Psilocybin effective for treatment-resistant major depression

21st November 2022

Psilocybin given as a single dose is effective in patients with treatment-resistant major depression in as little as three weeks

The use of a single dose of psilocybin leads to a significant improvement in symptoms among patients with treatment-resistant major depression according to the findings of a study by an international team of researchers.

Treatment-resistant depression (TRD) is a subset of major depressive disorder which does not respond to traditional and first-line therapeutic options. The estimate of TRD varies although according to a 2021 US study, among 8.9 million adults treated for major depression, 2.8 million (30.9%) had TRD. Psilocybin is the major psychoactive alkaloid of some species of mushrooms distributed worldwide and a known hallucinogen.

Interest in the use of psilocybin to help with the depression and anxiety associated with advanced stage cancer, revealed a positive trend toward improved mood and anxiety. More recently, two doses of the hallucinogen given to patients with major depression in the context of supportive psychotherapy, suggested that psilocybin combined with therapy is efficacious in the treatment of major depressive disorder.

To date, only a single, open-label feasibility trial has examined the value of psilocybin for the treatment of patients with treatment-resistant depression, offering support for its safety and efficacy and serving as the basis for further trials.

Consequently, in the present study, researchers recruited adults with TRD across 22 sites in 10 countries randomised them 1:1:1 to a single dose of psilocybin (10 mg, 25 mg) or 1 mg which served as a control. The treatment was given with a support session lasting6 to 8 hours and participants followed up for 12 weeks.

The primary endpoint was the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score which ranges from 0 to 60 with higher scores reflecting more severe depression. The researchers examined the change in scores for the 10 and 25 mg doses compared to the 1 mg dose. Secondary outcomes included a response, defined as a > 50% decrease from baseline to week 3 in the MADRS score and a sustained response, i.e., continuing from week 3 to 12.

Psilocybin and treatment response

A total of 233 individuals with a mean age of 39.8 years (52% female) were included and randomised to each arm of the study (ranging from 75 to 79 participants). At baseline, 68% of the entire cohort had a MADRS score indicating severe depression.

The reduction in MADRS scores were -6.6 (95% CI -10.2 to -2.9) for the 25 mg dose (p < 0.001 vs 1 mg dose) and -2.5 (95% CI -6.2 to 1.2) for the 10 mg dose (p = 0.18 vs 1 mg dose).

At 3 weeks, a response was also more likely in those given 25 mg compared to 1 mg (Odds ratio, OR = 2.9, 95% CI 1.2 – 6.6) but this was not significant for the 10 mg dose (OR = 1.2, 95% CI 0.5 – 3.01). However, the response to treatment was not sustained at 12 weeks for either dose.

Adverse effects included headaches (24%) and nausea (22%) and were much more common in the 25 mg dose group, although suicidal ideation or behaviour or self-injury was seen in each of the groups.

The authors concluded that psilocybin given as a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects, prompting the need for further studies of the treatment.

Citation
Goodwin GM et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Eng J Med 2022.

Psilocybin-assisted therapy in alcohol use disorder reduces heavy drinking days

30th August 2022

Psilocybin-assisted psychotherapy has been found to reduce the proportion of heavy drinking days in adults with alcohol use disorder

Psilocybin-assisted psychotherapy reduces the proportion of heavy drinking days as well as the mean number of drinks consumed per day, among adults with alcohol use disorder according to the findings of a randomised, placebo-controlled trial by a team of US and Mexican researchers.

The psychedelic compound psilocybin occurs naturally in the psychoactive psilocybe genus of mushrooms. It is one of a number of psychedelic drugs, together with lysergic acid diethylamide and mescaline, that were used extensively in the past for psychiatric patients, in particular, those with psychoneurotic’ disorders.

In recent years, some evidence has emerged to suggest a potential role for psilocybin to help smokers quit and psilocybin-assisted therapy is efficacious in treating major depressive disorder. Alcohol use disorder (AUD) could be amenable to treatment with psychedelics given that a meta-analysis of 6 trials found that a single dose of lysergic acid diethylamide is associated with a decrease in alcohol misuse.

To date, only a single, proof-of-concept’ study has shown that psilocybin-assisted treatment in combination with motivational enhancement therapy, found that abstinence increased significantly following psilocybin administration (p < 0.05).

For the present study, researchers decided to build upon the ‘proof-of-concept’ study and undertook a randomised, placebo-controlled trial, to evaluate whether 2 administered high-doses of psilocybin reduced the percentage of heavy drinking days (PHDD) in adults with AUD who underwent psychotherapy compared to placebo.

In the trial, participants were offered 12 weeks of psychotherapy and randomised to receive psilocybin or diphenhydramine (which served as the placebo) during two day long medication sessions after 4 and 8 weeks. Diphenhydramine was used as a placebo because the drug has noticeable subjective effects and therefore could possibly be mistaken for psilocybin by psychedelic-naïve participants.

After 38 weeks, individuals could continue and receive 4 additional psychotherapy sessions and assessment took place for a further 18 weeks. Psilocybin was given as a single oral capsule at a dose of 25 mg/70 kg and was increased to 30 mg/70 kg if there were no dose limiting adverse events and if the participants were happy for the increased dosage.

The dose of diphenhydramine was 50 mg at the first session but increased to 100 mg regardless of subjective response and all doses were administered by staff. The primary drinking outcome was the percentage of heavy drinking days during weeks 5 to 32 and which were assessed at weeks 8, 12, 24 and 36.

Psilocybin-assisted therapy and heavy drinking days

A total of 95 participants with a mean age of 45.8 years (44.2% female) were included and randomised to psilocybin (49) or placebo and individuals had been alcohol dependent for a mean of 14.2 years.

The PHHDs during weeks 5 to 36 were 9.7% for the psilocybin-assisted group and 23.6% for the placebo group (mean difference = 13.9%, 95% CI 3 – 24.7, p = 0.01). In other words, the PHDD in psilocybin-assisted treatment group was 41% of that observed for the diphenhydramine group.

At the 32-week follow-up, the mean number of drinks per day was 2.26 for the diphenhydramine group and 1.17 for the psilocybin group and this mean difference (1.09) was significant (p = 0.01).

The authors concluded that among individuals with AUD, psilocybin-assisted psychotherapy was associated with a reduction in both daily and heavy drinking. They called for future studies to support these findings in patients with AUD.

Citation
Bogenschutz MP et al. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial JAMA Psychiatry 2022