CHANGES IN SLEEP PATTERNS WITH PSILOCYBIN-ASSISTED PSYCHOTHERAPY: AN EXPLORATORY ANALYSIS OF A RANDOMIZED CLINICAL TRIAL FOR TREATMENT-RESISTANT DEPRESSION

Introduction

Sleep disturbances are highly prevalent in depression, with insomnia being the most commonly reported sleep issue. Beyond being a core feature of depressive disorders, sleep disturbances are also associated with poorer treatment outcomes and functional impairment, highlighting the importance of evaluating sleep-related outcomes in novel therapeutics. Psilocybin-assisted psychotherapy (PAP) has demonstrated promising antidepressant effects in treatment-resistant depression (TRD). However, psilocybin has been thought to disrupt sleep, raising concerns about its impact on a core symptom of depression and its overall tolerability profile. The objective of this analysis was to determine changes in sleep following PAP in a sample of individuals with TRD.

Methods

We conducted a randomized, waitlist-controlled clinical trial (NCT05029466) evaluating PAP in 30 participants with TRD, including those with major depressive disorder (MDD, n=26) and bipolar II disorder (BDII). All participants received a single 25 mg dose of psilocybin with preparatory and integration psychotherapy. The primary outcome of the trial was antidepressant efficacy. In this secondary analysis, sleep was assessed using sleep-related items from the Quick Inventory of Depressive Symptomatology (QIDS) and MontgomeryÅsberg Depression Rating Scale (MADRS) throughout the 6 month trial period. Sleep-related items captured various domains of sleep, including sleep onset, quality and early morning awakening, allowing for evaluation of both insomnia-related symptoms and overall sleep quality. As an exploratory analysis, we report our results descriptively and do not formally test for statistical significance, given the small sample size and multiple outcomes.

Results

30 participants received PAP for TRD. As previously reported, psilocybin was well tolerated, with no serious adverse events and robust, rapid antidepressant effects. Sleep, as measured by QIDS and MADRS items, did not worsen post-treatment. Instead, preliminary data suggest a trend toward improved sleep quality, with reductions in the QIDS sleep onset and insomnia item scores of 0.43 point (on a 3 point scale) between baseline (2.53±0.78) and primary endpoint (2.11±0.83), and by 0.7 between baseline and secondary endpoint (1.8±1.00). The MADRS sleep item data further corroborates this trend, with a decrease of 0.52 points on a 6 point scale between baseline (1.87±1.59) and primary endpoint (1.34 ± 1.56).

Conclusion

This secondary analysis provides preliminary evidence that psilocybin does not exacerbate sleep disturbances in individuals with TRD or BDII and may offer benefits. Notably, observed improvements occurred despite concerns that serotonergic psychedelics, such as psilocybin, may impair sleep, indicating small but potentially favourable sleep outcomes in the context of this clinical trial. Given the contrast with existing literature, further research is warranted to evaluate the effects of PAP on sleep using objective and comprehensive sleep measures in future clinical trials.