Psychedelics: Where we are now, why we got here, what we must do

This commentary (2018) provides a global overview of where we stand with regards to psychedelics research (for therapy) and the checkered history of these substances.

Abstract

“The purpose of this commentary is to provide an introduction to this special issue of Neuropharmacology with a historical perspective of psychedelic drug research, their use in psychiatric disorders, research-restricting regulatory controls, and their recent emergence as potential breakthrough therapies for several brain-related disorders. It begins with the discovery of lysergic acid diethylamide (LSD) and its promising development as a treatment for several types of mental illnesses during the 1940s. This was followed by its abuse and stigmatization in the 1960s that ultimately led to the placement of LSD and other psychedelic drugs into the most restrictively regulated drug schedule of the United States Controlled Substances Act (Schedule I) in 1970 and its international counterparts. These regulatory controls severely constrained development of psychedelic substances and their potential for clinical research in psychiatric disorders. Despite the limitations, there was continued research into brain mechanisms of action for psychedelic drugs with potential clinical applications which began during the 1990s and early 2000s. Finding pathways to accelerate clinical research in psychedelic drug development is supported by the growing body of research findings that are documented throughout this special issue of Neuropharmacology. Accumulated research to date suggests psychedelic drug assisted psychotherapy may emerge as a potential breakthrough treatment for several types of mental illnesses including depression, anxiety, post-traumatic stress disorder, and addiction that are refractory to current evidenced based therapies. This research equally shows promise in advancing the understanding of the brain, brain related functioning, and the consequential effects of untreated brain related diseases that have been implicated in causing and/or exacerbating numerous physical disease state conditions. The authors conclude that more must be done to effectively address mental illnesses and brain related diseases which have become so pervasive, destructive, and whose treatments are becoming increasingly resistant to current evidenced based therapies.”

Authors: Sean J. Belouin & Jack E. Henningfield

Notes

This paper is included in our ‘Top 10 Articles Introducing Psychedelic-Assisted Therapy‘

Summary

The purpose of this commentary is to provide an introduction to this special issue of Neuropharmacology by describing the history of psychedelic drug research, its abuse and stigmatization, and the recent emergence of psychedelic drug assisted psychotherapy as potential breakthrough therapies for several brain-related disorders.

1. Introduction

The history of psychedelic substance use, modern research efforts, and their potential clinical applications for treating mental health disorders evolved through ancient cultures, modern discovery, pop cultural movements, national and international politics, and well-intentioned laws.

The persistence of behavioral disorders, despite the failure of many promising medicines, suggests that increased scientific investigation of psychedelic substances for potential clinical application merits serious consideration among the many other efforts being pursued to address mental health illnesses.

This commentary aims to provide a brief historical context for psychedelic drug research, its modern rise, fall, and reemergence, and to provide key references for readers interested in pursuing these diverse issues for further inquiry.

1.1. The modern rise of psychedelic drug research and clinical application

Psychedelic plants have been used for millennia for ceremonial, medicinal, and recreational purposes. These include certain mushrooms, herbs, anticholinergic plant derivatives, cannabis, and numerous other substances used in medicine.

The modern era of research into the use of psychoactive substances was launched by the discovery of lysergic acid diethyl amide (LSD) in 1943. Two American psychiatrists personally brought LSD into the US to begin testing it. The Federal Food, Drug, and Cosmetic Act of 1938 allowed Sandoz to distribute LSD samples to experts for investigational research. It was heralded in the medical literature and popular press as a potential breakthrough in many areas of mental illness, including drug addiction.

Psychedelic substances were pursued vigorously by many leading researchers in psychiatry and the emerging fields of neuropharmacology and neuropsychopharmacology in the 1950s, with funding coming from pharmaceutical companies, institutions such as the US National Institute of Mental Health, and controversially from military and intelligence agencies.

In the early 1960s, research on psychotherapeutic agents including psychedelics contributed to the emergence of new research societies. However, there was still no federal legal requirement in the Federal FD&C Act of 1938 requiring pharmaceutical manufacturers to demonstrate proof of clinical efficacy through adequate and well controlled clinical trials.

The FDA required adequate and well-controlled studies for any new drug substance, and in 1966 they began evaluating all drugs approved between 1938 and 1962 for clinical efficacy. Of those 3443 marketed drug products, 2225 were found to be effective, 1051 were found ineffective, and 167 were still pending more research.

1.2. The US Controlled Substances Act and the fall of psychedelic drug research

Sandoz faced the loss of patent protection for Delysid in 1963, and the drug was entering popular culture as a “mind-altering” and “mind-enhancing” drug associated with various societal subcultures. Sandoz sought to distance themselves from any research in the US by transferring their remaining supplies to NIMH. Professor Timothy Leary’s celebrity status contributed to the stigmatization of LSD by the latter half of the 1960s.

The emerging counterculture movement that embraced LSD and related substances was fueled by the use of psychedelics, and the 1970 US Controlled Substances Act (CSA) codified harsh penalties for manufacture, possession, and use of many psychedelics, which hindered their research and medicinal development.

The stark characterization of LSD and related psychedelic substances contributed to misinformation, politicization, and irrational fear, which resulted in the near banning of clinical research with these substances.

The CSA emerged along with other international drug control treaties, and although there have been noted benefits, there have also been inadvertent consequences and deficiencies that have led to new treaties internationally, with new laws and legal interpretations at the national and international level.

Regardless of the general public health intent, the CSA severely restricted research on substances placed in Schedule I, which includes significant barriers and requirements that discourage scientists and clinicians from attempting to conduct research on Schedule I substances. The US CSA imposed barriers to researching drugs placed in Schedule I, and the US DHHS eliminated the need for the US PHS review in 2015, thus reducing one of many such barriers. To identify additional approaches to support and expedite research on Schedule I substances, a symposium was convened in June 2017 by the College on Problems of Drug Dependence.

1.3. Twenty-first century psychedelic drug research and development: a new era

Today, there is rapidly growing awareness, anticipation, and hope for the potential of several psychedelic drugs to become medically approved for various psychiatric disorders. These efforts began following the 1990s, when new generations of behavioral health researchers began an in-depth reexamination and rediscovery of potential uses these substances might hold.

MDMA, also known as ecstasy, was granted a Breakthrough Therapy Designation by the FDA in 2017 for the treatment of post-traumatic stress disorder (PTSD). If phase 3 clinical efficacy trials are successful, MDMA may be submitted for regulatory approval.

Psychedelic drug research should continue unhindered to determine its potential as new treatment options for people whose mental health disorders are refractory to current evidence based treatment modalities.

2. Public health need

Public health needs for new medicinal treatments are vast, but the pipeline for new medications is relatively small given the scope of mental health problems, and major pharmaceutical companies are hesitant to invest in the development of psychedelics because of the high failure rate to find acceptable medications.

Research shows that one or two doses of a medication can reduce severe symptoms of anxiety and depression for more than one year, and can improve quality of life in persons who have been diagnosed with PTSD.

The FDA has mechanisms that allow seriously ill individuals who are refractory to all recognized medically acceptable clinical therapies to be treated with medications that have not yet been approved. These programs are called Expanded Access programs or otherwise known as “compassionate use programs”.

3. Summary of major mental health challenges facing the United States

The United States confronts today a mental health crisis that is not contracting, but is expanding. Mental health disorders have infiltrated the foundational fabric of this nation, and have resulted in a steady-state depletion of its internal intellectual, innovative, and economic capacity.

Continued decline in mental health poses an existential strategic threat to the United States, as mental health disorders affect people across all demographics, socioeconomic classes, and cultures, and contribute directly to exacerbating disease state crises.

The US Federal Government, partnering state governments, local municipalities, and a battery of public and private partners have endeavored to stem the erosion of mental health in the United States, but the situation remains disappointingly similar to that of other nations.

To date, mental health disorders have not decreased despite numerous programs and regulations, and it is possible that everything possible has not been done. The President’s Commission on Combating Drug Addiction and the Opioid Crisis, the DHHS, and the broader medical community have all expressed significant distress over the long-term effects of an unhindered national mental health crisis.

3.1. Cumulative behavioral healthcare and societal costs

The NIMH estimates that the total costs associated with serious mental illness and substance use disorders are in excess of $300 billion per year. These disorders are also estimated to have a negative impact on local, state, and federal budgets.

3.2. Stigmatizing scientific medical problem solving

Social issues and stigmatization of mental health disorders hinder self-disclosure and help-seeking by those afflicted, including their families. It is important to address stigma for mental illness and addictions, and to expand scientific medical research.

Media coverage of psychedelic drug research has included eye-catching headlines and street and club terms, such as “magic mushrooms”, “ecstasy”, and “getting high”, which may increase or decrease overall stigmatization.

4. Evolving to address a critical national healthcare need

Despite formidable barriers to research, there has been slowly increasing research into the use of psychedelic containing drugs for the treatment of a variety of mental disorders. However, substantial, costly additional phase 3 clinical efficacy studies will be required to support any NDA for approved medicinal use.

The US Food and Drug Administration has recommended risk evaluation and mitigation strategies (REMS) for the use of psychoactive substances in assisted psychotherapeutic sessions. These requirements may contribute to the recognition of public health benefits while simultaneously minimizing potential risks to patients.

Research is essential to determine the risks, benefits, and conditions of psychedelic substances, and to determine if they should be approved for medicinal use. Only through rigorous, methodical and sustainable clinical trials will researchers be able to legitimately address critical efficacy questions.

When currently accepted mental health treatment modalities are exhausted, it’s important to brainstorm innovative paradigm shifting treatment endeavors. However, legacy fear often thwarts many attempts to counter sufficiently time-honored belief systems.

During the 1980s and early 90s, Barry Marshall and Robin Warren experienced medical establishment intimidation as they endeavored to clinically validate Helicobacter pylori’s role in causing duodenal ulcers and gastric ulcers.

Years earlier, at the closing of the 60s, psychedelics were coming under the microscope for their recreational misuse, which stalled research into their therapeutic efficacy.

Psychedelics have been organized under Schedule I of the CSA over the past one-half century, and only a handful of small scale clinical studies have been finalized to date.

5. Operationalizing forward

New medicines will not address mental and behavioral health challenges in the US and globally. Psychedelic type substances may prove to be the most appropriate, effective and acceptable therapies for certain populations of people with mental illness.

5.1. Research in new and emerging areas can be appropriately guided with the convening of a research summit

The Federal Government is uniquely positioned to lead a multi-day international summit on the state of the science surrounding the field of psychedelic research as part of overall psychotherapeutic treatments for mental health disorders. This summit provides Federal Government executive level decision makers with critical information necessary to identify phase 3 clinical research trials, address ethical issues surrounding the use of these agents, and update current policies and regulations to advance this research.

5.2. Funding research

There should be no illusions to the challenges that lay ahead in conducting this research, and it will take committed, combined, and collegial leadership from all affected Departments and agencies actively engaged to see this endeavor through.

6. Summary

We are facing a multigenerational crisis of epidemic proportions due to mental health related disorders with loss of life and profound reduction in quality of life. Mental health disorders are weakening the private and public sectors, and the Federal Government is responsible for tackling those challenges that are too great for the private sector to tackle itself. The private sector has a potential role and opportunity in co-developing profoundly needed new medicinal treatments.

This commentary has focused on the scientific foundation for understanding mental and behavioral disorders, and the clinical advances in potential treatments. However, personal and social factors, along with new emerging clinical scientific information, are relevant to the resurgence of interest in research and potential clinical uses of certain psychedelic substances.

Disclaimer

This publication represents the views of the authors and does not necessarily reflect the views of the US Public Health Service.

Acknowledgments of funding and grants

The authors would like to thank Evan Schnoll, Dan Wang, Yolanda Green, Anthony DeCicco, CAPT, USPHS (Retired), Ron Flegel, Coleen Sanderson, and Natalie Lembeck for their reflective insights.