Obsessive-compulsive disorder (OCD) is a common pathology (2-3% of the American population) that can cause significant disability. With current treatments, mainly cognitive behavioral therapy and selective serotonin reuptake inhibitors, 40 to 60% of patients show only partial recovery, and 10% are resistant to treatment. There is therefore an urgent need for new therapeutic approaches.
Mice carrying a homozygous deletion of the SAPAP3 gene (SAPAP 3 KO) express an excessive self-grooming phenotype, head and body tics, and anxiety. These behaviors strongly resemble the pathological body washing behaviors observed in humans in OCD.
There is growing interest in psilocybin, and other triptaminergic psychedelics, used as therapeutics for a range of psychiatric disorders such as depression, alcohol and nicotine addiction, and end-of-life anxiety. Based on preliminary work showing that psilocybin could alleviate OCD symptoms, a team of researchers undertook a 3-arm randomized controlled trial studying its effects on 50 SAPAP3 KO mice (28 males, 20 females).
Two treatments evaluated: psilocybin and hallucinogenic mushroom extract
Mice meeting the inclusion criteria were randomly assigned to a single peritoneal injection of 4.4 mg/kg psilocybin (PSIL), hallucinogenic mushroom extract (HME) containing the same dose of PSIL, or vehicle control. They were evaluated after 2, 12 and 21 days by an evaluator who was single-blind to treatment allocation, for grooming behaviors, tics, anxiety and other associated behaviors.
Placebo-treated mice (n = 18) demonstrated an increase of 118.71 ± 95.96% in total self-grooming score (primary outcome) over the 21 days of observation. On the other hand, this decreased by 14.60 ± 17.90% in mice treated with PSIL (n = 16) and by 19.20 ± 20.05% in mice treated with ECH (n = 16 ).
Secondary outcomes such as tics and anxiety all showed significant improvement with PSIL and ECH, over the 21 days of assessment. Although equivalent to PSIL in terms of overall effect on self-grooming, ECH showed greater efficacy in relieving head and body tics and anxiety.
Seven mice were removed from the study for developing dermatological lesions resulting from excessive self-grooming, but their final observations were included in the analyses. Among them, five were part of the control group and two of the PSIL group.
Long-term effects
In mice that responded to PSIL (n = 12/16) and ECH (n = 13/16), the beneficial effects of single-dose treatment persisted for up to 7 weeks.
Mice initially treated with placebo and non-responders showed a clear and durable response when treated with a single dose of PSIL or ECH, with an additional 3-week follow-up.
These results would warrant further clinical trials of psilocybin treatment in the management of OCD, particularly to understand the mechanisms underlying the long-term effects to relieve excessive washing behaviors observed in this study.
The question of psilocybin dosage, however, is worth considering. In this study, 4.4 mg/kg was administered, which would be approximately equivalent to 25 mg for a person weighing 70 kg. This dose causes a strong psychedelic experience in humans.
The only clinical trial studying psilocybin in OCD published to date reports that doses both lower and higher than this induced improvement in OCD symptoms. However, it should be noted that only acute effects lasting up to 24 hours have been reported. Thus, the dosage of psilocybin required in human studies to achieve long-term results remains to be determined.
