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

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.

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.

What evidence supports the effectiveness of the drug psilocybin for treating depression?

Research shows that psilocybin can quickly reduce symptoms of depression, with effects lasting after just one or two doses. It has been effective in treating major depressive disorder and other psychiatric conditions, with patients often experiencing significant improvements. ^{1 2 3 4 5}

Is psilocybin generally safe for humans?

Psilocybin, found in 'magic mushrooms,' can cause challenging experiences, but when given in controlled settings to screened and supported participants, the risk of lasting psychological distress or risky behavior is very low. Some studies have shown that psilocybin can be safe in healthy adults when administered in escalating doses, but it can also lead to temporary hallucinations and other effects on the central nervous system. ^{6 7 8 9 10}

How is the drug psilocybin unique in treating bipolar depression?

Psilocybin is unique because it works by activating serotonin receptors in the brain, which can improve mood and well-being, and it is being explored for its potential to treat mood disorders like bipolar depression. Unlike traditional treatments, psilocybin is a naturally occurring compound found in certain mushrooms and is known for its psychedelic effects. ^{3 11 12 13 14}

Research Team

Joshua Rosenblat, MD, MSc

Principal Investigator

University Health Network, Toronto

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 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 am between 18 and 65 years old.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Psilocybin in Palliative Care: An Update. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Assessing potential of psilocybin for depressive disorders. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

[Treatment with psilocybin: applications for patients with psychiatric disorders]. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

DARK Classics in Chemical Neuroscience: Psilocybin. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

The pharmacology of psilocybin. [2016]

11. Germany pubmed.ncbi.nlm.nih.gov

Occurrence of psilocybin in various higher fungi from several European countries. [2007]

12. United States pubmed.ncbi.nlm.nih.gov

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice. [2023]

13. United States 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. [2023]

14. England pubmed.ncbi.nlm.nih.gov

Role of psilocybin in the treatment of depression. [2020]