What are psychedelic compounds?

The types of compounds referred to as psychedelic compounds has expanded in popular culture. In general, the term refers to a group of substances that can produce temporary changes in a person’s mood, thoughts or perceptions of reality. They can also produce temporary changes in our senses, altering the way people see, hear, taste, smell or feel.

Psychedelic compounds come in many different forms, ranging from chemicals produced in a laboratory such as MDMA to natural compounds derived from plants, animals and fungi such as psilocybin. Researchers generally categorize the different compounds based on how they act in the brain.

Below are the basic categories of psychedelic compounds and some examples of each that are now being researched for their treatment potential:

  • Psilocybin (4-Phosphoryloxy-N,N-Dimethyltryptamine): Psilocybin, sometimes referred to as “magic mushrooms,” is a chemical compound found in certain mushrooms that grow in the United States, Mexico and South America. It is one of the most highly researched psychedelic compounds and is being studied as a potential treatment for variety of conditions including depression (both TRD and MDD), PTSD, AUD, anorexia nervosa and obsessive-compulsive disorder. 
  • LSD (D-Lysergic Acid Diethylamide): Commonly referred to as “acid,” LSD is a clear or white, odorless, lab-made (synthetic) substance derived from lysergic acid, which is found in fungi that grow on rye and other grains. LSD is being studied as a treatment for conditions such as cluster headaches, attention deficit hyperactivity disorder (ADHD), and GAD.
  • DMT (N,N-Dimethyltryptamine): DMT is a chemical compound found in plants native to the Amazon rainforest. DMT is often consumed as a tea, known as ayahuasca. DMT can also be synthesized in a lab. DMT is being studied as a treatment for many conditions including TRD, bipolar disorder, and AUD.  
  • Ketamine: Ketamine is a chemical compound used to induce anesthesia during surgery mainly in animals. A derivative of ketamine, called esketamine, has been FDA-approved to treat TRD since 2019, and both ketamine and its derivatives are being further studied as a treatment for conditions such as AUD, MDD, and acute suicidal ideation and behavior.
  • MDMA (3,4-Methylenedioxymethamphetamine): MDMA, also known as “ecstasy” or “molly,” is a lab-made (synthetic) drug that has some effects similar to stimulants such as methamphetamine in addition to producing psychedelic effects such as altered visual perceptions. MDMA is the furthest along in the FDA approval process, with advanced clinical trials in PTSD completed and being prepared for FDA review. MDMA is also being investigated as a potential treatment for other disorders, including eating disorders (anorexia nervosa and binge-eating disorder) and autism spectrum disorder.
  • Ibogaine: Ibogaine is a chemical compound that comes from the bark of certain plants, including the iboga shrub, which is used in religious ceremonies in Western Africa. While ibogaine does have psychedelic properties, it affects a different spectrum of brain activity than the other listed psychedelic drugs or dissociative drugs. Ibogaine is not as widely studied as the other compounds described and when it is, it is usually investigated in opioid withdrawal syndrome or AUD.

Why are psychedelic compounds now being considered as a potential treatment for brain disorders such as PTSD and depression?

Psychedelic compounds have been used for centuries in cultural and religious ceremonies. Some psychedelic compounds, specifically, LSD, received initial attention as a potential treatment for several psychiatric disorders in the 1940s. In the 1960s, the use of these drugs moved outside of research labs and into the public and became associated with both the counter-culture and concerns of abuse. This led to LSD and other psychedelic compounds without any proven medical use becoming regulated by the Drug Enforcement Administration (DEA) as Schedule I in the 1970s.  Being categorized as Schedule I adds several time- and cost-intensive hurdles to clinical research, and, as such, the investigation of these compounds as potential treatments practically stopped.

However, the urgent need to identify better therapies for disorders with high rates of treatment resistance such as TRD and PTSD, combined with early promising results from small studies largely led by foundations, has fueled renewed attention on these compounds, including from the pharmaceutical industry. This research is still in the early stages. As of July 2021, there were only 14 published studies of classical psychedelics, enrolling a total of 315 participants, most without the expected controls that allow regulators to know whether the compound works. In 2022, the publication of two additional studies with more rigorous designs demonstrated that the field is taking this potential category of treatment seriously.

In order to understand their potential as a therapeutic, we need more large clinical trials conducted with rigorous scientific standards using guidance provided by the FDA.

Why/how are psychedelic compounds challenging to study?

Psychedelic compounds are inherently more challenging to study with the same rigor as other therapeutics. Because of these challenges (listed below), there are still outstanding questions related to the safety and efficacy of these compounds, as well as to the durability of their clinical effects. In addition, due to the limited number and narrow population studied to date, we do not yet know who the appropriate candidate patients for successful use are. Further, because these potential treatments are incredibly resource intensive, many questions remain on the equitable access of these treatments for all those who need them, regardless of economic means, as well as whether and how they will be covered by insurance. Finally, quality clinical data will help move forward the entire field of psychiatric disorder research. 

Below are five issues that clinical trials studying psychedelic compounds must overcome: 

Psychedelic trials are difficult to blind. Psychedelic compounds produce extraordinary subjective reactions that are well-known (and expected) by the trial participants. This is called the “set” or mindset issue. In addition to the mindset people have coming into the clinical trials, participants are often required to participate in pre-therapy sessions that prepare them for what they will experience. This increases their expectation of an effect, makes it even clearer when they are not in the study arm getting the psychedelic, and further challenges the ability to distinguish a drug effect from a “placebo” effect. 

“Setting” refers to all that’s going on in your immediate environment during the psychedelic treatment session, such as the people around you and their behaviors, the type of furniture in the room, whether there is music playing, and even the smells and lighting of the room. Clinical trials need to determine how the environment in which the individual takes the compound enhances or detracts from the effects of the drug itself. 

Many of these compounds are being developed as tools to enhance the effectiveness of psychotherapy. For example, some compounds have a capacity to induce an altered or opened sense of self and relatedness to others, which may enhance the psychotherapy experience by increasing trust and openness. Other compounds are thought to increase plasticity, potentially facilitating the uncoupling of fear from the traumatic memory during trauma-focused psychotherapies. For those compounds where the psychedelic therapy is proposed as enhancing the effect of psychotherapy, the FDA will have to consider how they will label a compound that enhances a type of therapy that they do not regulate, i.e., psychotherapy. This also emphasizes the need for the FDA to understand what the drug effect is apart from the psychotherapy effect. In addition, the DEA has designated many psychedelic compounds as Schedule 1, so there are limitations as to who can study them and under what conditions, which reduces the amount of research into these compounds compared with non-Schedule 1 compounds. With fewer studies, it makes evaluating the true effect of these compounds based on a limited number of and relatively small studies very challenging.

A well-designed, regulatory-quality study should determine whether the subjective effects are a necessary part of the “mechanism of action” or whether compounds can be developed that have the same potential effects without the risk of hallucinations, dissociation, or the need of multiple therapists and hours of being watched in a clinic during the administration period. Some drug development companies are specifically developing drugs that act on the same pathways in the brain but do not produce the hallucinations or other effects typically associated with psychedelic compounds.

Many patients with intractable PTSD will likely have previously been on or currently be on drugs with an overlapping mechanism of action such as SSRIs or SNRIs. For some people, if SSRIs or SNRIs were not effective for a patient, then the expected effect of a psychedelic that also works through the serotonergic system may not be as great. In those that did see some benefit from SSRIs or SNRIs, long term use of serotonergic drugs can actually change how the body responds to serotonergic drugs and thus, psychedelic compounds may not be as effective for those people. From a safety perspective, there is also the risk of inducing serotonin syndrome (with symptoms ranging from mild, e.g., agitation, tremor, to more serious, e.g., seizure, vomiting) by using more than one of these serotonergic drugs at a time.

CVB's position regarding research of and advocacy for psychedelic compounds

Research of Psychedelic Compounds

Cohen Veterans Bioscience is a non-profit 501(c)(3) biomedical research and technology organization dedicated to advancing brain health by fast-tracking precision diagnostics and tailored therapeutics. CVB is committed to improving the lives of people affected by trauma-related and other brain disorders through advancing research into all therapeutics that demonstrate potential to treat the invisible wounds.

Early clinical research on the use of psychedelic compounds and psychedelic-assisted therapy to treat the invisible wounds has shown great promise, but the number of clinical trials involving these compounds is small and relatively few patients have been included in the studies. CVB advocates for rigorous biomedical research and the comprehensive evaluation and assessment of psychedelic agents’ effectiveness, safety and best candidates for treatments. 

Advocacy for Psychedelic Compounds

CVB promotes policies and legislation that will positively impact Veterans, first responders and all Americans in need of new solutions for debilitating conditions such as PTSD by advancing research into the potential of psychedelic compounds. 

Through the Coalition to Heal Invisible Wounds, CVB has three advocacy priorities: 

  1. To expand clinical research into psychedelic compounds to address critical gaps in the scientific knowledge and provide conclusive evidence on the safety and effectiveness of psychedelic therapies. These studies should employ rigorous research designs and include larger, more diverse populations.
  2. To compel the FDA to develop critical clinical trial guidance that addresses the unique challenges of designing and carrying out clinical trials with psychedelic compounds and improves regulatory certainty for those seeking to develop safe and effective therapies for these disorders. 
  3. To work with the DEA and other regulatory agencies to make it easier for qualified researchers to work with and conduct studies using psychedelic compounds to further understanding of how these drugs work in the brain.

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Advocacy Priorities

Our brain trauma roadmapping efforts in both post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) have demonstrated that meaningful investment in brain health is needed to advance diagnostics and treatments.

CVB advocates for sustainable and predictable growth of the NIH budget over the long term, including targeted funding for brain trauma-related disorders in an amount that is commensurate with the actual disease burden and reflects priority areas identified in our roadmapping efforts. We also support robust and continued funding for the BRAIN Initiative and a call-to-action that all data from the BRAIN Initiative be made openly accessible to the scientific community to advance progress.

Targeted Investment

Current treatment strategies for many brain diseases and disorders largely resemble “trial and error” and many diseases rely on a symptoms-based approach to diagnosis and treatment. In brain health, doctors need better tools to tailor treatments to the right patient and the right condition.

We support Federal funding that moves beyond an incremental approach to brain science, including funding deep phenotype cohorts to enable biomarker discovery, adaptive clinical trial designs and promoting data sharing to enhance discovery and development.

Precision Therapeutic Approaches

Accelerating research discovery—particularly in the field of brain health—requires researchers to build upon the best available scientific evidence in order to avoid needless starts and stops and duplicated efforts.

For these reasons, CVB advocates for policies that ensure best research practices based on proven approaches, which are implemented at all stages of the research process—from design to execution to reporting.

Through the implementation of best practices, we ensure all research is conducted to the highest standards and through an approach that ensures public confidence. In addition, CVB advocates for improved biomedical workforce training at all levels to protect the United States’ competitiveness as a scientific enterprise.

Our nation’s Veterans and service members need action for the brain trauma conditions that are taking their lives at record numbers — TBI and PTSD — collectively referred to as the invisible wounds of war.

Major federal investments have improved access to mental health care, but Veterans and service members need more treatment options.

Despite decades of promising research and more than $1.1 billion spent on clinical trials, no new drugs for PTSD and TBI have successfully advanced through clinical trials to achieve FDA approval. And the research pipeline for new devices and therapies is thin as many pharmaceutical companies long ago abandoned research into PTSD and TBI.

CVB advocates for policies and reforms to help close these research gaps to more effectively address the invisible wounds and bring new solutions for brain trauma to Veterans and service members.

Promoting policies for Veterans

Veterans Advisory Council

The Veterans Advisory Council (VAC) is comprised of senior leaders who have a deep, personal commitment to helping us discover new solutions for the invisible wounds of war. The VAC members share the perspectives, challenges, and needs of the Veterans community to inform CVB’s research and advocacy efforts that will help improve the health of Veterans. The VAC’s priorities are to increase awareness of brain trauma as a risk factor for suicide, reinforce legislation and other measures to advance evidence-driven approaches for the invisible wounds of war and serve as a voice by providing advice and strategic recommendations for CVB’s mission and objectives.

Coalition to Heal Invisible Wounds

Co-founded by Cohen Veterans Bioscience, the Coalition to Heal Invisible Wounds brings together leading non-profit organizations seeking to advance a comprehensive research-focused advocacy agenda to address the invisible wounds of war—PTSD and TBI—as well as to address co-morbid conditions such as pain and substance use disorders, which are known to dramatically increase the risk of suicide among Veterans and service members.

About Psychedelics-Assisted Therapy Clinical Research

Many Americans suffer from brain disorders where existing treatment options are limited and often inadequate. The increase in study of psychedelic and related compounds for multiple brain disorders has the potential to add a new class of drug to the existing treatment options. There are studies in the advanced stages of the clinical trial process (Phase III) investigating the use of MDMA to treat post-traumatic stress disorder (PTSD), psilocybin to treat treatment-resistant depression (TRD) and ketamine (a version of which is already approved for TRD) to treat alcohol use disorder. There are also studies in earlier stages of clinical research investigating these and other psychedelic compounds for a number of other conditions such as eating disorders, major depressive disorder (MDD) and generalized anxiety disorder (GAD). 

Veterans seeking relief for the long-term effects of these conditions have shown high interest in participating in research critical to determining the potential efficacy of psychedelic compounds. As we still do not fully understand the safety and efficacy of these compounds, we need rigorous research to determine whether and how these compounds can be integrated into clinical care. These studies also need to determine how they work in the brain, in which people they work and why, and finally, which compounds are best suited for which conditions. 

News and Events

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Have Questions? Interested in Learning More?

Contact our Director of Advocacy and Policy to learn more about how you can become involved with our advocacy efforts.

Dr. Chantelle Ferland-Beckham, Ph.D.
Senior Director, External Affairs
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Patrick Bellgowan, PhD, Deputy Associate Director, NINDS

Dr. Bellgowan shared an overview of TBI, including the causes of injury, categorized as blunt force, blast exposure, and penetrating injury. The factors impacting TBI are complex and interrelated, and include severity of injury, age, gender, injury type, history of prior TBI, genetics, and social determinants of health. Understanding the diagnostics and treatment of TBI is an evolving landscape. One of the issues facing experts is how to define and categorize TBI. The National Institutes of Health (NIH) are investing across the research spectrum with at least 11 of the institutes involved in the TBI portfolio. NINDS leads this work within NIH. Dr. Bellgowan shared that while federal agencies historically worked in silos on this issue, a 2012 Executive Order established the National Research Action Plan (NRAP), asking all federal agencies to work together to improve access to mental health services for veterans, service members, and military families. An interagency task force was established to implement the order and the Department of Health and Human Services (HHS), the Department of Veterans Affairs (VA), and the Department of Defense (DOD) have since coordinated efforts to combat TBI.

Dr. Ramoni followed and shared how the VA is contributing to the NRAP, first noting that to accelerate progress in TBI diagnosis and treatment we must build on the NRAP to more precisely diagnose sub-types of TBI that are similar in their types and length of symptoms and respond to the same treatments. An important path toward progress is to leverage data that already exists. The VA has data in their electronic health records dating back to 1999, which includes complete medical record information on 16.6 million veterans and partial information on another 10 million veterans. Additionally, the Million Veterans Program, a national research program to discover how genes, lifestyle, and military exposures affect health and illness, has data on over 830,000 veteran volunteers. The VA is working to establish a VA Data Commons in collaboration with the University of Chicago and the Open Commons Consortium. This will allow approved VA and non-VA researchers to access de-identified data from VA’s electronic health records. A pilot is expected to launch in 2022.

Rachel Ramoni, D.M.D., Sc.D

Rachel B. Ramoni, DMD, ScD, Chief Research & Development Officer, U.S. Department of Veterans Affairs

Magali Haas, MD, PhD, CEO & President, Cohen Veterans Bioscience

Next Dr. Haas discussed CVB’s mission to advance brain health by advancing precision medicine solutions. Dr. Haas shared an update on the Brain Trauma Blueprint, a roadmap to advance a first generation of targeted solutions for TBI, focusing on the chronic sequelae. The Brain Trauma Blueprint is born from the recognition that there are currently no FDA-approved therapies for TBI, and was the basis for the 2019 State of the Science Summit on TBI, which brought together over 100 thought leaders across the research ecosystem to identify the research gaps that have stymied progress as well as specific recommendations to overcome these gaps through a consensus research roadmap. The specific recommendations are to be published as part of a six part publication series in the Journal of Neurotrauma. If these efforts to align resources toward these gaps and priorities is successful, it will help catalyze a first generation of targeted treatments for TBI. The Brain Trauma Blueprint has already led to new public-private partnerships and collaborations, many of which were described in this briefing. Dr. Haas outlined some of the most pressing needs identified through the Brain Trauma Blueprint, including the need for a national surveillance system for all severities of TBI. At this time, the United States does not have a reliable method for tracking TBI; rather, it only tracks individuals affected by TBI based on emergency room encounters. It is important that a national surveillance system to track the number of individuals who sustain TBI, including those who do not seek care in an emergency setting.

Dr. Stone discussed his work toward developing a Normative Neuroimaging Library, supported by CVB. The field of neuroimaging is more than 100 years old. Since that time there has been significant expansion of capabilities around neuroimaging, but the ability to be able to pull information from the images and the clinical processes to interpret the images and manage care have remained relatively static. Current approaches are helpful for moderate to severe TBI where routine neuroimaging exams can reveal urgent findings. However, routine neuroimaging approaches have a relatively limited role in mild TBI and concussion, which constitute the vast majority of TBI seen in the U.S. In recent years, there have been advanced neuroimaging techniques that have allowed us to push the boundaries in what we can see, but these approaches require the acquisition of a large volume of images and require computational tools to derive certain measures. A Normative Neuroimaging Library will provide the foundational building blocks to bridge the gap between research and clinical applications for advanced neuroimaging and will address the rapidly expanding need for quantitative, diagnostic neuroimaging tools.

James R. Stone, MD, PhD, Associate Professor, Radiology & Medical Imaging, University of Virginia School of Medicine

Jamshid Ghajar, MD, PhD, President, Brain Trauma Foundation, Director, Stanford Brain Performance Center

The final speaker on the panel, Dr. Ghajar, discussed the Brain Trauma Blueprint and the impact of evidence-based solutions for diagnostics and treatment on coma, or severe TBI. Prior to the year 2000, there were no evidence-based guidelines in
place for individuals with severe TBI. Patients received very little brain pressure monitoring, were given steroids, were under-resuscitated and mortality was 50%. The Brain Trauma Foundation (BTF) created 21st century evidence-based guidelines calling for brain pressure monitoring, no steroids, no hyperventilation, full resuscitation and full feeding. As compliance with the guidelines went up, mortality went down, dropping to 25%. The CDC issued a report on the impact
of the BTF guidelines and similarly found a 50% decrease in death as well as
cost savings. Now the guidelines, which are constantly updated, are used in
every trauma center in the U.S. as well as internationally. The BTF continues to establish and update evidence-based guidelines for different areas including hospitals, ambulance care and the military. With the Brain Trauma Blueprint, there is a roadmap to move forward with further evidence-based solutions.

Dr. Matthew Rizzo, Chair of the American Brain Coalition, closed the briefing by encouraging Members of Congress to join the Congressional Neuroscience Caucus and Congressional Brain Injury Task Force and asked congressional staffers in the audience to support federal funding for biomedical research, including brain injury research.

About the Brain Trauma Blueprint

The Brain Trauma Blueprint is a framework to advance precision diagnostics and therapeutics for brain trauma through a process of community stakeholder consensus roadmapping and collaborative execution. More information can be found here.