavioural patterns when combined with psychological support. The authors call for further research in clinical populations to determine consistent safety and efficacy profiles, to explore dose and infusion strategies that lengthen the experience if needed, and to investigate psychological mechanisms such as insight, emotional breakthrough and psychological flexibility in relation to DMT outcomes. A number of study‑level limitations are reiterated, including potential regression to the mean, floor effects in healthy samples, and the need for therapeutic contexts and clinical trials to fully characterise DMT's potential.
Here we report mental health outcomes in relation to IV DMT in two separate studies. Reductions in depression severity were observed in both a small placebo-controlled study, and a larger sample from just the DMT arm. These results were supplemented by reductions in trait Neuroticism in the placebo-controlled sample. Consistent with previous psychedelic research implicating a causal role for experiential factors in relation to mental health changes, a significant relationship was found between acute experiences of 'Oceanic Boundlessness' induced by DMT and post-DMT improvements in depression and anxiety. Together, these results tentatively support further research into the therapeutic potential of DMT in psychiatry. Depression symptomatology was the main outcome assessed in a number of recent clinical trials involving psychedelics, and they have consistently been found to be reduced after psychedelic therapy in psychiatric patient populationsand in healthy volunteers in retrospective surveys. Our current findings are consistent with reductions in depression symptoms found in previous studies, as well as others that have reported reductions in the Neuroticism personality domain following the administration of psychedelics to individuals with depression. Interestingly, a recent study showed evidence for reduced depression in six participants with major depression 1 day after 21 mg/70 kg of DMT administration, consistent with preclinical behavioural models of depression. Tempering enthusiasm, we failed to replicate decreases in Neuroticism in the prospective sample, and we did not find increases in positive psychological factors such as well-being, optimism, gratitude, nature-relatedness, and meaning in life after DMT, which is contrary to the findings of several controlled and non-controlled healthy volunteersand clinical studiesinvolving psychedelics. Speculatively, one could argue that a more therapeutically supportive context (e.g., not being inside of an MRI scanner with an EEG cap for a neuroscience experiment) or a longer experience (such as the one enabled by longer infusions of DMT) may be necessary for larger improvements in these measures. Recent evidence suggests that the effects of DMT can be extended by at least 30 min(and thus, the efficacy of therapeutic action may also be elevated) while still inducing effects significantly shorter than those induced by psilocybin and LSD. There is also the possibility that the effects of DMT on mental health outcomes have been limited by ceiling effects from an already healthy population. Finally, we found that decreases in depression and anxiety were significantly associated with the quality of the acute experiences induced by DMT, as measured by the 5D-ASC subscale Oceanic Boundlessness. This finding is consistent with a large number of studies that have found positive relationships between acute 'peak' , 'mystical' or emotional experiences and improvements in mental health outcomes with psychedelics. Future work is needed to assess whether other variables that have been shown to contribute to improved mental health outcomes with psychedelics, such as insight, emotional breakthrough, and psychological flexibility, play a similar role with DMT. As with other psychedelics, psychological mechanisms underlying the therapeutic potential of DMT are complemented by neurobiological mechanisms of action. As with other psychedelics, DMT is primarily associated with stimulation of 5-HT2A receptors, while most conventional antidepressants increase serotonin receptor agonism non-selectively. It has been proposed that 5-HT2AR agonist psychedelics can be effective in the treatment of depression (and other psychiatric disorders) via their ability to relax and (with psychological support) revise entrenched pathological habits of mind and/or behaviour. In contrast, conventional antidepressants have been proposed to promote a type of 'passive coping' , incubating against stress (e.g., via stimulation of inhibitory post-synaptic 5-HT1A receptors in stress circuitry). Harnessing increased cortical plasticityto aid the revision of cognitive and behavioural habits, could lead to more enduring benefits with psychedelic therapy compared with conventional antidepressants. It is important to note some limitations of the present studies. Firstly, in the placebo-controlled sample, different doses were used, which may have generated variability in the outcomes we reported. Secondly, the studies differed in methodology and timing of assessment of mental health outcomes (see "Methods"), which may have increased this variability. This becomes particularly relevant when the datasets are pooled for analysis examining the predictive relationship of Oceanic Boundlessness scores and mood symptomatology, and thus limits the generalizability of this correlational finding. Thirdly, data from an EEG-fMRI study consisting of a prospective dataset and this study design did not allow for an assessment of the effect of a placebo session on mental health outcomes, as all study volunteers received both DMT and placebo on the same study visit and no follow-ups for a placebo condition were possible. We were therefore limited to (prospective) baseline (pre DMT) versus post DMT contrasts on these analyses. Despite this limitation, the findings are largely consistent with the placebo-controlled findings we also report, as well as those from other placebo-controlled studies with DMT 28 and ayahuasca. Moreover, our studies were primarily neuroscientific rather than therapeutic-and previous work has shown that having a therapeutic intent and receiving the psychedelic in a therapeutic context positively modulates relevant mental health outcomes, whereas neuroimaging environments (such as an fMRI environment in the second study) are associated with less positive responses. Thus, further work is needed to assess whether DMT is equally sensitive to contextual modulation and whether the present signal can be improved upon as we suspect it can. Thus, for several reasons, the present findings may under-estimate the 'true' magnitude of improvement possible with IV DMT. Relatedly, it is important to note that these studies were conducted with psychedelic-experienced healthy volunteers and not individuals with a psychiatric disorder, and thus these findings may not extend to psychedelicnaïve clinical populations. To attend to this discrepancy (and prevent floor effects which would hinder statistical analysis), we removed individuals scoring the most extreme score possible on mental health outcomes from further analyses. While this may limit this sample representativeness' for healthy populations, we believe it better informs the potential applicability of DMT for individuals with mood symptomatology. While studies employing structurally-similar compounds are showing promising results in clinical populations, it is important to note that there might be additional challenges with the employment of DMT for clinical purposes. These include: (1) the short-duration of action associated with DMT administration compared with other psychedelics, as it is reasonable to assume that a longer experience is required for therapeutic benefits in certain difficult-to-treat clinical populations. This possibility may be implied by some recent evidence suggesting an important role for psychological insight in moderating responses to psychedelics; and (2) DMT is associated with especially extravagant psychological effects (e.g. exploring 'alternate realms' and sensing other sentient presences or entities) that while intense, are so short-lived that insight may be compromised. Special consideration might be required for helping individuals 'integrate' the unusual psychological effects of DMT in order to remain psychologically grounded. An open-label study employing psilocybin for treatmentresistant depression found effect sizes that were 2-3 times larger compared with the effect sizes we report here using the same QIDS-16-SR measure. The statistical phenomenon known as 'regression to the mean'-i.e., that extreme values gravitate towards the average with repeat measures-may partly account for this, as well as 'floor effects' when baseline symptom severity scores are low-to-negligible in healthy populations. For these reasons, we suspect that larger effect sizes may be observed if a population with more severe anxious/depressive symptoms was recruited for a DMT trial. In conclusion, the present study tentatively suggests that intravenous DMT may have some utility in improving mild symptoms of depression in already healthy populations. Our findings are generally consistent with those from recent clinical trials involving other psychedelics, as well as healthy volunteer studies. Rapid-acting, short half-life psychedelics are appealing candidates for further research due to their potentially superior costeffectiveness, as well as their potential for flexible dosing. Further research is required to examine whether shortacting psychedelic interventions, such as DMT, have consistent safety and efficacy profiles.
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