The therapeutic potential of psychedelic drugs: past, present, and future

This review (2017) looks at the potential of psychedelics to be used in treatment of mental disorders, with a focus on psilocybin for depression.

Abstract

“Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three separate clinical trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.”

Authors: Robin L. Carhart-Harris & Guy M. Goodwin

Notes

This paper is included in our ‘Top 10 Articles for Psychedelic Novices‘

Summary

A BRIEF HISTORY OF PSYCHEDELIC RESEARCH

Psychedelic drugs, and particularly LSD, awakened a significant cultural zeitgeist in mid-twentieth century. They were widely used by psychologists and psychiatrists in research and clinical practice, but their use was increasingly prevented from advancing thinking and practice in psychology and psychiatry.

These foundational studies complement a small number of early phase clinical trials on psilocybin for obsessive compulsive disorder, psilocybin for alcohol and tobacco addiction, and psilocybin and ayahuasca for major depressive disorder. However, most of these trials report on small sample sizes.

PSYCHEDELICS FOR MENTAL ILLNESS

Plant-based psychedelics have been used for hundreds of years for holistic healing, and there remains an active culture of self-medication with psychedelics for mental health.

Psychologists and psychiatrists began using psychedelics in the 1950s, and found that 79% of patients showed improvement post treatment. Moreover, a meta-analysis of studies of LSD for alcoholism was similarly supportive of its potential.

In 2006, a double-blind randomized controlled (DB-RC) study of psilocybin in healthy volunteers found that psilocybin was more effective than methylphenidate at improving psychological well-being. Since then, several studies have been conducted on psilocybin in patients with symptoms of depression and anxiety.

Psilocybin, and psychedelics more generally, share some similarities with conventional antidepressants (ie, serotonergic modulation), but also possess some important differences. These differences include a greater role for 5-HT2AR signaling with psychedelics, and emphasis on emotional release.

I predict that psilocybin with psychological support (PwPS) will become an early option in the treatment of depression if the science is allowed to progress without political interference.

Psilocybin’s acute and putative antidepressant effects are muted by chronic antidepressant medication strategies, making it challenging to treat medication-heavy, treatment-resistant depressed patients with psilocybin.

FINDING SIGNAL AMIDST THE PSYCHEDELIC NOISE

As a clinician committed to the view that neuroscience should inform psychiatry, psychedelics have always looked like a serious opportunity. However, their illegal status stopped serious research in humans until quite recently.

Psychedelics can take us back to the future, but finding a medical role for psilocybin must not be underestimated. Two similar designed but independent studies gave the same result, so the results deserve to be taken seriously.

THE PATIENT POPULATION

Ross et al (2016) suggested that existential/spiritual well being is particularly relevant to depression in cancer patients.

In a case series of 128 patients, only 20% indicated they would appreciate psychological help for distress, depression, or anxiety.

Depressive symptoms can occur in cancer patients and a nurse intervention can help. The intervention was found to be effective in reducing depressive symptoms and anxiety and fatigue.

The case for a particular unmet need in cancer patients is actually quite difficult to sustain, as one risks recruiting people with a particular interest in psychedelic experience.

THE TRIAL DESIGN

In two cancer studies, people who took psilocybin experienced heightened states of consciousness with marked emotional accompaniments (anxiety, tearfulness, and in a few cases, paranoid ideation). The results were difficult to judge without great care in preserving raters to be blind.

THE OUTCOME MEASURES

Both trials use self, community, and clinician reports to assess outcome, which is entirely subjective. More objective measures are possible, such as motor activity or geolocation, but subjective response remains the regulatory standard against which psychotropic drugs will be measured.

DOES THE PSILOCYBIN EXPERIENCE REALLY BELONG IN MEDICINE?

Psilocybin is a psychoactive drug with an older cultural history as a constituent of magic mushrooms. Many believe that its use should be a recreational right, like access to alcohol, cigarettes, and increasingly cannabis.

Psychedelics are illegal in Belgium, but euthanasia is already available for people with neuropsychiatric disorders. Forty-eight patients were accepted for euthanasia and 35 completed, and six others died by suicide.

HOW TO MOVE THE FIELD FORWARD (GMG AND RLC-H)

Our shared interest in the development of psychedelics, and particularly psilocybin, for medical use is a major point of convergence. However, our views on the so-called ‘mystical’ elements of the psychedelic experience differ slightly, and our views on the choice of patient population for this development differ significantly.

Focusing on treatment-resistant depression, we both recognize that a significant number of patients treated first line with either a SSRI or CBT fail to respond adequately. A single psychedelic intervention might find a place in the treatment pathway.

If it is to be TRD, then patient recruitment can be based on pre-existing criteria, and patients meeting them will not be rare or excessively treatment resistant. However, there is a significant challenge to the issue of continuing medication, most commonly with SSRIs.

Moving on from questions of the optimal patient population, a multiple dose trial comparing 1, 10 and 25 mg of psilocybin seems to overcome some of the problems any trial of a psychedelic will face, and would allow participants to enter the study knowing they would receive active drug.

Comparing psilocybin with ketamine could be a next step to advance the evidence base for TRD, but the subjective effects of psilocybin remain a major challenge.

Psilocybin works through a different mechanism than traditional antidepressants, and without psychotherapy it may even worsen a patient’s condition. However, minimizing the active psychological work of the therapy is undesirable and should not jeopardize patient safety.

A psilocybin trial is easier to conduct than a study requiring continuing adherence to a daily oral dose of an antidepressant, because exposure to the treatment can be completely controlled and follow-up can be relatively pragmatic.

In the short term, a door has been opened for the medical repurposing of psychedelics. It is important to design the optimal trial to demonstrate efficacy, agree its validity with regulatory authorities and fund it.

FUNDING AND DISCLOSURE

GMG is a senior investigator at the NIHR, RLC-H is supported by the Alex Mosley Charitable Trust and the Beckley Foundation, and is advising Compass Pathways on psilocybin as a medicine.