Psilocybin for Bipolar Depression

(Psilo-BD Trial)

Overseen By Zoe Doyle, BScN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University Health Network, Toronto

Must be taking: Lamotrigine

Must not be taking: Anticonvulsants, Benzodiazepines, Psychedelics, Steroids

Disqualifiers: Pregnancy, Mania, Substance use disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a single dose of psilocybin, combined with therapy, can aid those with bipolar depression unresponsive to other treatments. Researchers focus on how this treatment affects brain activity, particularly in the amygdala, which is linked to emotions. Individuals with Bipolar II Disorder who have experienced major depressive episodes unresponsive to at least two treatments may find this study suitable. Participants will receive one dose of psilocybin and therapy, with brain scans monitoring any changes. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants a chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

Yes, you will need to stop taking your current medications for at least one month before the trial starts, but you must continue taking lamotrigine throughout the study.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that psilocybin, the treatment tested in this trial, has promising safety results from earlier studies. One study found that a single dose of psilocybin was well-tolerated by people with depression unresponsive to other treatments. Participants experienced few serious side effects, with most reporting only mild to moderate effects, such as temporary changes in mood or perception.

Another study found that psilocybin was generally well-tolerated when used with psychological support. Participants did not report any unexpected negative effects, suggesting that psilocybin is relatively safe in controlled settings with support available.

Overall, these findings suggest that psilocybin is safe for human use in clinical settings, with minimal side effects. However, it is important to remember that this is a Phase 1 trial, meaning the treatment is still in early testing stages to confirm its safety and effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for bipolar depression, which often involve mood stabilizers and antipsychotic medications, psilocybin is derived from psychedelic mushrooms and offers a completely different approach. Researchers are excited about psilocybin because it acts on serotonin receptors in the brain, potentially providing rapid relief from depressive symptoms after just a single dose. This is a significant departure from traditional medications that typically require weeks to take effect. Additionally, psilocybin is used in conjunction with supportive therapy, which could enhance and prolong its benefits for individuals with bipolar depression.

What evidence suggests that psilocybin might be an effective treatment for bipolar depression?

Research has shown that psilocybin, a substance found in certain mushrooms, may help treat depression, even in individuals with bipolar II disorder. In this trial, participants will receive a single dose of psilocybin, which studies have found can greatly reduce depression symptoms, leading to improved mood and mental health stability. Importantly, one study found that psilocybin did not increase suicidal thoughts or cause manic episodes, suggesting it is a safe option for individuals with bipolar depression. Another study noted a significant drop in depression symptoms soon after treatment. These findings suggest that psilocybin could be a promising treatment for those who haven't benefited from traditional therapies. ^{2 6 7 8 9}

Who Is on the Research Team?

Joshua Rosenblat, MD, MSc

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

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 am willing to follow all the study's requirements.

I have been diagnosed with Bipolar II and am currently having a major depressive episode without psychosis.

I have signed the informed consent form.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single 25 mg dose of oral psilocybin with preparatory, monitoring, and integration psychotherapy sessions

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including fMRI and MADRS score assessments

4 weeks

Multiple visits (in-person and virtual)

Open-label extension (optional)

Participants may opt into continuation of treatment long-term if eligible

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview 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.

How Is the Trial Designed?

Group I: Single Dose Psilocybin Experimental Treatment 2 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

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Centre for Addiction and Mental Health

Collaborator

Trials

388

Recruited

84,200+

Published Research Related to This Trial

Psilocybin-containing mushrooms, commonly known as hallucinogenic or 'magic' mushrooms, rapidly affect the central nervous system within 0.5-1 hour of ingestion, leading to effects such as ataxia, hyperkinesis, and hallucinations.

The review discusses the significant toxicity associated with these mushrooms, highlighting the need for awareness and understanding of their pharmacology, clinical effects, and potential treatment for adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. Reingardiene, D., Vilcinskaite, J., Lazauskas, R.[2018]

A study analyzed over 100 species of fungi from Europe for the presence of psilocybin and related compounds, identifying several genera that contain these hallucinogenic substances.

Only two species, Psilocybe semilanceata and Panaeolus subbalteatus, were found in sufficient quantities in Middle and Northern Europe to potentially be abused for their psilocybin content.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Occurrence of psilocybin in various higher fungi from several European countries. Stijve, T., Kuyper, TW.[2007]

Psilocybin, a prodrug for psilocin, shows strong agonist activity at the serotonin 5-HT2A receptor, which is responsible for its psychedelic effects, and has been shown to have nanomolar affinity for various serotonin receptor subtypes in both in vitro and in vivo studies.

In mouse experiments, psilocybin and related compounds induced head twitch responses, a sign of psychedelic activity, which were blocked by a 5-HT2A antagonist, confirming the involvement of this receptor in their effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice. Glatfelter, GC., Pottie, E., Partilla, JS., et al.[2023]

A survey of 541 individuals with bipolar disorder revealed that while psilocybin use can lead to new or increased symptoms, particularly manic symptoms and anxiety, many respondents still found the experience more helpful than harmful.

The findings suggest that psilocybin may have potential benefits for mental health in bipolar disorder, but clinical trials should closely monitor for the emergence or intensification of bipolar symptoms following its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks and benefits of psilocybin use in people with bipolar disorder: An international web-based survey on experiences of 'magic mushroom' consumption. Morton, E., Sakai, K., Ashtari, A., et al.[2023]

Psilocybin, a naturally occurring compound similar to LSD, has been found to not cause serious health issues or dependency, suggesting a favorable safety profile.

Recent studies indicate that psilocybin may enhance feelings of wellbeing and is being investigated for its potential therapeutic effects on mood and anxiety disorders due to its action on the 5-HT2A serotonin receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of psilocybin in the treatment of depression. Mahapatra, A., Gupta, R.[2020]

Psilocybin shows promising effects in alleviating anxiety, depression, and emotional distress in palliative care patients, with a favorable safety profile, based on recent studies and reports.

Despite its potential benefits, psilocybin is not yet approved for therapeutic use in the U.S., and significant barriers exist for access, particularly for vulnerable populations like the elderly and those in palliative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin in Palliative Care: An Update. Whinkin, E., Opalka, M., Watters, C., et al.[2023]

Psilocybin, a serotonergic psychedelic, has shown promise in treating various psychiatric disorders, including depression and substance use disorders, with 9 clinical trials conducted between 2000 and 2020.

The treatment is generally well tolerated with limited side effects, and some patients with treatment-resistant conditions have experienced significant long-term improvements after just a few sessions, indicating its potential efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment with psilocybin: applications for patients with psychiatric disorders]. Breeksema, JJ., Koolen, MHB., Somers, M., et al.[2021]

In a placebo-controlled study involving individuals with moderate to severe major depressive disorder, psilocybin (0.3 mg/kg) showed larger antidepressant effect sizes compared to placebo, with 66.7% of participants responding and 46.7% achieving remission after treatment.

The antidepressant effects of psilocybin persisted for an average of 2 months, indicating its potential as a long-lasting treatment option for depression, although the strength of the mystical experience during dosing did not correlate with these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. Sloshower, J., Skosnik, PD., Safi-Aghdam, H., et al.[2023]

In a study involving 12 healthy adults, escalating doses of psilocybin (0.3, 0.45, and 0.6 mg/kg) were administered safely, with no serious adverse events reported, indicating a favorable safety profile for this psychedelic compound.

The pharmacokinetics of psilocin, the active metabolite of psilocybin, were linear across the tested doses, with an elimination half-life of about 3 hours, suggesting that no dose adjustments are necessary for individuals with mild to moderate renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Brown, RT., Nicholas, CR., Cozzi, NV., et al.[2022]

Psilocybin, a hallucinogenic compound found in certain mushrooms, has been associated with increasing rates of drug abuse, highlighting the need for comprehensive pharmacological understanding.

Despite its historical use in the 1960s for experimental medical purposes, recent research has only begun to uncover the pharmacological properties of psilocybin, indicating a gap in knowledge that needs to be addressed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacology of psilocybin. Passie, T., Seifert, J., Schneider, U., et al.[2016]

Psilocybin has shown promise in clinical trials for reducing symptoms of depression, indicating its potential as a novel treatment option.

Patients with treatment-resistant depression (TRD) may benefit the most from psilocybin therapy, although the risks associated with its use are still not fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing potential of psilocybin for depressive disorders. Kozak, Z., Johnson, MW., Aaronson, ST.[2023]

Psilocybin, a compound found in 'magic mushrooms', has shown potential in recent studies for treating various mental health conditions, including obsessive-compulsive disorder, alcohol and tobacco addiction, and major depressive disorder, particularly in terminally ill cancer patients.

Despite its classification as a Schedule I drug in 1970, which halted much research, there is a renewed interest in psilocybin's therapeutic effects, highlighting its importance in both historical and contemporary neuroscience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DARK Classics in Chemical Neuroscience: Psilocybin. Geiger, HA., Wurst, MG., Daniels, RN.[2019]

In a survey of 1993 individuals who experienced challenging psilocybin trips, 39% rated their experience as one of the most difficult of their lives, with 11% reporting risks of physical harm, particularly influenced by dose and lack of support.

Despite the challenges, 84% of respondents felt they benefited from the experience, suggesting that while adverse effects can occur, the overall incidence of serious psychological distress is low, especially in controlled settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. Carbonaro, TM., Bradstreet, MP., Barrett, FS., et al.[2018]

In a study of 27 patients with moderate to severe major depressive disorder, psilocybin-assisted treatment showed significant and lasting antidepressant effects, with 75% of participants experiencing a treatment response and 58% achieving remission after 12 months.

There were no serious adverse events related to psilocybin, indicating a favorable safety profile, and participants reported meaningful personal and spiritual experiences that correlated with increased well-being, although these did not directly predict improvements in depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Gukasyan, N., Davis, AK., Barrett, FS., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05065294

Psilocybin Therapy for Depression in Bipolar II Disorder The primary goal of this study is to examine the safety, tolerability, and feasibility of psilocybin therapy in people with Bipolar II Disorder (BD II).

2. psychiatrictimes.com psychiatrictimes.com/view/comp360-psilocybin-for-treatment-resistant-depression-positive-phase-3-efficacy-data

COMP360 Psilocybin for Treatment-Resistant Depression A single dose of COMP360 25 mg compared with placebo demonstrated a highly statistically significant reduction in symptom severity (P<0.001) and ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10701666/

Single-Dose Synthetic Psilocybin With Psychotherapy for ... The findings suggest efficacy and safety of psilocybin in bipolar II depression and support further study of psychedelics in this population.

4. ir.compasspathways.com ir.compasspathways.com/News--Events-/news/news-details/2023/Study-results-of-psilocybin-treatment-in-bipolar-II-depression-published-in-JAMA-Psychiatry/default.aspx

Study results of psilocybin treatment in bipolar II ... There was no increase in the suicidality score based on the MADRS, no manic symptoms and no unexpected adverse events or difficulties with the ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032724020317

Psychedelic use and bipolar disorder – An investigation of ... Results showed a significant reduction in depressive symptoms and cannabis use, an increase in the number of days without mental health symptoms ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05624268

Efficacy, Safety, and Tolerability of COMP360 in ... Study Overview. Brief Summary. Efficacy, Safety, and Tolerability of a single administration of COMP360 in participants with treatment-resistant depression ( ...

7. journals.sagepub.com journals.sagepub.com/doi/10.1177/02698811251362390

Investigating the safety and tolerability of single-dose ... A Phase 2 trial examining single-dose COMP360 psilocybin suggested that treatment was well-tolerated, produced a rapid decrease in depressive ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05711940

NCT05711940 | Efficacy, Safety, and Tolerability of Two ... The aim is to assess the efficacy of COMP360, administered with psychological support in adult participants with TRD, in improving symptoms of depression.

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032724020494

The role of the psychedelic experience in psilocybin ... Clinical trials have revealed that psilocybin has a large, rapid, and persistent effect in the improvement of symptoms of depression and ...