New research propels psychedelics into the mainstream

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Psychiatry is on the brink of taking psychedelic drugs mainstream, writes The New York Times. Researchers and corporates stand poised to get involved, but the rapid opening of access could have risky consequences.

Andrew Jacobs writes for the NYT:

It’s been a long, strange trip in the four decades since Rick Doblin, a pioneering psychedelics researcher, dropped his first hit of acid in college and decided to dedicate his life to the healing powers of mind-altering compounds. Even as antidrug campaigns led to the criminalisation of Ecstasy, LSD and magic mushrooms, and drove most researchers from the field, Dr Doblin continued his quixotic crusade.

Dr Doblin’s quest to win mainstream acceptance of psychedelics took a significant leap forward last week when Nature Medicine published the results of his lab’s study on MDMA, popularly known as Ecstasy and Molly. The study, the first Phase 3 clinical trial conducted with psychedelic-assisted therapy, found that MDMA paired with counselling brought marked relief to patients with severe post-traumatic stress disorder.

The results, coming weeks after a New England Journal of Medicine study that highlighted the benefits of treating depression with psilocybin, the psychoactive ingredient in magic mushrooms, have excited scientists, psychotherapists and entrepreneurs in the rapidly expanding field of psychedelic medicine. They say it is only a matter of time before the US Food and Drug Administration grants approval for psychoactive compounds to be used therapeutically — for MDMA as soon as 2023, psilocybin a year or two later.

After decades of demonisation and criminalisation, psychedelic drugs are on the cusp of entering mainstream psychiatry, with profound implications for a field that in recent decades has seen few pharmacological advancements for the treatment of mental disorders and addiction.

The nation’s top universities are racing to set up psychedelic research centers, and investors are pouring millions of dollars into start-ups. States and cities across the country are beginning to loosen restrictions on the drugs, the first steps in what some hope will lead to the federal decriminalisation of psychedelics for therapeutic and even recreational use.

The question for many is how far — and how fast — the pendulum should swing. Even researchers who champion psychedelic-assisted therapy say the drive to commercialise the drugs, combined with a growing movement to liberalise existing prohibitions, could prove risky, especially for those with severe psychiatric disorders, and derail the field’s slow, methodical return to mainstream acceptance.

Dr Doblin’s organization, MAPS, is largely focused on winning approval for drug-assisted therapies and promoting them around the globe, but it is also pushing for the federal legalisation of psychedelics though with strict licensing requirements for adult recreational use.

Numerous studies have shown that classic psychedelics like LSD and psilocybin are not addictive and cause no organ damage in even high doses. And contrary to popular lore, Ecstasy does not leave holes in users’ brains, studies say, nor will a bad acid trip lead to chromosome damage.

But most scientists agree that more research is needed on other possible side effects — like how the drugs might affect those with cardiac problems. And while the steady accumulation of encouraging data has softened the skepticism of prominent scientists, some researchers warn against the headlong embrace of psychedelics without stringent oversight. Although “bad trips” are rare, a handful of anecdotal reports suggest that psychedelics can induce psychosis in those with underlying mental disorders.

Dr Michael Bogenschutz, a professor of psychiatry who runs the four-month-old Center for Psychedelic Medicine at NYU Langone Health, said most of the clinical studies to date had been conducted with relatively small numbers of people who were carefully vetted to screen out those with schizophrenia and other serious mental problems. That makes it hard to know whether there will be potential adverse reactions if the drugs are taken by millions without any guidance or supervision.

Johns Hopkins, Yale, the University of California Berkeley, and Mount Sinai Hospital in New York are among the institutions that have recently established psychedelic research divisions or are planning to do so. And scientists are conducting studies on whether psychedelics can be effective in treating everything from depression, autism and opioid addiction to anorexia and the anxieties experienced by the terminally ill.

More than a dozen start-ups have jumped into the fray, and the handful of companies that have gone public are collectively valued at more than $2bn. Field Trip Health, a two-year-old Canadian company, has raised $150m to finance dozens of high-end ketamine clinics in cities across North America. Compass Pathways has raised $240m and is conducting 22 clinical trials across 10 countries of psilocybin therapy for treatment-resistant depression.

Decades in the Wilderness

Long before Nancy Reagan warned the nation to just say no to drugs, researchers like William A Richards were legally using psychedelics to help alcoholics go dry and cancer patients cope with end-of-life anxiety.

But as the drugs left the lab in the 1960s and were embraced by the counterculture movement, the country’s political establishment reacted with alarm. By the time the Drug Enforcement Administration issued its emergency ban on MDMA in 1985, funding for psychedelic research had largely disappeared.

These days, the Center for Psychedelic and Consciousness Research at Johns Hopkins, created two years ago with $17m in private funding, is studying, among other things, psilocybin for smoking cessation and the treatment of depression associated with Alzheimer’s as well as more spiritual explorations involving religious clergy.

Though researchers are still trying to understand the cognitive and therapeutic mechanics of psychedelics, they have concluded that psilocybin, DMT and other psychoactive chemicals can help people feel more tolerance, understanding and empathy. They also induce neuroplasticity, the brain’s ability to change and reorganise thought patterns, enabling people with psychological disorders to find new ways to process anxiety, depression or deeply embedded trauma.

The Trip Business

The future of psychedelic medicine can already be glimpsed at a suite of plush, soothingly decorated “journey rooms” that occupy the top floor of an office building in Midtown Manhattan. The clinic, run by Field Trip Health, is a year-old venture where patients wear eyeshades and listen to electronic music and Tibetan chanting, as they are administered six ketamine injections over the course of several weeks.

The 90-minute trips are interspersed with therapist-guided “integration sessions” to help participants process their experiences and work on achieving their mental health goals. A typical course of four sessions starts at $4,100, though some insurance companies reimburse patients for a portion of the cost.

Ketamine is not a classic psychedelic; it is an anaesthetic perhaps best known as both a club drug and a horse tranquilizer. But at higher doses, it can produce hallucinations, and it has shown promise treating major depression and severe PTSD, though the effects tend to be less enduring than therapies with psilocybin or MDMA. Ketamine, however, has a distinct advantage over those other drugs: It is the only one in the US that is legally available to patients outside a clinical study.

To veteran scientists who lived through the nation’s earlier star-crossed love affair with psychedelics, the new corporate boosterism is both thrilling and troubling. They are mindful about potential missteps.

Dr Charles Grob, a professor of psychiatry at UCLA’s school of medicine who has spent decades researching hallucinogens, worries that commercialisation and a rush toward recreational use could prompt a public backlash, especially if increased availability of the drugs leads to a wave of troubling psychotic reactions.

What is needed, he said, are rigorous protocols and a system to train and credential psychedelic medicine professionals. “We have to be very attentive to safety parameters, because if conditions are not properly maintained, there is a risk for some people to go off the rails psychologically,” he said. “And if the primary motivator is extracting profit, I feel the field is more vulnerable to mishaps.”

Dr Doblin shares some of those concerns. Winning FDA.approval would give MAPS at least six years of exclusivity to market its MDMA-guided treatments for PTSD, with a potential windfall of $750m. Most of that money, he said, would help train a generation of psychedelic practitioners, fund lobbying efforts and promote new therapies around the world. “Our goal is mass mental health,” he said, explaining the organisation’s rejection of private investment. “It’s not to amass a whole bunch of money.”

Despite his optimism, Dr Doblin is not blind to the possibility that society’s fascination with psychedelics could sour. “We’ve made so much progress so fast but there are so many challenges ahead,” he said. “I realise,” he said, “we could screw things up at the last minute so I’m not planning to celebrate any time soon.”

* This is a shortened version of the New York Times article. See below how to access the full version.

Nature Medicine study

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

Authors: Jennifer M. Mitchell, Michael Bogenschutz, […]Rick Doblin

Published in Nature Medicine on 10 May 2021

Abstract

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

New England Journal of Medicine study

Trial of Psilocybin versus Escitalopram for Depression

Authors: Robin Carhart-Harris, Ph.D., Bruna Giribaldi, B.Sc., Rosalind Watts, D.Clin.Psy., Michelle Baker-Jones, B.A., Ashleigh Murphy-Beiner, M.Sc., Roberta Murphy, M.D., Jonny Martell, M.D., Allan Blemings, M.Sc., David Erritzoe, M.D., and David J. Nutt, M.D.

Published in the NEJM on 15 April 2021

Abstract

BACKGROUND
Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.

METHODS
In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.

RESULTS
A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups.

CONCLUSIONS
On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants.

 

Full New York Times report (Restricted access – registration or subscription required)

 

Full study in Nature Medicine (Open access)

 

Full study in New England Journal of Medicine (Restricted access)

 

See also from the MedicalBrief archives:

 

Repeated ketamine infusions reduce PTSD symptom severity

 

Results from world’s first MDMA – aka ‘ecstasy’ – alcohol use disorder trial


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