Psychedelic Safe, Possibly Effective for Refractory Depression

Nancy A. Melville

July 06, 2016

In the latest research probing the psychiatric benefits of a psychogenic drug, researchers report that psilocybin, the active ingredient in "magic mushrooms," is safe and is potentially efficacious in the treatment of major depression.

"To our knowledge, this is the first investigation of the safety and efficacy of psilocybin as a treatment for major depression," write the research team from the Division of Brain Sciences, Center for Neuropsychopharmacology, at Imperial College London, United Kingdom.

"Our findings imply that psilocybin might have value as a treatment option in the management of treatment-resistant depression."

The study was published in the July issue of Lancet Psychiatry.

Impressive Results

The small, open-label study involved 12 volunteers with moderate to severe unipolar, treatment-resistant depression. The patients included six men and six women; five of the patients reported previous experience with psilocybin.

The participants were treated with two oral doses of psilocybin 7 days apart, the first at a low safety dose of 10 mg, and the second, at a higher dose of 25 mg to assess the treatment effect.

Because the drug induces a state of altered consciousness for several hours, patients were closely monitored throughout the experience and received nondirective support of at least two staff members in a relaxing, controlled environment. Counseling was provided before and after the treatment.

Patients reported the onset of the psychedelic effects from the psilocybin approximately 30 to 60 minutes following dosing. The effects peaked 2 to 3 hours after dosing and subsided after a period of at least 6 hours after dosing.

There were no reports of serious or unexpected adverse events related to the treatment; however, all patients experienced transient anxiety during the period of drug onset. Nine patients experienced transient confusion or thought disorders, four had mild or transient nausea, and four experienced transient headaches.

Assessments of depressive symptoms, using the 16-item Quick Inventory of Depressive Symptoms (QIDS), showed significant reductions at 1 week relative to baseline (mean QIDS difference, -11.8; P = .002). Improvements were sustained at 3 months (mean QIDS difference, -9.2; P = .003) following the high-dose treatment.

The response rate was 67% (n = 8) at 1 week after treatment; 7 of 8 patents met the criteria for remission; 58% (n = 7) had the sustained response at 3 months; and 42% (n = 5) remained in remission.

Patients reported marked and sustained improvements in anxiety and anhedonia.

Study coauthor Camilla Day, MD, noted that the results, though preliminary, are impressive in comparison with response rates for patients with refractory depression reported in other research.

"For a similar treatment-resistant population in the [NIH-funded Sequenced Treatment Alternatives to Relieve Depression] STAR-D study at level 3 and 4, they found remission rates of 12% to 25% and 13%, respectively," she told Medscape Medical News.

"Obviously this is a small, open-label feasibility project, and so we are aiming to do a randomized controlled trial to find out the true response rate, as we know that placebo response rates have been found to be around 30%."

Ego Dissolution

The authors note that psilocybin has a favorable toxicity profile and is not associated with compulsive drug-seeking behavior.

Psilocybin is a component of psilocin (4-hydroxy-dimethyltryptamine), a serotonin receptor agonist. Its primary psychoactive effects are mediated by serotonin 2A (5-HT2A) receptor agonism, which makes psilocybin a unique candidate for use in the treatment of refractory depression, the authors note.

"Psilocybin therefore has a novel pharmacology in the context of currently available antidepressant medications, because selective serotonin-reuptake inhibitors [SSRIs] are not direct 5-HT2A receptor agonists."

In one recent study, intravenous injection of psilocybin was shown to be associated with reduced blood flow in the medial prefrontal cortex, which, importantly, is also targeted by SSRIs when hyperactive, as reported by Medscape Medical News.

According to Dr Day, the effects of psilocybin may arise from a multifactorial combination of the drug's mechanisms, therapeutic guidance during the psilocybin treatment session, and the patient's own perceptions of the experience.

"Although we have not published the qualitative results yet, we believe that one factor that predicts a good response from psilocybin is the 'rapport' between the patient and the guide or therapist," she explained.

"We believe that the therapeutic effect from psilocybin comes from an altered state of consciousness known as ego dissolution, where patients are able to experience a new, more 'connected' way of seeing themselves and the world, and then reintegrate this into their life afterwards."

Important New Evidence

Although the new study is the first examine the effects of psilocybin in patients with major depression, the drug has been shown in previous studies to be beneficial in the treatment of alcohol and tobacco dependence. In a study published in JAMA in 2011, a single dose of psilocybin was found to reduce anxiety and depression in patients with end-stage cancer.

Charles S. Grob, MD, a senior author on the latter study of cancer patients and a professor of psychiatry and pediatrics at the University of California, Los Angeles, School of Medicine, said the new research adds important evidence on the use of psilocybin in psychiatry.

"The study provides further support that under optimal conditions with careful monitoring, psilocybin treatment can be safely administered," Dr Grob told Medscape Medical News.

Dr Grob noted that the new study targets patients who may represent the best candidates for treatment.

"The case for the psilocybin treatment model may be strongest with patient populations that have been refractory, or nonresponsive, to conventional treatments," he said.

"Such conditions may include, although not limited to, refractory major depression, anxiety disorders, chronic posttraumatic stress disorder, obsessive-compulsive disorder, and alcoholism and drug addiction."

According to Phil Cowen, MD, of the Department of Psychiatry at the University of Oxford, United Kingdom, a key challenge in moving forward with placebo-controlled trials will be finding a condition that represents a valid placebo.

"I think the main practical issue is how one could ever devise a plausible 'blind' placebo for a psychedelic drug," he told Medscape Medical News.

"There is also the question about how to get psilocybin made to a sufficient purity that allows it to be used in a clinical trial in humans. This involves both substantial cost and regulatory issues."

Psilocybin is currently a Schedule I drug, with no medically accepted use for treatment in the United States. For the study, the researchers obtained psilocybin from THC-pharm (Frankfurt, Germany) and had a manufacturer formulate the product into 5-mg capsules with licensing for Schedule I drugs.

In an accompanying commentary, Dr Cowen noted the importance of the fact that nearly half of the patients in the study had previous experience with psilocybin.

"Presumably, these participants had experienced a positive psychological response to psilocybin previously, and believed that the drug could help them," Dr Cowen writes.

"This is significant in an open-label study because, as acknowledged by the authors, it increases the likelihood of expectancy effects. Perhaps related to this factor was the substantial clinical response to the first low-dose treatment of 10 mg psilocybin."

The finding raises the question of whether the low dose alone may have lasting benefits, Dr Cowen noted.

He added that the results at 3 months "are promising but not completely compelling, with about half the group showing significant depressive symptoms.

"Further follow-ups using detailed qualitative interviews with patients and family could be very helpful in enriching the assessment," he said.

The study was funded by a grant from the Medical Research Council. One coauthor has received research funding and lecture honoraria from Servier and lecture honoraria from Lundbeck. The other authors have disclosed no relevant financial relationships. Dr Cowen has been a member of an advisory board for Lundbeck in the past 3 years. Dr Grob has disclosed no relevant financial relationships.

Lancet Psychiatry. 2016;3:592-593, 619-627. Full text, Commentary

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