A Primer On Psychedelic Medicine
This post by Laura Berk and Andrew Barr is about psychedelics and mental health. If you’d like to learn more, here is our curated resource guide.
More likely than not, you wouldn’t be alive today without the phenomenal progress of medicine. Scientists have successfully developed numerous vaccines, cures, and other remedies that have changed the trajectory of humanity. Think of the polio vaccine, cancer treatments, even the simple flu shot. We’ve come a long way since the days of bloodletting.
When it comes to mental health, we haven’t come so far.
Yet.
Consider, what if we identified a drug that was 10 times more effective at treating depression and PTSD than antidepressants? And this drug would be effective in four or fewer doses, with no significant side effects, and yield substantial therapeutic results immediately?
Given a drug with that power, hundreds of millions of people would be able to rid themselves of debilitating mental illness. They would have a chance at a regular life — they’d be able to get out of bed in the morning, develop stable relationships, be productive at work, and have the opportunity to thrive.
Psychedelics could provide this mental health breakthrough — we may be on the edge of a new era in treating mental illness.
“It seems possible that at some point in the future psilocybin will become a name as familiar as penicillin” — David Nichols, Founder of the Heffter Research Institute
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We (Laura and Andrew) have worked in entrepreneurship, venture capital, and behavioral health for the last 10 years. We’re both incredibly passionate about mental health and became aware of the potential in psychedelic medicine. Despite a healthy dose of initial skepticism, we decided to explore the topic together. We started by digging into the scientific literature, reading dozens of articles, books and newsletters, and meeting with a wide range of leaders in the field including academic researchers, mental health clinicians, drug policy experts, tech entrepreneurs, and investors.
This piece is a condensed version of our learnings, meant to help people in adjacent fields (including tech, healthcare, and government) achieve a basic understanding of the psychedelic medicine space.
Mental health in America is bad and getting worse
Tens of millions of Americans are suffering from anxiety, stress, depression, loneliness, and unresolved trauma. 1 in 5 American adults experience mental illness in a given year. Half of us will have a mental illness in our lifetimes. Depression is the leading cause of disability worldwide. COVID-19 has dramatically exacerbated this.¹
The problem is only getting worse. The rates of “deaths of despair” are rising: Over the last 20 years, we’ve seen a 35% rise in the suicide death rate and a 400% rise in drug overdose deaths. More than 3 in 5 Americans report being lonely. And with COVID-19, we’re seeing a secondary mental health pandemic as rates of anxiety triple and rates of depression quadruple. The CDC found that 11% of American adults reported seriously considering suicide in June 2020.
And, 57% of people with mental illness receive no treatment. It takes, on average, 11 years from onset of symptoms for people to receive treatment. Stigma is still an issue. Insurance coverage is minimal, so care is unaffordable for most. Even for those lucky enough to get help, current treatments often take months or years to yield significant results: Only 28% of people treated with standard antidepressants achieve remission within 10–14 weeks after beginning treatment.
The boom, the bust, and the resurgence of psychedelic medicine
Psychedelics have been around for thousands of years; psychoactive substances such as ayahuasca have been used by countless indigenous peoples in religious ceremonies, cultural rituals, and for medicinal purposes. Clinical research in the U.S. began in earnest in the early 20th century and, in the 1950s, researchers began experimenting with psychedelic-assisted psychotherapy (dose(s) of a psychedelic plus therapy sessions). For the next two decades, many clinical researchers and practitioners deemed LSD (or acid) and psilocybin (the active ingredient in magic mushrooms) to be miracle drugs — tens of thousands of patients were treated with psychedelic-assisted psychotherapy.
In the 60s, there was a meteoric rise in non-clinical psychedelic use closely associated with the counterculture. In January 1967, Timothy Leary, a former Harvard psychologist, told a crowd of 30,000 people in San Francisco to “turn on, tune in, drop out.” A political and moral panic arose as the government sought to maintain support for the Vietnam War and many feared what looked like a radical threat to the establishment. In 1970, in direct reaction to this, LSD and psilocybin became Schedule I drugs, classified alongside cocaine and heroin. This had a massive cooling effect, with medical research all but stopping for the next two decades.
Slowly though, starting in the mid 80s, pockets of the scientific community began to refocus their attention on legally understanding the potential of these compounds. In 1986, MAPS (the Multidisciplinary Association for Psychedelic Studies) was founded to help promote education and research on the therapeutic potential of psychedelics and has since become the most influential organization in psychedelic medicine. The Heffter Research Institute, founded in 1993, sparked psilocybin research, and the Beckley Foundation, founded in 1998, focuses on drug policy reform and funding psychedelic research. By 2000, the newly established psychedelic research center at Johns Hopkins University became the first U.S. group to obtain regulatory approval to restart research, marking a turning point in the science of psychedelic medicine. Since 2009, researchers at Imperial College London, another key institutional locus, have conducted crucial studies on psychedelics’ impact on the brain. It took two decades for the field to develop and amass a foundation of compelling clinical studies to stand behind. Now, there are 10+ prominent research centers studying these compounds.
The results from clinical studies on psychedelics are unprecedented
Treating mental health conditions involves a nuanced, multi-pronged effort, typically over months or years. There is no quick fix — treating and managing mental health conditions is far from easy. Our mental health requires constant attention and we typically adjust a treatment regimen in response to our changing mental health state.
Standard treatment for people with the most prevalent mental health conditions is antidepressants, which are prescribed to manage both depression and anxiety.² And antidepressants are often paired with therapy. Yet these drugs have only modest effects: they improve symptoms for just 20 more people out of 100 compared to placebo and less than a third see remission within 10–14 weeks of beginning treatment for depression symptoms. After an average treatment period of six weeks for depression, average symptom score reduction versus placebo is just ~2 points on the 50-point Hamilton Depression Rating Scale (HAM-D).³
In contrast, a representative randomized control trial at Johns Hopkins of psilocybin-assisted psychotherapy for depression resulted in 83% of participants seeing a >50% reduction in depression scores and 58% experiencing full remission. Psilocybin-assisted psychotherapy yielded a ~16 point drop in GRID-HAMD score measured at both five weeks and six months post-session.⁴ Johns Hopkins’ most recent clinical trial results show a 14–15 point drop in GRID-HAMD score one week and four weeks post-intervention. Ketamine-assisted psychotherapy yields a ~13 point drop in HAM-D score one day after infusion and a 6 point drop one week after.
Studies on MDMA-assisted psychotherapy for people with treatment-resistant PTSD (people for whom two or more medications have been unsuccessful) yielded a 68% cure rate, meaning no identifiable PTSD symptoms remained one year post-treatment. In comparison, a study with veterans who completed one of the two leading non-psychedelic treatments for PTSD reported that two-thirds of patients still had PTSD after treatment.
Clinical studies on psychedelics to date have been small, with participant numbers in the dozens, but results have been statistically-significant and yielded larger effect sizes than standard treatments.⁵
An overview of how four key psychedelics improve mental health:
- Psilocybin and LSD significantly reduce symptoms of depression and anxiety. Evidence also indicates both can help with treating substance use issues.⁷
- MDMA dramatically increases empathy and trust while decreasing fear, making it easier to discuss and overwrite fearful and intrusive memories, particularly for those with PTSD.
- Ketamine rapidly reduces depressive symptoms and suicidal ideation; however, the effects wear off after days or weeks, meaning people often need additional infusions.
These compounds have also demonstrated tremendous value for people without serious mental health conditions. In one Johns Hopkins study, 80% of participants said their psilocybin-assisted therapy experience was one of the five most meaningful experiences of their lives.
Your brain on psychedelics
It’s safe to say that scientists still have much to learn about psychedelics, but we do already have some sense for how they impact the brain. All psychedelics, including psilocybin, LSD, MDMA, ketamine, ibogaine, and ayahuasca, act by affecting the brain’s neurotransmitters, most commonly targeting serotonin (which is associated with happiness and general wellbeing).⁸ Raising serotonin levels can yield a general sense of euphoria, but these compounds also seem to change which areas of the brain are most active; they increase connectivity between parts of the brain that may not usually talk to one another and increase neuroplasticity. Psychedelics flood the brain with serotonin and enhance emotional receptivity, leading to increased emotional processing and connection. Thus, the definition of the word psychedelics: mind-manifesting. Brain scans of patients on psychedelics have shown a significant drop in activity in the Default Mode Network, the brain’s quarterback or “orchestra conductor” — where we believe the human ego lives.⁹ This drop in activity can lead to a heightened feeling of internal and external connectedness and likely helps enable the spiritual experiences many people report having on psychedelics.
These changes in brain chemistry create subjective experiences that can result in a reduction of psychological distress: irrational and otherwise destructive thought patterns and behaviors can be unraveled or even broken, helping people move on from years of being stuck. Often this takes the form of an existential reckoning that enables people to change the way they perceive themselves, their memories and beliefs, and their level of connectedness with others. Worldview fundamentally shifts: people report increased connectedness to nature, decreased authoritarian political views, increased sense of awe and wonder, and a significantly reduced fear of death — months after their experience. As the ego is quieted, an increase in neuroplasticity enables us to create new mental models for understanding reality. Individuals with mental health conditions characterized by deeply ingrained habits of rumination and an excessive focus on self-identity, such as depression and addiction, have the greatest opportunity for healing — psychedelics facilitate a mental reset. The substances tend to bring into focus whatever emotions and thoughts are already present inside our heads and magnify what’s going on outside. And, almost universally, people report a focal feeling — love.
Therapy plays a key role in facilitating and accelerating the healing process as well as helping patients to integrate their experiences — taking these medicines alone isn’t enough. Psychedelic-assisted therapy creates a controlled space for the intentional use of these medicines. Studies show that the strict connections that grip and limit the brain’s function loosen, enabling people to reprocess their traumatic memories or free themselves of mental rigidity. An expert guide can help people build new, more constructive narratives about themselves and their relationship with the world; this work helps the unconscious become conscious.
Like any powerful tool, psychedelics aren’t risk-free. They are not as physiologically risky as other Schedule 1 substances such as cocaine and heroin, however there are potential contraindications. People with cardiovascular conditions may be at greater risk of experiencing physiological changes that could adversely affect their condition such as significantly increased or decreased heart rate and increased blood pressure. There can also be psychological risk: certain compounds can exacerbate pre-existing conditions or trigger latent mental health disorders (in rare cases they have triggered a psychotic episode). The experience of being on psychedelics can be traumatic and destabilizing, both during and afterward. When emotions surface that have been long-suppressed, a person may become worse off psychologically. In one survey capturing psilocybin users “worst trips,” 39% of participants rated their most difficult trip as one of the top five most challenging experiences in their lives, with 11% reporting putting themselves or others at risk of physical harm.
In general, psychedelics are far safer than many people have been led to assume, particularly when administered with a controlled dose and setting. Their potential for addiction is generally low (with the notable exceptions of ketamine and MDMA). “Bad” psychedelic trips — experienced during clinical research or recreational use — are often linked to one or more of the following: improper dose, impure compound, mixing with other (often dangerous) substances, lack of preparation, improper setting, certain pre-existing health conditions, and/or a genetic predisposition for severe mental illness. In legal clinical settings, with the right preparation, facilitation, and integration, these risks are dramatically reduced.
The world of psychedelic medicine is undergoing a renaissance
The market is evolving quickly, with lots of moving pieces. For the sake of simplicity, we break down the landscape into three buckets: Research, Treatment, and Enabling Organizations. To date, the majority of investment has been toward research to prove efficacy and ultimately help drive regulatory approval. There are a range of supporting advocacy organizations that aim to help this nascent industry grow in a successful and ethical direction as well as a growing number of media organizations covering new developments. We’ve seen an increasing number of organizations start in the last few years with the goal of providing psychedelic-assisted therapy (generally either with ketamine, which is the one psychedelic substance legally available for clinical use in the U.S., or in countries such as Jamaica or The Netherlands where psilocybin is legal).¹⁰ There are also organizations working to train future generations of practitioners in psychedelic-assisted therapy. There are even companies building specialized software to support these providers’ clinical practices. While it’s still early, there is a true ecosystem beginning to take shape. We will map out the landscape and what’s been happening in greater depth in an upcoming piece. In the meantime, this chart provides a rough overview of the market as it stands now.
What’s going to happen next?
The scientific evidence supporting psychedelic medicine is overwhelmingly positive, but it is still unknown how these substances will be used and adopted at scale. In the next five years, we’ll likely see continued growth in research on psychedelic medicine and psychedelic-assisted mental health treatment in the U.S. More and larger research studies need to be conducted to replicate the findings of initial studies, including the effect sizes. Funding is pouring in like never before and more research institutions are dedicating resources to understanding these compounds. However, the scientific foundation for the industry’s growth must be built before these compounds are available more broadly.
First, current clinical trials need to be successfully completed. In particular, the industry is awaiting the expected 2021 completion of MAPS’ phase 3 trials (potentially delayed to 2022 by COVID-19) studying MDMA-assisted psychotherapy to treat PTSD. Designated as a “breakthrough therapy” for PTSD treatment by the FDA in 2017, MDMA is considered the “lead domino” of the psychedelic compounds in terms of the progress and persuasiveness of the current clinical trials. With FDA approval, this treatment could set an important precedent for future research.
Psilocybin is next up and could be approved for treatment-resistant depression (championed by Compass Pathways, currently in phase IIb) or Major Depressive Disorder (championed by Usona Institute, currently in phase II) as early as 2023. But, even if results are unequivocally positive, there will likely be setbacks and delays along the way, including difficulties running clinical trials during a pandemic.
There is a clear opportunity for psychedelics to revolutionize the way we treat mental health. Psychedelics could provide a chance for millions of people with mental illness to get their lives back. The current scientific evidence is impressive and continued research into the neuroscience of psychedelics will help ensure a positive impact in fighting psychological suffering. In addition to regulatory approval, the industry will need much more infrastructure before these treatments become widely available to those who need them, including standardized, high-quality training of practitioners and development of effective clinical care delivery models.
It’s rare to witness the renaissance of an industry — especially one with so much potential to truly change millions of lives for the better. And also an industry with more than its fair share of baggage and complexity.
The path forward will require brilliant researchers, disciplined entrepreneurs, empathetic clinicians, thoughtful lawmakers, and many other supporters to safely unlock the possibility of these compounds.
If you want to learn more, look out for the rest of the series — we’ll be releasing additional short posts going into more depth on the science of psychedelics, the state of mental health, and the business landscape. Sign up here to get the full series in your inbox. And tell us if you’re interested in getting more involved in this space through volunteering, investing, working full time in psychedelic medicine, or by building a company. We’re happy to try and help connect you with opportunities. And, here is our curated resource guide of readings, short videos, and podcasts.
Acknowledgements: Thank you to Milan Griffes, Kevin Weiss, Mattan Griffel, David Burstein, Alex Simon, Shirelle Noble, Miles Bird, Julia Lipton, Matt Johnson Ph.D., Nick Hardy Ph.D., Clio Smurro, Iva Grabic MD, Kareen Patterson, Anaïs Radonich Galvin, Fede Menapace, Evan Brandoff, Katherine Lu and many others for lending their time and expertise over the last six months as we’ve conducted research and written this series.
[1] https://www.cdc.gov/nchs/covid19/pulse/mental-health.htm
[2] The name is a misnomer.
[3] More on antidepressant efficacy or lack thereof here and here.
[4] The GRID-HAMD is an improved version of the Hamilton Depression Rating Scale.
[5] Statistical effect size measures how clinically-significant the effect of the therapeutic intervention is — the significance of a result and how big the impact is.
[6] SSRIs (Selective serotonin reuptake inhibitors) are the most-prescribed class of antidepressants.
[7] Psilocybin helps alcohol and nicotine addicts reduce their usage and improve long-term abstinence rates. LSD seems to be an effective treatment for alcoholism too.
[8] Ketamine works on NMDA rather than serotonin receptors and increases levels of the neurotransmitter glutamate.
[9] The largest drops in DMN activity lead to temporary “ego dissolution,” the loss of a sense of self.
[10] Ketamine has been in use for over 50 years, primarily for pain management / anesthesia. Because of its FDA approval for these initial uses, it can legally be used “off-label” to treat other conditions.
