Psilocybin + Pimavanserin for Depression

Recruiting at 1 trial location

Overseen By Depression and Anxiety Center Icahn School of Medicine at Mount Sinai

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: Antipsychotics, Antidepressants, Mood stabilizers, others

Disqualifiers: Substance use disorder, Psychotic disorder, Severe depression, Suicidal ideation, others

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: 1 day

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to treat Major Depressive Disorder (MDD) by testing the effects of a one-time dose of psilocybin, a compound found in some mushrooms, combined with either pimavanserin (a medication often used to treat hallucinations and delusions) or a placebo. The goal is to determine how these combinations can improve symptoms of depression over several weeks. Individuals diagnosed with MDD who are not currently using certain medications or substances might be suitable for this study. Researchers will evaluate participants multiple times up to five weeks after treatment to track changes in their condition.

As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people, offering participants a chance to contribute to important advancements in depression treatment.

Will I have to stop taking my current medications?

The trial requires participants to stop taking any serotonergic drugs for at least 2 weeks or 5 half-lives (whichever is longer) before receiving psilocybin. Additionally, certain medications like antipsychotics, serotonergic antidepressants, mood stabilizers, and some enzyme inhibitors are not allowed during the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found no serious side effects linked to psilocybin, suggesting it is generally safe to use. Many participants also reported meaningful personal experiences. The FDA has approved pimavanserin for treating hallucinations and delusions in people with Parkinson's disease, indicating it has passed strict safety tests for that use. While this does not guarantee it is equally safe for treating depression, it is a positive sign. So far, the combination of psilocybin and pimavanserin appears well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of psilocybin and pimavanserin for treating depression because these compounds offer a new approach compared to traditional antidepressants like SSRIs and SNRIs. Unlike typical treatments that often take weeks to show effects, psilocybin may produce rapid mood improvements due to its psychedelic properties, which can lead to profound changes in perception and mood. Pimavanserin, known for its use in Parkinson's disease psychosis, works differently by targeting serotonin receptors without the dopamine-related side effects common in other treatments. Together, these drugs could offer a faster, potentially more effective treatment option for depression, especially for patients who haven't responded well to existing medications.

What evidence suggests that this trial's treatments could be effective for Major Depressive Disorder?

This trial will compare the effects of Psilocybin combined with Pimavanserin versus Psilocybin with a placebo. Research has shown that psilocybin can quickly and lastingly improve depression symptoms. Studies have found that patients often feel significantly less depressed even the day after taking it, with positive effects lasting for weeks. Psilocybin has also helped with depression related to cancer and cases where other treatments have failed.

Pimavanserin is primarily used to treat symptoms in Parkinson's disease, such as hallucinations and delusions, suggesting it can affect brain chemistry linked to mood. Although limited data exists on using psilocybin and pimavanserin together, the known effects of each suggest they might help manage depression. ^{6 7 8 9 10}

Who Is on the Research Team?

James M Murrough, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Rachel Fremont

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

This trial is for individuals with Major Depressive Disorder (MDD). Specific eligibility criteria are not provided, but typically participants must meet diagnostic criteria for MDD and may need to be within a certain age range or health status.

Inclusion Criteria

24-item Hamilton Rating Scale for Depression (HRSD) ≥16

Capable of providing informed consent and complying with study procedures

Currently using or agreeing to use a highly effective contraception, if person of childbearing potential (such as condoms, IUD, or oral contraceptive), for duration of the study. Male participants agree to use highly effective contraception with partners of childbearing potential

Exclusion Criteria

I am allergic to psilocybin or pimavanserin.

I have a history of mania.

Any severity of substance use disorder in the last 6 months (excluding tobacco use disorder) as determined by DSM-V criteria via the SCID

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of psilocybin and either pimavanserin or placebo

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 weeks

Several visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Pimavanserin
• Psilocybin

Trial Overview The study is testing the effects of a single dose of psilocybin in combination with either pimavanserin or a placebo. Participants will be assigned to one of these treatments randomly and monitored over five weeks post-dosing.

How Is the Trial Designed?

Group I: Psilocybin + Pimavanserin Active Control 2 Interventions

single dose Psilocybin and single dose Pimavanserin

Group II: Psilocybin + Placebo Placebo Group 2 Interventions

single dose Psilocybin and single dose Placebo

Pimavanserin is already approved in United States for the following indications:

Approved in United States as Nuplazid for:

• Hallucinations and delusions associated with Parkinson's disease psychosis

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

Published Research Related to This Trial

A single dose of psilocybin (0.5-20 mg/kg) significantly increases the expression of genes related to neuroplasticity in the prefrontal cortex and hippocampus, suggesting its potential therapeutic effects for mental health disorders.

The study highlights that psilocybin's effects on gene expression are dose-dependent and predominantly observed in the prefrontal cortex, emphasizing the need to assess both gene expression and protein translation to understand its rapid effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. Jefsen, OH., Elfving, B., Wegener, G., et al.[2022]

In a study using the Flinders Sensitive Line rat model of depression, neither psilocin nor psilocybin demonstrated an antidepressant-like effect, as measured by the forced swim test, which assesses immobility and swimming behavior.

Despite previous positive results in humans, this study suggests that the Flinders Sensitive Line model may not be suitable for testing the effects of psilocybin, indicating a need for alternative animal models or behavioral tests in future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat. Jefsen, O., Højgaard, K., Christiansen, SL., et al.[2020]

Recent FDA-approved clinical studies suggest that psilocybin-assisted psychotherapy may effectively treat conditions like depression, anxiety, and certain addictions, indicating its potential as a valuable therapeutic tool.

If early clinical findings are confirmed by larger studies, psilocybin could significantly influence psychiatric medicine and expand treatment options for mental health disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin: from ancient magic to modern medicine. Nichols, DE.[2021]

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]

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]

This study found that the binding of serotonin 2A receptors (5-HT2AR) in the brain can predict how long the peak effects of psilocybin last and how quickly individuals return to normal consciousness after its effects wear off.

Higher levels of 5-HT2AR binding were associated with lower scores on the Mystical Experience Questionnaire, suggesting that individual differences in receptor availability may influence the subjective experience of psilocybin, which could have implications for its therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. Stenbæk, DS., Madsen, MK., Ozenne, B., et al.[2022]

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]

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]

This study identified phenylethylamine in Psilocybe semilanceata mushrooms, which may contribute to adverse reactions during psilocybin intoxication, as evidenced by a case involving three young men who experienced severe symptoms.

The levels of phenylethylamine in these mushrooms can vary significantly, with the highest concentration found in the case of hospitalization, suggesting that this compound could play a role in the tachycardia and other symptoms not directly linked to psilocybin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Presence of phenylethylamine in hallucinogenic Psilocybe mushroom: possible role in adverse reactions. Beck, O., Helander, A., Karlson-Stiber, C., et al.[2019]

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 (PY) is rapidly converted to its active form, psilocin (PI), in the body, with peak plasma levels occurring approximately 105 minutes after oral administration and 1.9 minutes after intravenous injection, indicating a quick onset of action.

The study found that psilocin has an estimated absolute bioavailability of about 52.7% when taken orally, suggesting that a significant portion of the drug is effectively absorbed into the bloodstream.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man. Hasler, F., Bourquin, D., Brenneisen, R., et al.[2019]

The PsiDeR trial is testing the feasibility of psilocybin-assisted therapy for major depressive disorder (MDD) in 60 participants who have not responded to at least two standard treatments, focusing on recruitment and dropout rates as primary outcomes.

Participants will receive either 25 mg of psilocybin or a placebo, along with psychological therapy, with the primary measure of depression assessed at 3 weeks, indicating a structured approach to evaluate both safety and efficacy of this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted therapy for the treatment of resistant major depressive disorder (PsiDeR): protocol for a randomised, placebo-controlled feasibility trial. Rucker, J., Jafari, H., Mantingh, T., et al.[2022]

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]

Citations

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Psilocybin as Transformative Fast‐Acting Antidepressant Since then, extended results have shown that psilocybin is effective in treating patients with cancer and depression [28], in major depressive ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S027858462500003X

Clinical and preclinical evidence of psilocybin as ... Clinical trials have revealed that psilocybin has a large, rapid, and persistent effect in the improvement of symptoms of depression and anxiety.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12226623/

Psilocybin therapy for treatment resistant depression MADRS score change at week 3 was the primary outcome of the study though a large reduction in depressive symptoms was evident on the day following psilocybin ...

4. nature.com nature.com/articles/s41386-025-02097-0

Psilocybin therapy for mood dysfunction in Parkinson's ... We observed significant and sustained improvements in depression and anxiety, consistent with prior studies of psilocybin therapy for major ...

5. researchgate.net researchgate.net/publication/383358461_The_role_of_psilocybin_in_depressive_disorders

The role of psilocybin in depressive disorders Background: Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06592833?term=Nuplazid&rank=10

NCT06592833 | Psilocybin With Pimavanserin Compared ... Each individual will be treated with a single dose of pimavanserin or placebo plus a single dose of psilocybin. Evaluations will be taken before dosing and ...

7. withpower.com withpower.com/trial/psilocybin-pimavanserin-for-depression-6901e

Psilocybin + Pimavanserin for Depression There were no serious adverse events related to psilocybin, indicating a favorable safety profile, and participants reported meaningful personal and spiritual ...

8. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/533544

Psilocybin With Pimavanserin Compared to ... This is an interventional, parallel arm assignment treatment study in individuals with Major Depressive Disorder (MDD).

9. mountsinai.org mountsinai.org/clinical-trials/psilocybin-with-pimavanserin-compared-to-psilocybin-alone-for-treatment-of-major-depressive-disorder

Psilocybin With Pimavanserin Compared to ... Summary: This is an interventional, parallel arm assignment treatment study in individuals with Major Depressive Disorder (MDD).

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10375870/

Psilocybin for treatment-resistant depression without ... Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and ...