The double-blind, multi-site randomised controlled trial will evaluate psilocybin’s potential in reducing opioid cravings and improving emotional well-being in individuals struggling with OUD but who continue to use non-prescribed opioids despite adherence to methadone treatment.
Participants will be randomised to receive a single administration of 30, 20, or 1 mg of psilocybin, with weekly urine drug tests and ongoing self-report of drug use collected for 24 weeks post-administration, along with other endpoints to understand OUD-related neuropsychopathology and functional outcomes.
The study has a few notable trial design features, including the fact that the overall design is adaptive. Bogenschutz explained that the study allows for an interim analysis for futility based on data from the first ninety participants. If either or both of the 30 or 20 mg arms demonstrate “unacceptable safety or a low (<25%) probability of demonstrating a significant effect in the full study”, Bogenschutz said, “that arm will be dropped.” (Of course, if both dose arms were to be dropped, the study itself would be terminated. If either of the active arms remains, the study continues enrolling.)
We asked Bogenschutz about the rationale behind the 20 mg dose. He emphasised the fact that the adaptive trial design, which takes stock of each arm’s performance after 90 patients have been dosed, “provides an opportunity to fine-tune the dosage before settling on a most promising dose.” “The tendency has been to use the largest dosage that we think has adequate safety,” he continued, “but, except for the Compass Pathways phase 2b trial (1 mg vs. 10 mg vs. 25 mg in TRD), we don’t have any evidence regarding the dose-response curve.”
Given that there is very little data on psilocybin in OUD patients, Bogenschutz added, and a total dearth in patients taking methadone, the researcher believes the present trial design is wise.
But some might wonder whether the 30 mg dose is high enough for this particular patient population.
While 25 mg has become the dose of choice in studies of psilocybin for depressive disorders, there is reason to believe that other patient populations might respond better to different doses (in Bogenschutz’s earlier alcohol use disorder (AUD) study, his team administered doses of either 30mg/70kg or 40mg/70kg, which were among the highest doses of the drug given in modern-day trials), especially where background medication is at play. Might methadone, in this case, attenuate psilocybin’s effects given that it inhibits serotonin reuptake? If so, it might warrant an even higher dose than 30 mg.
Researchers at Johns Hopkins University, for example, registered a clinical trial of psilocybin for OUD in patients also taking methadone (NCT05242029). The study, which has since been withdrawn for lack of funding, planned to administer a 40 mg dose to participants.
We asked Bogenschutz, who reminded us that methadone is a relatively weak serotonin transporter inhibitor, at least relative to SSRIs. On that note, he also shared that the trial will allow patients on SSRIs to participate. What’s more, in Bogenschutz’s earlier psilocybin for AUD study, the higher 40mg/70kg dose was only offered in the second session, and only to the minority of patients who tolerated the 25 mg/70 kg first dose and had relatively low-intensity experiences. Given that the present study evaluates a single dose of psilocybin, the NYU researcher believes a 30 mg dose might be more appropriate.
The trial will take place across four sites in New York and New Mexico, with an enrollment target of 240 participants. Investigators aim to enrol predominantly from low-income minority populations, an important effort given a lack of socioeconomic diversity among many psychedelic trial cohorts. “A high proportion of the populations of opioid treatment programs are socioeconomically disadvantaged people of color who have been severely underrepresented in the previous research on psychedelics”, Bogenschutz told us. Participants will include individuals with co-occurring substance use and psychiatric disorders.
In terms of the extra-pharmacological container within which psilocybin will be given, the non-profit drug development company says participants will receive ‘manualised, non-directive clinical support’, as opposed to mentioning ‘psychotherapy’, a word that seems to have become more frightening than Halloween to the average psychedelic drug developer. The omission is interesting, as B.More’s website proclaims: “We believe psilocybin-assisted psychotherapy is the answer to alcoholism and other substance use disorders”…