An international team of researchers has published results of a preliminary clinical trial testing a formulation of 5-MeO-DMT, a potent and rapid-acting psychedelic drug, in patients with treatment-resistant depression. The results, they said, were encouraging and provide a basis for continued testing in larger trials.

Found naturally in the venom of a species of toad that lives in the Colorado River and in certain plant species, 5-MeO-DMT is known for its intense but short-duration psychedelic impacts, which include sensory, auditory, and profound consciousness-altering effects, and can include hallucinations. An Ireland-based drug development company called GH Research has synthesized the compound, also called mebufotenin, in its labs and created a version for clinical testing in people. In the company’s formulation, the drug, given the product name GH001, is converted to an aerosol and administered (at a range of dosages) via inhalation in a vaporizer, a method used in delivering other drugs, e.g., for asthma and COPD).

Early-stage human testing has been conducted by the company in healthy volunteers and in various individuals with psychiatric conditions, mainly to demonstrate safety. In those trials, called open-label, individuals who received the drug knew they were getting it. The newly reported Phase 2b trial was double-blinded and placebo-controlled; neither those receiving the drug nor those who were administering it and assessing its effects knew which trial participants were receiving the active compound and which were receiving a placebo.

The team’s senior leader was Michael E. Thase, M.D., of the University of Pennsylvania, and first author of the paper, which appeared in JAMA Psychiatry, was Wieslaw J. Cubala, M.D., Ph.D., of the Medical University of Gdánsk, Poland. The team also included Madhukar H. Trivedi, M.D.,, a 2002 BBRF Independent Investigator and 1992 Young Investigator, and Michael Bauer, M.D., Ph.D., a 2005 BBRF Independent Investigator and 1999 Young Investigator. Velichka Valcheva, M.D., the CEO of GH Research, which funded the trial, was also a team member and co-author.

At 16 sites in Europe, the team recruited 81 individuals with treatment-resistant depression: 40 received treatments with GH001 and 41 received placebo. The participants, 46 of whom were female, were in their early 40s, on average, had suffered depression over roughly a dozen years and were about one year into their current major depressive episode. Depression severity across the cohort was moderate to severe (typical scores of about 29 on the 60-point MADRS assessment scale); all had failed to respond to at least two prior treatment courses with oral antidepressants. All such medicines and other forms of treatment were halted several weeks prior to the current trial.

After they were randomized, the trial participants received baseline psychiatric assessments. Then, in a single day, GH001 and placebo were administered. For the sake of safety, each individual getting the active psychedelic drug was dosed individually, on an escalating-dose basis. A first dose was given at 6mg, after which, if there were no safety issues (i.e., no adverse reaction to the drug’s intense psychoactive effects), a second dose, at 12 mg, was given an hour later. An hour after the second dose, those who fared well received a third and final dose at 18mg. To maintain “blinding,” all of the individuals in the placebo group received three separate “doses” of an inactive compound. All patients had been informed prior to these procedures that the study drug had potential psychoactive effects so that those who did receive it would not be surprised.

Drug efficacy assessments were made 2 hours after the final dose. Safety was assessed after each dose was administered and when the participants were discharged later in the day. Follow-up efficacy and safety assessments were made via telephone on day 2, and in-person on the 8th day following the test.

After this, all trial participants were enrolled in a 6-month follow-up in which they were eligible for up to five escalating-dose treatment sessions. This meant that even those in the placebo group in the first part of the trial were now eligible to receive GH001 therapy.  

The current paper, which focuses mainly on results of the first, 8-day phase of the trial, notes that among the 40 individuals who received the active drug, 9 (22%) received one 6mg dose; 21 (53%) received 6 and 12mg doses; and 10 (25%) received 6, 12, and 18mg doses. The drug’s psychoactive effects in these patients was, as expected, relatively brief: 9-14 minutes, on average (with a range of between a few minutes to just under an hour).

The drug appeared to be quite effective: those receiving it “achieved rapid reductions in symptoms of depression,” with improvements in scores on the MADRS scale judged “statistically significant and clinically meaningful.” From a 29 score, a typical recipient of the active drug scored 15.5 points lower 8 days later—a score corresponding with mild to moderate depression symptoms. “GH001 treatment also resulted in large improvements in symptoms of anxiety, global illness severity, and patient-reported quality of life vs. placebo at day 8.” At that same point, 8 days after the treatment was received, 23 of the 40 individuals receiving the active drug (57%) were in clinical remission, compared with none of the 41 who received placebo.

Relatively minor side effects were reported, with nausea being most common (42%), followed by excess saliva production (seen in various other drugs, including some antipsychotics) and paresthesia (a "pins and needles" sensation, tingling, or numbness, a common effect of psychedelic drugs), both reported by 20% of the 40 subjects getting GH001. All of these effects were transient, and there were no instances of severe side effects or impact on, for example, suicidal ideation.

Analysis of the second, 6-month phase of the trial is preliminary. Of the 23 who were in remission at the start of this second phase (all having received active drug in the first phase), 3 (13%) were still in remission after 6 months and received no further treatments. The 20 other participants in remission met criteria for additional treatment during the 6-month follow-up, beginning between weeks 2 and 12 of the period. Five received 1 or 2 treatments, while 15 received 3-4 treatments over the 6 months. After the 6-month period expired, 20 of 23 (87%) who had achieved remission after 8 days had regained that status after further “maintenance” treatments. The drug continued to be “well-tolerated, with no serious treatment-related adverse events over 6 months.”

The team noted that none of the trial participants received coaching or psychotherapeutic interventions over the full duration of the trial’s two parts. This is in contrast to some other trials of psychedelic drugs, in which guidance and coaching are integral parts of the treatment and are regarded not only a safety measure but may be related to therapeutic effects.

In addition to the “rapid, large, and significant reductions” in depression symptoms generated after a single day of treatment in the first phase of the study, the team said, “initial results from the 6-month follow-up suggest GH001 achieved long-term remission in patients with treatment-resistant depression, with infrequent dosing. The favorable safety and tolerability profile [of GH001], including short duration of psychoactive effects and rapid [patient] readiness for discharge [post-treatment] further supports its suitability for clinical use.”

Subsequent trials, which would involve larger numbers of patients, should include those with more severe depression symptoms and longer histories of treatment resistance as well as time since first illness onset, the team said.