Psilocybin for Bipolar Depression (Psilo-BD Trial)
Palo Alto (17 mi)Overseen byJoshua Rosenblat, MD, MSc
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University Health Network, Toronto
No Placebo Group
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?This study is an open-label, single-arm, proof-of-concept study, wherein treatment resistant bipolar depression (TRBD) participants will receive one 25 mg dose of oral psilocybin accompanied by preparatory, monitoring, and integration psychotherapy sessions (psilocybin-assisted psychotherapy, or PAP). Using fMRI (functional magnetic resonance imaging), the findings of this study will provide data on the neurobiological mechanism of psilocybin in TRBD.
The primary objective is to understand the dynamic role of amygdala activity by evaluating the neurobiological effects of a single psychedelic dose (25 mg) of oral psilocybin in individuals with a moderate to severe major depressive episode and a primary diagnosis of Bipolar II Disorder, with 2 or more failed treatment trials (i.e., treatment resistant bipolar depression \[TRBD\]). Neurobiological effects will be determined by evaluating the association between post-treatment right amygdala activity during the facial affect task (determined by fMRI one day after the psilocybin dose) and antidepressant effects (determined by changes in the Montgomery-Åsberg Depression Rating Scale \[MADRS\] scores over time, during the one-week period post-psilocybin dose). This is a single-arm, open-label clinical trial wherein all participants will receive the same study intervention.
Hypothesis: Increased right amygdala activity on fMRI with emotional stimuli one day after psilocybin treatment will be associated with greater antidepressant effects in the one-week period post-treatment in individuals with TRBD.
Is the drug psilocybin a promising treatment for bipolar depression?Psilocybin shows promise as a treatment for bipolar depression because it has been effective in reducing symptoms of depression in several studies. It may also improve mood and well-being by working on serotonin receptors in the brain.35101114
What safety data exists for psilocybin treatment?Psilocybin has been studied for its pharmacology, pharmacodynamics, and pharmacokinetics, showing rapid effects on the central nervous system. Adverse effects include ataxia, hyperkinesis, and hallucinations. A survey of 1993 individuals reported that 11% put themselves or others at risk, with 2.6% behaving aggressively and 2.7% needing medical help. However, in controlled settings with screened participants, the risk of adverse effects is low. Recent studies have shown promise for treating depression and substance use disorders, with a safety profile established in healthy adults at escalating doses.12467
What data supports the idea that Psilocybin for Bipolar Depression is an effective treatment?The available research shows that psilocybin has been effective in reducing symptoms of depression in several studies. For example, it has been shown to produce rapid and lasting antidepressant effects in patients with major depressive disorder. Although these studies focus on depression in general, they suggest that psilocybin could be beneficial for bipolar depression as well. Additionally, psilocybin is well tolerated with limited side effects, and even patients with treatment-resistant disorders have shown significant improvements after just one or a few sessions. However, more research is needed specifically for bipolar depression to confirm these findings.89121314
Do I have to stop taking my current medications for the trial?Yes, you will need to taper off your current medications for at least 1 month before the trial, unless you are taking lamotrigine, which you must continue throughout the study.
Eligibility Criteria
Adults aged 18-65 with Bipolar II Disorder, currently in a moderate to severe depressive episode without psychotic features, who haven't improved after two or more treatments. They must be able or planning to take lamotrigine, understand English well enough for consent and questionnaires, and agree to use effective contraception if capable of becoming pregnant.Inclusion Criteria
I have been diagnosed with Bipolar II and am currently having a major depressive episode without psychosis.
I am between 18 and 65 years old.
My current depression is severe, and I haven't improved after trying two or more treatments.
I am currently on lamotrigine or will start it soon and won't change it during the study.
Treatment Details
The trial tests the effects of a single dose of psilocybin (25 mg) on brain function in treatment-resistant bipolar depression. Participants will undergo fMRI scans and receive psychotherapy sessions alongside the psilocybin to explore changes in amygdala activity and its link to antidepressant effects.
1Treatment groups
Experimental Treatment
Group I: Single Dose PsilocybinExperimental Treatment2 Interventions
Single dose of orally administered 25 mg of psilocybin taken in conjunction with supportive therapy
Psilocybin is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Psilocybin for:
- Treatment-resistant depression (TRD) under Breakthrough Therapy designation
🇪🇺 Approved in European Union as Psilocybin for:
- Treatment-resistant depression (TRD) under PRIME designation
Find a clinic near you
Research locations nearbySelect from list below to view details:
Toronto Western Hospital - University Health NetworkToronto, Canada
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Who is running the clinical trial?
University Health Network, TorontoLead Sponsor
Centre for Addiction and Mental HealthCollaborator
References
The pharmacology of psilocybin. [2016]Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.
[Hallucinogenic mushrooms]. [2018]The group of hallucinogenic mushrooms (species of the genera Conocybe, Gymnopilus, Panaeolus, Pluteus, Psilocybe, and Stropharia) is psilocybin-containing mushrooms. These "magic", psychoactive fungi have the serotonergic hallucinogen psilocybin. Toxicity of these mushrooms is substantial because of the popularity of hallucinogens. Psilocybin and its active metabolite psilocin are similar to lysergic acid diethylamide. These hallucinogens affect the central nervous system rapidly (within 0.5-1 hour after ingestion), producing ataxia, hyperkinesis, and hallucinations. In this review article there are discussed about history of use of hallucinogenic mushrooms and epidemiology; pharmacology, pharmacodynamics, somatic effects and pharmacokinetics of psilocybin, the clinical effects of psilocybin and psilocin, signs and symptoms of ingestion of hallucinogenic mushrooms, treatment and prognosis.
Occurrence of psilocybin in various higher fungi from several European countries. [2007]Using high performance liquid and thin-layer chromatographic methods more than 100 species of fungi from Europe belonging to 18 genera were analysed for the hallucinogenic compound psilocybin and for some related tryptamine derivatives. Psilocybin, psilocin and/or baeocystin were found in 3 PSILOCYBE 1 PANAEOLUS, 5 INOCYBES and one PLUTEUS. PSILOCYBE SEMILANCEATA and PANAEOLUS SUBBALTEATUS proved to be the only psilocybin-containing fungi that can be gathered in Middle and Northern Europe in sufficient quantities to permit abuse.
Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. [2018]Acute and enduring adverse effects of psilocybin have been reported anecdotally, but have not been well characterized. For this study, 1993 individuals (mean age 30 yrs; 78% male) completed an online survey about their single most psychologically difficult or challenging experience (worst "bad trip") after consuming psilocybin mushrooms. Thirty-nine percent rated it among the top five most challenging experiences of his/her lifetime. Eleven percent put self or others at risk of physical harm; factors increasing the likelihood of risk included estimated dose, duration and difficulty of the experience, and absence of physical comfort and social support. Of the respondents, 2.6% behaved in a physically aggressive or violent manner and 2.7% received medical help. Of those whose experience occurred >1 year before, 7.6% sought treatment for enduring psychological symptoms. Three cases appeared associated with onset of enduring psychotic symptoms and three cases with attempted suicide. Multiple regression analysis showed degree of difficulty was positively associated, and duration was negatively associated, with enduring increases in well-being. Difficulty of experience was positively associated with dose. Despite difficulties, 84% endorsed benefiting from the experience. The incidence of risky behavior or enduring psychological distress is extremely low when psilocybin is given in laboratory studies to screened, prepared, and supported participants.
Role of psilocybin in the treatment of depression. [2020]Psilocybin is a naturally occurring alkaloid, pharmacologically similar to the classic hallucinogen lysergic acid diethylamide (LSD). Although primarily used as a recreational drug or an entheogen in particular cultural settings, recent population based studies have shown that it does not lead to serious physical or mental health problems or dependent use. In view of recent work demonstrating psilocybin's potential to increase subjective sense of wellbeing and because of its novel mechanism of 5-HT2A serotonin receptor agonism, it is being explored for possible therapeutic utility in mood and anxiety disorders.
Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. [2022]Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults.
DARK Classics in Chemical Neuroscience: Psilocybin. [2019]Psilocybin is found in a family of mushrooms commonly known as "magic mushrooms" that have been used throughout history to induce hallucinations. In the late 1950s Albert Hofmann, of Sandoz Laboratories, identified and synthesized the psychoactive compounds psilocybin and psilocin which are found in psilocybe mushrooms. Psilocybin was marketed by Sandoz as Indocybin for basic psychopharmacological and therapeutic clinical research. Psilocybin saw a rapid rise in popularity during the 1960s and was classed as a Schedule I drug in 1970. This led to a significant decrease in psilocybin research. Recently, however, preliminary studies with psilocybin have shown promise as potential for the treatment of obsessive compulsive disorder, alcohol addiction, tobacco addiction, and major depressive disorder, and the treatment of depression in terminally ill cancer patients. This review describes in detail the synthesis, metabolism, pharmacology, adverse drug reactions, and importance of psilocybin to neuroscience in the past and present.
[Treatment with psilocybin: applications for patients with psychiatric disorders]. [2021]After a cessation of almost 40 years, there is renewed interest into therapeutic applicationsof the serotonergic psychedelic psilocybin for the treatment of patients with various psychiatric disorders. PubMed was searched for clinical trials into "psilocybin" between 2000 and 2020, complemented by handsearching. Articles were also screened for explanatory models and working mechanisms. Psilocybin has been studied in 9 clinical trials: for the treatment of substance use disorders, depression, end-of-life anxiety, demoralization, and obsessive-compulsive disorder. Results show that psilocybin is well tolerated, with only limited side-effects, while even patients with treatment-resistant disorders sometimes show marked, long-term improvements after one or a few sessions. Initial results are encouraging, but there are several limitations. More research is needed to determine which patient populations can benefit, what role setting and the placebo response play, and how these novel treatments can be optimized.
Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. [2022]Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive disorder (MDD), but little is known about long-term outcomes.
Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice. [2023]4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing mushrooms, including the secondary amine 4-phosphoryloxy-N-methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin), but these compounds are not well studied. Here, we investigated the structure-activity relationships for psilocybin, baeocystin, and aeruginascin, as compared to their 4-acetoxy and 4-hydroxy analogues, using in vitro and in vivo methods. Broad receptor screening using radioligand binding assays in transfected cells revealed that secondary and tertiary tryptamines with either 4-acetoxy or 4-hydroxy substitutions display nanomolar affinity for most human 5-HT receptor subtypes tested, including the 5-HT2A and the serotonin 1A receptor (5-HT1A). The same compounds displayed affinity for 5-HT2A and 5-HT1A in mouse brain tissue in vitro and exhibited agonist efficacy in assays examining 5-HT2A-mediated calcium mobilization and β-arrestin 2 recruitment. In mouse experiments, only the tertiary amines psilocin, psilocybin, and 4-acetoxy-N,N-dimethyltryptamine (psilacetin) induced head twitch responses (ED50 0.11-0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by 5-HT2A antagonist pretreatment, supporting 5-HT2A involvement. Both secondary and tertiary amines decreased body temperature and locomotor activity at higher doses, the effects of which were blocked by 5-HT1A antagonist pretreatment. Across all assays, the pharmacological effects of 4-acetoxy and 4-hydroxy compounds were similar, and these compounds were more potent than their 4-phosphoryloxy counterparts. Importantly, psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own.
Risks and benefits of psilocybin use in people with bipolar disorder: An international web-based survey on experiences of 'magic mushroom' consumption. [2023]Psilocybin, the primary psychoactive component of psychedelic 'magic mushrooms', may have potential for treating depressive symptoms, and consequent applications for bipolar disorder (BD). Knowledge of the risks and benefits of psilocybin in BD is limited to case studies.
Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. [2023]Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature.
Psilocybin in Palliative Care: An Update. [2023]This review article summarizes clinically and socially relevant developments over the past five years in the therapeutic use of the classical tryptamine psychedelic substance psilocybin, with respect to the common challenges faced by palliative care patients and their care teams. Psilocybin is available in whole fungal and isolated forms but is not yet approved for therapeutic use in the United States. Using targeted database and gray literature searches, and author recall, key sources were identified, reviewed, and synthesized as to the safety and efficacy of psilocybin in palliative care.
Assessing potential of psilocybin for depressive disorders. [2023]There has been increasing interest in the role psilocybin may play in the treatment of depressive disorders. Several clinical trials have shown psilocybin to have efficacy in reducing symptoms of depression.