The Neuroplastic Revolution: Are Psychedelics, Ketamine, and Esketamine the Future of Mental Healthcare?
A clinician’s field guide to where we actually are and what’s real versus hype
The Question in the Room
The patient across from me is successful by every conventional measure: thriving business, loving family, objectively good life. She’s also been depressed for three years. We’ve tried two SSRIs, therapy, lifestyle interventions through our six-pillar program at MindWell. She’s optimized her sleep, cleaned up her diet, and exercises regularly. She’s done everything right. And she’s still struggling. This is not uncommon.
“What about ketamine?” she asks. “Or psilocybin? I keep reading about them. My therapist sent me an article from The New York Times about how they’re curing treatment-resistant depression.”
I pause, because this is the conversation that happens weekly now, sometimes daily. Five years ago, it was rare. Now it’s routine. Patients arrive with podcast episodes saved, studies their friends forwarded, and questions about flying to Oregon for legal psilocybin sessions or whether they should try ayahuasca in Costa Rica.
The honest answer is complex. Yes, something remarkable is happening in psychedelic research, and it’s not just hype, but a genuine scientific revolution. We’re learning that these compounds work through mechanisms fundamentally different from anything in psychiatry. They not only modulate neurotransmitters, but they also seem to directly promote structural brain changes, reopening windows of neuroplasticity where healing can occur.
But, and this is crucial, the gap between “promising research” and “available, effective treatment” remains vast. Between clinical trials in controlled settings and real-world practice. Between what’s possible and what’s accessible. Between understanding mechanisms and knowing who will respond.
As a physician running a mental health clinic that uses ketamine, currently the only legal psychedelic medicine, I’m living in this gap every day. This is what I’ve learned about where we actually are, what the science genuinely shows, and what it means for the future of treating depression, trauma, and addiction.
Ancient Knowledge, Forgotten Wisdom
The story of psychedelic medicine doesn’t begin in Silicon Valley or Johns Hopkins. It begins thousands of years ago, in ceremonies conducted under starlight across multiple continents.
Archaeological evidence places psilocybin mushroom use in Spain’s Cuenca region at approximately 6,000 years ago. Frescos in Southeastern Algerian caves depict mushroom-bearing shamans from around 5000 BCE. Mayan “mushroom stones” from Guatemala date to 1500 BCE, suggesting organized ceremonial use. The Rigveda, composed between 2000-1400 BCE, references Soma, likely a psychoactive plant used in Vedic rituals.
In the Amazon basin, Indigenous groups including the Shipibo-Konibo, Quechua, and Tucano peoples developed sophisticated healing practices around ayahuasca—a brew combining Banisteriopsis caapi vine with DMT-containing plants like Psychotria viridis. The word itself, from Quechua, translates to “spirit rope” or “liana of the soul.” These weren’t recreational substances; they were—and remain—sacred medicines used in contexts involving elaborate dietary preparations (dietas), healing songs (icaros), and shamanic guidance.
The Mazatec people of Mexico’s Sierra Mazateca used psilocybin mushrooms—teonanácatl or “flesh of the gods”—in healing ceremonies called veladas. The Native American Church incorporated peyote, the mescaline-containing cactus, into religious ceremonies that served not only spiritual purposes but also provided, as anthropologists note, a “needs-based solution to psychological problems Native Americans were encountering in the newly enforced reservation system.”
What matters for today: What these diverse traditions shared was an understanding that these substances, used within specific ceremonial contexts with intention and support, could facilitate profound healing. Indigenous practitioners recognized the importance of what we now call “set and setting” (the mindset of the person and the physical and social environment) centuries before Western scientists would rediscover these principles. This is a core insight that modern clinical trials are validating and that determines outcomes in our clinic every day.
PART II: THE FIRST WAVE (1943-1970)
The Accidental Discovery
The Western scientific story begins with Swiss chemist Albert Hofmann at Sandoz Pharmaceuticals in Basel. In 1938, while synthesizing derivatives of ergot alkaloids, Hofmann created LSD-25 (lysergic acid diethylamide). The compound sat unused until April 16, 1943, when Hofmann accidentally absorbed a small amount through his skin. He experienced what he later described as “fantastic, vivid images with intense colours.”
Three days later, Hofmann intentionally ingested 250 micrograms, what he thought would be a threshold dose (later research would show this to be approximately 2-3 times a typical dose). During his bicycle ride home, now commemorated annually as “Bicycle Day” by psychedelic researchers, Hofmann experienced the first documented LSD trip, complete with visual distortions, time dilation, and profound alterations in consciousness.
Saskatchewan: The Birthplace of Psychedelic Medicine
Surprisingly, the systematic medical investigation of psychedelics didn’t begin in California but in the prairie province of Saskatchewan, Canada. In 1951, British psychiatrist Humphry Osmond arrived at Weyburn Mental Hospital, a bleak 19th-century institution. Osmond, along with biochemist Abram Hoffer, had become interested in mescaline’s structural similarity to adrenaline, hypothesizing that schizophrenia might result from biochemical abnormalities. This was a radical departure from the psychoanalytic theories dominating psychiatry at the time.
Osmond and Hoffer initially used LSD as a “model psychosis” to understand schizophrenia. But their work took an unexpected turn when they began treating alcoholics. Their first study in 1953 involved two patients given single 200-microgram doses of LSD. One stopped drinking immediately; the other six months later—a 50% success rate that proved remarkably consistent as they expanded their work.
Between 1954 and 1960, Osmond and Hoffer treated approximately 2,000 alcoholic patients under carefully controlled conditions. They reported that roughly 50% achieved sobriety for 6-12 months or longer following a single LSD session. This wasn’t the result they’d predicted: rather than frightening patients with an artificial delirium tremens-like experience, LSD appeared to produce profound mystical experiences that fundamentally reoriented patients’ relationship with alcohol.
Bill Wilson, co-founder of Alcoholics Anonymous, was among Osmond’s patients. Wilson found the experience so meaningful that he advocated for LSD research, seeing it as a potential catalyst for the spiritual awakening central to AA’s recovery model.
Coining a New Language
In 1956, Osmond needed a term for these consciousness-altering substances. After exchanging rhyming couplets with novelist Aldous Huxley (whom Osmond had introduced to mescaline in 1953, leading to Huxley’s famous book The Doors of Perception), Osmond proposed “psychedelic” at a 1957 New York Academy of Sciences meeting. From the Greek psyche (mind or soul) and deloun (to manifest or reveal), the term meant “mind-manifesting” or capturing the idea that these substances revealed otherwise hidden aspects of consciousness rather than simply creating hallucinations.
The Golden Age
Throughout the 1950s and early 1960s, psychedelic research flourished. At England’s Powick Hospital, psychiatrist Ronald Sandison developed “psycholytic therapy,” using small, repeated doses of LSD as an adjunct to psychoanalysis. Czech psychiatrist Stanislav Grof explored LSD’s potential for end-of-life anxiety, trauma processing, and understanding non-ordinary states of consciousness.
In the United States, research expanded to multiple institutions. Studies at Spring Grove State Hospital in Maryland investigated LSD-assisted therapy for alcoholism, heroin addiction, depression, and anxiety in terminal cancer patients. Between 1950 and the mid-1960s, over 40,000 patients were administered LSD in therapeutic contexts, generating more than 1,000 clinical papers documenting generally positive results.
The research on end-of-life anxiety proved particularly compelling. Studies consistently showed that single LSD sessions, combined with psychotherapy, could dramatically reduce anxiety and depression in dying cancer patients. Many reported profound spiritual experiences that allowed them to accept death with peace, reconcile with family members, and find meaning in their final months.
This research hits close to home for me. My first wife, Lindsey, died of colon cancer at 29. In her final months, she certainly struggled with anxiety and existential distress. These treatments that had shown such promise in the 1960s were completely unavailable—lost to prohibition, buried by the War on Drugs. I can't know if they would have helped her, but she deserved the chance to find out. Thousands of patients since have been denied that same chance
The Failures of Early Research
Despite promising results, the early psychedelic research had significant methodological limitations. As historian Erika Dyck notes in her 2005 examination of the Saskatchewan studies published in the Canadian Journal of Psychiatry, these trials “failed for two reasons, one scientific and the other cultural.”
Scientifically, the research predated modern standards for randomized controlled trials (RCTs). Osmond and Hoffer’s studies lacked placebo controls, proper blinding, and standardized outcome measures. When the Addiction Research Foundation in Toronto conducted a controlled trial in the early 1960s—comparing 800-microgram LSD doses to ephedrine and treatment-as-usual—they found improvements across all conditions but no superiority for LSD.
Osmond and Hoffer argued that this trial didn’t reflect their approach: the Toronto study administered very high doses without preparation, therapeutic support, or integration—essentially violating all the principles they’d found crucial for success. But the damage was done. As the field evolved toward evidence-based medicine requiring RCTs, psychedelic research struggled to meet the new standards.
In our practice: This historical tension remains relevant. I see patients who benefit enormously from ketamine alone or when it’s embedded in comprehensive therapy and lifestyle work, proper preparation, therapeutic dosing sessions, and integration afterwards. I’ve also seen patients receive ketamine at other clinics with minimal support who report “interesting experiences” but no lasting benefit. Set and setting determine outcomes.
THE LONG PROHIBITION (1966-2000)
From Medicine to Menace
The cultural context in which psychedelic research existed changed dramatically in the mid-1960s. Several factors converged to transform these substances from promising medicines into symbols of social disorder.
Timothy Leary, a Harvard psychology professor who’d begun legitimate research on psilocybin’s potential for personality change and treatment of recidivism, became increasingly evangelical about psychedelics’ consciousness-expanding potential. After leaving Harvard in 1963, he encouraged widespread, uncontrolled use with his famous exhortation to “turn on, tune in, drop out.” LSD became associated with the countercultural movement, anti-war protests, and rejection of traditional social values.
Media coverage amplified concerns. Reports of “bad trips,” accidental deaths, and chromosomal damage (later disproven but widely publicized) fueled public alarm. The recreational use of LSD and other psychedelics by college students and young people was not only seen as individual experimentation, but also as symptomatic of larger social unrest: the Civil Rights Movement, Vietnam War protests, the environmental movement, and various challenges to established authority.
The Political Response
Political leaders responded decisively. In 1966, President Lyndon Johnson signed the Drug Abuse Control Act, making possession of psychedelics a crime. But the defining moment came on October 27, 1970, when President Richard Nixon signed the Comprehensive Drug Abuse Prevention and Control Act.
Title II of this act—the Controlled Substances Act (CSA)—established a scheduling system that would shape drug policy for the next 50 years. The CSA created five schedules based theoretically on three criteria: potential for abuse, accepted medical use, and addiction potential. LSD, psilocybin, mescaline, and DMT were placed in Schedule I, defined as substances with high abuse potential, no accepted medical use, and lack of accepted safety even under medical supervision.
This classification put these compounds alongside heroin, despite minimal evidence of physical addiction and a safety profile dramatically different from opioids. (Later research would consistently show psychedelics to have among the lowest addiction liability and physical harm potential of any psychoactive substances.)
The political motivations behind the “War on Drugs” have been extensively documented. Nixon's domestic policy chief, John Ehrlichman, admitted in a 1994 interview that the drug war had explicit political objectives: “We knew we couldn’t make it illegal to be either against the war or black, but by getting the public to associate the hippies with marijuana and blacks with heroin, and then criminalizing both heavily, we could disrupt those communities.”
The Chilling Effect
The consequences for research were immediate and severe. LSD and other classical psychedelics were classified under international treaties (the 1971 UN Convention on Psychotropic Substances) that made research extraordinarily difficult even for scientists with legitimate questions.
Obtaining DEA licenses, securing supply, managing storage requirements, and navigating extensive regulatory oversight made psychedelic research prohibitively expensive and bureaucratically burdensome. Funding disappeared as government agencies withdrew support. The Shafer Commission, formed to study marijuana’s effects and recommend policy, actually concluded in 1972 that cannabis possession should be decriminalized, but Nixon rejected the recommendation.
For nearly three decades, psychedelic research essentially ceased in Western institutions. A generation of scientists abandoned a promising line of inquiry. The thousands of patients who might have benefited from psychedelic-assisted therapy were denied access, while conventional treatments for conditions like treatment-resistant depression, PTSD, and addiction showed limited efficacy.
THE NEUROSCIENCE REVOLUTION
Understanding the Brain’s Stress Response
To understand why psychedelics are now generating such excitement, we need to understand what happens in the brains of people with chronic stress-related psychiatric disorders.
Depression, PTSD, anxiety disorders, and addiction share a common neurobiological signature: atrophy of neurons in the prefrontal cortex (PFC), particularly in layer V pyramidal neurons. The PFC is critical for emotional regulation, decision-making, and behavioral flexibility. Post-mortem studies of depressed patients consistently show decreased dendritic spine density and reduced dendritic arborization in these regions.
Beyond correlation, animal models demonstrate that chronic stress directly causes dendritic retraction in the PFC. Rats exposed to chronic unpredictable stress show decreased dendritic branching, reduced spine density, and impaired performance on PFC-dependent tasks. These structural changes correlate with behavioral symptoms resembling depression and anxiety.
Traditional antidepressants like SSRIs can eventually work on these deficits, but the process is slow—typically requiring 4-8 weeks of daily dosing before clinical improvement. Even then, remission rates for major depressive disorder hover around 30-40% for first-line treatments, with each failed trial reducing the likelihood of response to subsequent interventions.
What this means in practice: When we explain this to patients, we describe it simply: chronic stress and depression cause your brain cells to shrink and lose connections, like a tree losing branches. Traditional antidepressants slowly help regrow them, if they work at all. But ketamine, and possibly other psychedelics, appear to kickstart that regrowth process much more rapidly and robustly.
Psychedelics as Psychoplastogens
In 2018, David Olson’s laboratory at UC Davis introduced the term “psychoplastogen” in a paper published in Cell Reports to describe compounds that rapidly and durably promote structural and functional neural plasticity. Unlike traditional antidepressants that require chronic administration to produce structural changes, psychedelics can induce robust neuroplastic responses following a single dose—and these changes persist long after the acute effects have subsided.
The data is striking. In cultured cortical neurons, psychedelics including LSD, psilocybin, DMT, and DOI (a research compound) increase dendritic arbor complexity, promote spinogenesis (formation of new dendritic spines), and increase synapse number. These effects occur within hours and persist for days after the compounds are removed from the culture medium.
In vivo studies confirm these findings. A single dose of psilocybin administered to mice increases dendritic spine density in the medial frontal cortex by approximately 10% within 24 hours, creating changes that persist for at least a month, as demonstrated in a 2024 study published in the Journal of Psychopharmacology. Similar effects have been observed with DMT, LSD, and various other psychedelics.
Importantly, these structural changes are accompanied by functional improvements. Mice exposed to chronic unpredictable stress (an animal model of depression) show expected deficits: decreased dendritic spine density, elevated anxiety-like behavior, and cognitive inflexibility. A single dose of psilocybin not only partially reverses the structural deficits but also produces rapid and sustained antidepressant-like effects on behavior.
Translation: The brain physically rebuilds connections that stress had eroded. It’s structural repair. Think of it like the difference between putting a coat of paint on a damaged wall versus actually fixing the foundation.
The Molecular Mechanisms: A Complex Picture Emerges
For years, the consensus held that psychedelics exerted their effects primarily through activation of serotonin 2A (5-HT2A) receptors. These receptors are densely expressed in layer V pyramidal neurons of the PFC, and their activation is necessary for psychedelics’ subjective effects. Blocking 5-HT2A receptors with antagonists like ketanserin prevents both the hallucinogenic effects and, researchers initially believed, the therapeutic effects.
But this picture has grown considerably more complex. Multiple converging lines of evidence now suggest that psychedelics’ neuroplastic and therapeutic effects involve several additional mechanisms.
Discovery 1: The TrkB Connection
In 2023, researchers at the University of Helsinki and the University of California, Davis published a breakthrough finding in Cell: psychedelics bind directly to TrkB (tropomyosin receptor kinase B), the receptor for brain-derived neurotrophic factor (BDNF), with affinities 1,000-fold higher than conventional antidepressants.
BDNF is a growth factor critical for neuronal survival, differentiation, and synaptic plasticity. It acts through TrkB receptors, triggering intracellular signaling cascades involving the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and phospholipase C gamma (PLCγ) pathways. These pathways ultimately activate the mechanistic target of rapamycin (mTOR), a master regulator of protein synthesis and cellular growth.
The Finnish-UC Davis study showed that psychedelics like LSD and psilocin bind to the transmembrane domain of TrkB dimers at a site distinct from where BDNF binds. This binding acts as a positive allosteric modulator. It doesn’t activate TrkB directly but enhances its response to endogenous BDNF.
In plain language: BDNF is like fertilizer for brain cells, and psychedelics don’t replace or increase it, but they make brain cells vastly more responsive to the BDNF already present. It’s like turning up the volume on a growth signal your brain is already producing.
Critically, a point mutation in the TrkB binding site that prevents psychedelic binding also prevents their plasticity-promoting and antidepressant-like effects, but doesn’t affect the head-twitch response (the mouse analog of human hallucinations) mediated by 5-HT2A receptors. This provides molecular evidence that the neuroplastic/therapeutic effects can be dissociated from the hallucinogenic effects.
Discovery 2: The Intracellular Receptor Hypothesis
Perhaps the most surprising recent discovery involves where psychedelics actually exert their effects. In a 2023 Science paper, David Olson’s group demonstrated that a substantial proportion of 5-HT2A receptors in cortical neurons aren’t located on the cell surface but rather in intracellular compartments, particularly the Golgi apparatus.
Because psychedelics are lipophilic (fat-soluble), they can cross the cell membrane and access these intracellular receptors…something serotonin itself cannot do. This may explain a longstanding mystery: why serotonin, despite being a 5-HT2A agonist, doesn’t produce psychedelic-like neuroplastic effects when applied to cultured neurons.
The researchers showed that membrane-impermeable analogs of psychedelics (chemically modified to prevent cell entry) only promote neurite growth when delivered directly into cells via electroporation. Conversely, a membrane-impermeable 5-HT2A antagonist only blocks psychedelic effects when delivered intracellularly.
The intracellular receptor hypothesis elegantly explains several observations. The Golgi and other intracellular compartments are slightly acidic compared to the cytosol. This acidic environment may protonate psychedelics, causing them to become “trapped” inside cells where they can produce sustained signaling—potentially explaining why brief exposure to psychedelics produces long-lasting neuroplastic effects.
What this means: Psychedelics likely work from the inside out. They get inside brain cells and activate receptors serotonin can’t reach, then get trapped there, continuing to signal for hours. This creates lasting changes rather than just temporary effects.
The Complete Cascade
Integrating these findings, a working model emerges of how psychedelics may trigger neuroplasticity:
Cell entry: Psychedelics cross the cell membrane and activate intracellular 5-HT2A receptors, likely in the Golgi
Glutamate signaling: This triggers increased cortical glutamate levels, leading to enhanced AMPA receptor activity
BDNF release: AMPA activation triggers activity-dependent BDNF secretion
TrkB enhancement: Psychedelics bound to TrkB amplify its response to BDNF
mTOR activation: TrkB activation triggers downstream signaling through PI3K/AKT and MAPK pathways, converging on mTOR
Protein synthesis: mTOR drives production of plasticity-related proteins, including synaptic proteins (PSD-95, GluA1, synapsin-1), cytoskeletal proteins, and more BDNF, creating a positive feedback loop
Structural changes: These molecular changes translate into observable alterations—increased dendritic branching, enhanced spinogenesis, new synapse formation—that persist for weeks after acute drug exposure
This represents a fundamentally different mechanism from traditional antidepressants. SSRIs work by increasing extracellular serotonin over weeks, eventually desensitizing certain receptors and slowly promoting plasticity. Psychedelics appear to directly kickstart plasticity mechanisms, producing rapid changes that are then sustained by endogenous processes, the brain’s own growth systems.
The Critical Period Hypothesis
Another fascinating line of research, published by Gül Dölen’s laboratory in a 2023 Nature paper, suggests psychedelics may reopen “critical periods” or developmental windows of heightened neural plasticity normally restricted to youth.
Dölen’s group (formerly at Johns Hopkins, now at UC Berkeley) demonstrated that psychedelics, including psilocybin, MDMA, LSD, DMT, and ibogaine, can reopen the critical period for social reward learning in mice. These critical periods normally close in adolescence, constraining the brain’s ability to rewire social behaviors.
Multiple psychedelics, despite having different primary molecular targets, all shared this ability to restore juvenile-like plasticity. The common mechanism appeared to involve metaplasticity—plasticity of plasticity itself—mediated through changes in the balance of excitatory and inhibitory neurotransmission.
Why this matters clinically: Many psychiatric disorders involve maladaptive learning that becomes deeply entrenched: PTSD’s fear conditioning, addiction’s reward associations, social anxiety’s avoidance patterns. If psychedelics create temporary windows of enhanced plasticity, therapeutic interventions during and after the experience might be unusually effective at “unlearning” pathological patterns.
This framework also explains why “set and setting” matter so profoundly. If you’re in a state of enhanced plasticity, whatever learning occurs, shaped by therapeutic context, mindset, and integration work, gets encoded more deeply than normal waking experience.
In our clinic: This is exactly what we observe with ketamine. The sessions where patients use the altered state to work on therapeutic insights, paired with integration afterwards, tend to produce more lasting change than sessions where patients just “trip.” One patient with treatment-resistant depression used her ketamine sessions to practice self-compassion while in the neuroplastic window, then reinforced those patterns through daily meditation and therapy between sessions. Six months later, she’s in remission. Another patient with similar severity had ketamine sessions without integration work and saw no sustained benefit. The window of plasticity is real, but it’s what you build during that window that determines outcomes.
THE CLINICAL EVIDENCE
Ketamine: The Pioneer Returns
Technically a dissociative anesthetic rather than a classical psychedelic, ketamine deserves special mention as the first psychoplastogen to achieve widespread clinical use. Approved by the FDA in 1970 as an anesthetic, ketamine’s antidepressant properties were discovered in the 1990s.
In a landmark 2000 study published in Biological Psychiatry, Yale researchers showed that a single sub-anesthetic dose of ketamine produced rapid antidepressant effects in treatment-resistant depression patients—responses evident within hours and lasting up to a week. Dozens of subsequent studies confirmed these findings.
In 2019, the FDA approved esketamine (Spravato)—the S-enantiomer of ketamine—as a nasal spray for treatment-resistant depression and later for acute suicidal ideation in major depressive disorder. This marked the first approval of a rapid-acting antidepressant with a novel mechanism of action in decades.
Current data shows that approximately 50-80% of treatment-resistant depression patients respond to ketamine, with many experiencing symptom reduction within 24 hours. However, effects typically require repeated dosing, and questions remain about optimal protocols, long-term safety, and abuse potential (ketamine has some addiction liability, unlike classical psychedelics).
Ketamine works through NMDA receptor antagonism, but it shares psychedelics’ downstream effects: increased glutamate signaling, BDNF release, mTOR activation, and enhanced synaptic plasticity. Recent evidence suggests it too may bind to TrkB, contributing to its antidepressant effects.
At MindWell: We see ketamine work remarkably well for some patients—particularly those with clear stress/trauma components and strong therapeutic alliance. We see that many of our treatment-resistant patients show meaningful response, in line with the data. But it’s not magic; some don’t respond significantly, and a few others can’t tolerate the dissociative effects. Maintenance dosing can be logistically and financially challenging. The patients who do best seem to be those who combine ketamine with integration and our lifestyle medicine pillars: using the neuroplastic window to build healthier patterns around sleep, nutrition, movement, stress management, and social connection.
Psilocybin for Depression
The modern psychedelic clinical trials began in earnest in the 2000s with studies on psilocybin. Roland Griffiths at Johns Hopkins conducted groundbreaking work showing that single psilocybin sessions could produce lasting increases in openness, life satisfaction, and mystical-type experiences in healthy volunteers.
The depression trials followed. In a 2016 open-label study at Imperial College London published in The Lancet Psychiatry, 12 patients with treatment-resistant depression received two psilocybin sessions (10mg and 25mg, one week apart). All patients showed some symptom reduction, with 8 of 12 meeting criteria for response at one week and 7 maintaining response at three months.
Compass Pathways’ phase 2b trial, published in 2022 in The New England Journal of Medicine, enrolled 233 patients with treatment-resistant depression across 22 sites in 10 countries. Patients received a single dose of psilocybin (25mg, 10mg, or 1mg) with psychological support. At three weeks, response rates were 37% (25mg dose), 20% (10mg), and 10% (1mg control), with sustained response in over 50% of the 25mg group at three months.
A 2024 phase 2 trial from the Usona Institute showed similar promising results for major depressive disorder (MDD). Recent meta-analyses published in JAMA Psychiatry and Nature Medicine suggest sustained remission rates of approximately 50% at six months for depression patients receiving psilocybin-assisted therapy—dramatically higher than the 30-40% remission rates typical for conventional antidepressants.
These results catalyzed two phase 3 trials by Compass Pathways for treatment-resistant depression, with results expected in Q2 2025. The Usona Institute launched its first phase 3 trial for MDD in March 2024.
Cautiously Optimistic: These are impressive numbers, but they come from highly selected patients in controlled research settings with extensive therapeutic support. Real-world effectiveness may differ. We need to see how these treatments perform in community settings with diverse patient populations before declaring victory.
MDMA for PTSD
MDMA (3,4-methylenedioxymethamphetamine) isn’t a classical psychedelic. It’s classified as an entactogen or empathogen, producing feelings of emotional closeness and reduced fear responses rather than perceptual alterations. But its therapeutic applications have generated perhaps the most clinical excitement.
The Multidisciplinary Association for Psychedelic Studies (MAPS), founded in 1986, spent decades advocating for and conducting MDMA research. Their work culminated in two phase 3 trials (MAPP1 and MAPP2) of MDMA-assisted therapy for PTSD.
The results were striking. In MAPP1, published in Nature Medicine in 2021, 67% of participants in the MDMA group no longer met PTSD diagnostic criteria at two months post-treatment, compared to 32% in the placebo group. MAPP2 showed 71% of participants (particularly first responders and veterans) maintained symptom relief at 12 months.
The treatment protocol involved three 8-hour MDMA-assisted therapy sessions spaced 3-4 weeks apart, combined with preparatory and integration sessions. MDMA appeared to work by reducing fear responses and defensive reactions, allowing patients to process traumatic memories that would normally trigger overwhelming anxiety.
However, in August 2024, the FDA declined to approve MAPS’ New Drug Application, requesting an additional phase 3 trial. The FDA advisory committee had raised concerns about blinding (MDMA’s effects make true blinding nearly impossible), inadequate monitoring of cardiovascular effects and potential for abuse, and allegations of therapist misconduct in one trial site.
This setback was significant but not necessarily fatal. MAPS’ sponsor, Lykos Therapeutics, is working with the FDA to design another trial. Meanwhile, attention has shifted to psilocybin, which may now become the first classical psychedelic to achieve FDA approval.
LSD for Anxiety
MindMed’s MM-120 (LSD d-tartrate) is in development for generalized anxiety disorder (GAD). A phase 2b dose-finding trial completed in 2023 showed promising results, with various doses (25μg to 200μg) demonstrating anxiety reduction compared to placebo.
GAD is a particularly difficult condition to treat, with existing medications showing modest efficacy and significant side effects. MindMed plans to initiate phase 3 trials in 2025, with data potentially available by late 2026.
Other Compounds and Indications
The research pipeline has expanded dramatically:
Ibogaine for opioid use disorder and traumatic brain injury (multiple sponsors in phase 1/2)
5-MeO-DMT for treatment-resistant depression (GH Research phase 2)
DMT combined with harmaline (pharmahuasca) for depression (Small Pharma phase 2)
Psilocybin for anorexia nervosa, chronic pain, obsessive-compulsive disorder, and Parkinson’s-related depression (various academic centers, see clinicaltrials.ucsf.edu)
Ketamine for alcohol use disorder (Awakn Life Sciences phase 3, showing 86% abstinence at 6 months in phase 2)
As of late 2024, at least 278 clinical trials involving classical psychedelics, MDMA, and related compounds have been registered on clinicaltrials.gov—a dramatic increase from fewer than 10 trials before 2017.
Meta-Analytic Evidence
Several recent systematic reviews and meta-analyses have synthesized the growing evidence base:
A 2023 JAMA Psychiatry meta-analysis of psychedelics for psychiatric disorders found moderate to large effect sizes for depression and PTSD outcomes, with effects maintained at follow-up periods of 1-12 months
A 2024 analysis in Nature Medicine examining psilocybin trials specifically reported an overall response rate of approximately 50-60% for treatment-resistant depression, with about 40-50% achieving remission—substantially higher than typical antidepressant response rates
A systematic review in Neuropsychopharmacology (2024) concluded that psychedelic-assisted therapy shows “encouraging efficacy signals” but called for larger, more rigorous trials with active placebo controls and longer follow-up periods
THE CHALLENGES AHEAD
Methodological Quandaries
Psychedelic clinical trials face unique challenges that standard RCT frameworks struggle to accommodate. The most fundamental is blinding: psychedelics’ profound subjective effects make it nearly impossible to create a convincing placebo. Participants almost always know whether they received the active drug.
This creates potential for expectancy effects, where improvements might result partly from beliefs about treatment rather than the drug’s pharmacological actions. Various strategies have been attempted—using low doses as “active placebos” (which may have some therapeutic effects), using non-psychedelic comparators like niacin (which causes flushing that signals drug administration), or comparing different psychedelics to each other.
Another challenge involves the role of subjective experience. Many researchers believe the quality of the acute psychedelic experience, particularly mystical-type experiences involving ego dissolution, unity, and transcendence, predicts therapeutic outcomes. Statistical analyses often show correlations between acute subjective effects and subsequent clinical improvement.
This raises a thorny question: Can psychedelics’ therapeutic effects be separated from their subjective effects? Or is the experience itself therapeutic? If so, how should we design trials and development programs?
Some researchers are developing non-hallucinogenic psychoplastogens, or, said in another way, compounds that promote structural plasticity without producing altered states of consciousness. Compounds like tabernanthalog (TBG), based on ibogaine’s structure but non-hallucinogenic, show plasticity-promoting and antidepressant-like effects in animal models. Whether these will prove clinically effective remains to be determined.
My skepticism on this: The subjective experience may not be incidental. The “trip” forces confrontation with difficult material, provides perspective shift, creates the mystical experiences that correlate with outcomes. I’m not convinced you can strip that away and keep equivalent efficacy. But I could be wrong…that’s an empirical question only trials will answer.
The Integration Question
Another unresolved issue is the role of psychotherapy. Current protocols combine drug administration with substantial therapeutic support: preparatory sessions to build alliance and set intentions, continuous support during the 6-8 hour dosing session, and integration sessions to process insights and translate them into behavioral change.
This raises questions about what’s necessary versus sufficient. Is the extensive therapy crucial for outcomes? Could a briefer protocol work? What therapeutic modalities are most effective? Different trials have used different approaches—from acceptance and commitment therapy to psychodynamic therapy to supportive counseling—with no clear consensus on optimal methods.
A 2024 debate in The American Journal of Psychiatry highlighted this uncertainty. Some researchers argue that the acute experience plus basic support may be sufficient, making elaborate psychotherapeutic protocols unnecessarily expensive and limiting scalability. Others contend that integration work is essential for sustaining benefits and translating mystical experiences into meaningful life changes.
The answer likely varies by condition and individual. For someone with treatment-resistant depression seeking symptom relief, perhaps less intensive support suffices. For someone processing complex trauma, extensive therapeutic work may be essential.
In practice: I’ve seen both patterns. One patient had a profound ketamine experience, felt dramatically better for a week, then gradually regressed because she had no framework for integrating insights or changing behavior patterns. Another patient did intensive integration work—journaling about each session, discussing insights with her therapist, deliberately practicing new ways of relating to herself—and maintained improvement at six months. And still other patients see great results from ketamine sessions alone without assisted therapy programs. The neuroplastic window creates opportunity, but integration determines whether it translates into lasting change.
Safety Considerations
While psychedelics’ physiological safety profile is remarkably good—they’re non-toxic, don’t cause physical dependence, and have extremely low addiction potential—psychological risks remain.
Adverse events in trials have included transient anxiety, paranoia, and in rare cases (less than 1% in controlled settings), psychosis-like symptoms lasting more than 24 hours. People with personal or strong family histories of psychotic disorders are typically excluded from trials due to concerns about precipitation of latent psychosis.
Cardiovascular effects merit monitoring. Psychedelics can cause transient increases in blood pressure and heart rate during acute effects. While this appears safe for healthy individuals, people with cardiovascular disease require careful screening and monitoring.
MDMA specifically has different safety considerations. It can cause significant increases in body temperature, especially in crowded, hot environments—one reason it’s associated with adverse events in uncontrolled recreational settings. In clinical trials with appropriate monitoring and temperature control, serious adverse events have been rare but not absent.
Long-term safety data remains limited. Most trials follow participants for 3-12 months post-treatment. Questions about repeated dosing safety, optimal inter-dose intervals, and lifetime exposure limits remain unanswered.
Patient Safety and Advocacy
While the promise of psychedelic therapies is real, it’s crucial to emphasize that these treatments should not be pursued through the black market or underground settings.
Illicit psychedelics carry significant risks that are entirely absent in clinical settings:
Unpredictable dosing: Street drugs vary wildly in potency. What’s sold as “psilocybin” or “LSD” may contain completely different substances or dangerous adulterants
Contamination: Illicit substances may be cut with toxic compounds, from fentanyl to research chemicals with unknown safety profiles
No medical screening: Conditions that contraindicate psychedelic use—family history of psychosis, certain cardiovascular issues, medication interactions—go unidentified
Lack of therapeutic container: Without proper preparation, medical supervision during dosing, and professional integration support, the risk of adverse psychological outcomes increases dramatically
No emergency support: If a medical or psychiatric emergency occurs, there’s no trained team to intervene
The absence of these safeguards can lead to severe psychological harm, dangerous medical complications, or trauma that makes legitimate treatment more difficult later.
Instead, patients and clinicians should advocate for expanded legal access to psychedelic therapies through proper channels:
Support research and policy reform: Organizations like the Multidisciplinary Association for Psychedelic Studies (MAPS), the Coalition for Psychedelic Safety and Education, and the Psychedelic Medicine Coalition work to ensure safe, equitable access through clinical research, public education, and policy change
Participate in clinical trials: Many trials are actively recruiting participants. ClinicalTrials.gov lists ongoing studies, many of which provide treatment at no cost
Explore legal options: Oregon and Colorado have implemented regulated psilocybin services. While not medical treatment per se, these programs offer legal, supervised access
Advocate locally: Contact state legislators about medical access programs, decriminalization efforts, and research funding
Use available legal options: Ketamine and esketamine (FDA-approved) are available through legitimate medical clinics
The goal isn’t to make these medicines available faster by circumventing safety; it’s to make them available safely and equitably to all who could benefit. That requires patience, advocacy, and collective pressure on regulatory systems—not resort to black markets that endanger both individuals and the broader movement toward legitimate access.
For clinicians: We have a responsibility to educate patients about these risks while validating their frustration with limited access. I tell patients: “I understand the urgency. You’re suffering, and you want relief. But the difference between a therapeutic outcome and a traumatic one often comes down to proper screening, dosing, preparation, and support. Underground treatments gamble with all of that. Let’s work together to find safe options and advocate for better access.”
Equity and Access
A troubling pattern is emerging: psychedelic therapy risks becoming a treatment for the wealthy. Current ketamine clinics charge $400-800 per session (MindWell is less than that), typically requiring multiple sessions. When MDMA and psilocybin achieve approval, they’ll likely be even more expensive—at least initially.
The therapy-intensive nature of current protocols exacerbates this. Each patient requires 20-40 hours of clinician time (preparation, dosing session with two therapists present, integration). This doesn’t scale easily, particularly in under-resourced areas already facing severe mental health provider shortages.
Insurance coverage remains uncertain. While some insurers now cover ketamine and esketamine for depression, coverage for future psychedelics will depend on FDA approvals, pricing negotiations, and political considerations. There’s real risk of creating a two-tiered system where privileged patients access cutting-edge treatments while marginalized communities—who often face higher rates of trauma, depression, and substance use disorders—are left with conventional options.
The MindWell dilemma: We offer options for patients who can’t afford standard pricing, but even subsidized, it’s not accessible to many who’d benefit. When psilocybin is approved, how do we make it available without becoming a boutique clinic serving only the wealthy? This is the question on my mind.
Indigenous Rights and Biopiracy
The commodification of psychedelic medicines raises profound ethical questions about intellectual property, cultural appropriation, and benefit-sharing with Indigenous communities.
A 2023 paper in The Lancet Regional Health-Americas by Indigenous researchers and advocates outlined these concerns. For millennia, Indigenous peoples cultivated relationships with these plant medicines, developing sophisticated knowledge about their cultivation, preparation, and ceremonial use. Now, pharmaceutical companies are patenting psychedelic compounds, treatment protocols, and even genetic variants of psychedelic plants using knowledge, in part, derived directly from Indigenous practices.
Yuria Celidwen, a researcher of Nahua and Maya heritage, notes that Western psychedelic facilitators charge thousands of dollars for ceremonies appropriated from Indigenous traditions, while Indigenous medicine practitioners remain impoverished. International demand has driven unsustainable harvesting of iboga in Africa, ayahuasca ingredients in the Amazon, and peyote in North America—threatening both plant populations and ceremonial access for Indigenous communities.
The paper proposes eight principles for ethical engagement:
Recognition of Indigenous sovereignty over traditional medicines
Fair and equitable benefit-sharing
Protection against biopiracy and inappropriate patenting
Support for sustainable harvesting practices
Meaningful participation of Indigenous peoples in research
Respect for ceremonial contexts and spiritual dimensions
Protection of Indigenous intellectual property rights
Support for Indigenous-led healing and research
These are urgent questions about justice, sustainability, and respect for the knowledge systems that preserved these medicines when Western science dismissed them.
What I’m grappling with: Using ketamine feels less ethically fraught because it’s synthetic, developed through Western pharmaceutical research. But as our field expands to plant medicines, how do we participate in ways that honor rather than exploit Indigenous knowledge? I don’t have all the answers, but I’m committed to learning from Indigenous voices and supporting equitable benefit-sharing structures as they emerge.
THE PATH FORWARD
Regulatory Landscape
Multiple psychedelic compounds have received FDA Breakthrough Therapy designation: a status granted when preliminary evidence suggests substantial improvement over existing treatments. These include psilocybin for treatment-resistant depression and major depressive disorder, MDMA for PTSD, and LSD for GAD.
Breakthrough designation provides several advantages: more intensive FDA guidance during development, organizational commitment for senior FDA involvement, and rolling review of application components before final submission. However, as MDMA’s rejection demonstrates, breakthrough status doesn’t guarantee approval.
Current best estimates suggest:
Psilocybin: Potential approval for treatment-resistant depression in 2027-2028 (pending Compass Pathways phase 3 results expected 2026)
MDMA: Unknown timeline following FDA’s request for additional phase 3 trial
LSD: Phase 3 trials starting 2025, potential approval 2028-2030
Esketamine (Spravato): Already approved for treatment-resistant depression and acute suicidal ideation
State-level initiatives are also progressing. Oregon implemented regulated psilocybin services in 2023, allowing licensed facilitators to administer psilocybin in supervised settings. Colorado voters approved similar measures in 2022. Multiple other states have introduced psychedelics-related legislation, ranging from decriminalization to medical access programs.
The Broader Renaissance
The psychedelic renaissance extends beyond psychiatry. Research is exploring applications in:
Neurology: Cluster headaches (psilocybin shows remarkable efficacy in small trials), stroke rehabilitation, traumatic brain injury (ibogaine phase 2 trials for veterans)
Palliative Care: End-of-life anxiety and depression in terminal illness (building on the promising 1960s research)
Substance Use Disorders: Alcohol use disorder (psilocybin and ketamine), opioid use disorder (ibogaine), tobacco cessation
Neuroplasticity Enhancement: Potential applications in learning, creativity, and cognitive enhancement (highly speculative but being explored)
The academic infrastructure is also expanding. Major universities have established dedicated psychedelic research centers:
Johns Hopkins Center for Psychedelic and Consciousness Research (2020)
UC Berkeley Center for the Science of Psychedelics (2020)
Imperial College London Centre for Psychedelic Research (2019)
Mount Sinai Center for Psychedelic Psychotherapy and Trauma Research (2021)
UCSF Translational Psychedelic Research Program
These centers combine basic neuroscience, clinical trials, training programs for therapists, and policy research.
The Investment Landscape
Private capital has flooded into the psychedelic space. The global psychedelic drugs market, valued at $3.8 billion in 2020, is projected to reach $11.82 billion by 2029. Publicly traded companies, including Compass Pathways, ATAI Life Sciences, MindMed, Numinus Wellness, and others, are conducting clinical development programs.
This influx of capital accelerates research but also raises concerns about commercialization priorities. Will companies focus on conditions affecting the most people (depression, anxiety) or the most profitable markets? How will pricing decisions balance investor returns against patient access? Will the pursuit of patentable compounds overshadow research on unpatentable natural substances?
What We Still Don’t Know
Despite remarkable progress, fundamental questions remain:
Mechanism: How exactly do intracellular 5-HT2A receptor activation, TrkB binding, and AMPA receptor signaling interact to produce lasting neuroplastic changes? What’s the role of each component?
Biomarkers: Can we identify who’s likely to respond before treatment? Are there genetic, neuroimaging, or physiological markers that predict outcomes?
Dosing: What’s the optimal dose for different conditions and individuals? How do we personalize dosing? What’s the role of repeated vs. single-dose treatments?
Experience: Can therapeutic effects be achieved without mystical experiences? If so, do non-hallucinogenic alternatives offer equivalent efficacy?
Mechanisms of integration: What therapeutic approaches work best? How crucial is the integration phase? Can we optimize this process?
Long-term effects: What happens with repeated treatments over years? Are there cumulative benefits or risks? What are appropriate lifetime exposure limits?
Comparative effectiveness: How do psychedelics compare directly to existing treatments? To each other? What are the indications for each compound?
What Psychedelics + Lifestyle Medicine Might Actually Achieve
At MindWell, we’re already seeing how ketamine integrates with our lifestyle medicine approach: the six pillars of sleep, nutrition, movement, stress management, social connection, and avoidance of dangerous substances.
The pattern I observe: Psychedelics create windows of insight and motivation. Lifestyle changes provide the structure that sustains improvement. Combined, they’re more powerful than either alone.
One patient with treatment-resistant depression had tried multiple antidepressants and therapy for years. After ketamine sessions combined with our lifestyle medicine program:
During the neuroplastic window, she experienced profound shifts in self-perception, seeing herself with compassion rather than criticism
Between sessions, she used that insight to build new patterns: establishing a sleep routine (had been sleeping 4-5 hours), starting daily walks (had been sedentary), joining a support group (had been isolated)
Six months later, she maintains remission. I don’t think ketamine “cured” her, but instead it opened a window where she could build the foundation for sustained wellbeing
Contrast this with another patient who had ketamine sessions at a different clinic with no lifestyle support. He reported “interesting experiences” but returned to the same patterns: poor sleep, inflammatory diet, and social isolation. His depression improved temporarily but returned within weeks.
A realistic vision for the next decade:
Psychedelic-assisted therapy becomes one tool among many for treatment-resistant cases. Probably not a panacea, but a great option when first and second-line treatments fail. Used in combination with:
Evidence-based psychotherapy
Lifestyle medicine interventions
Community support and connection
Ongoing monitoring and adjustment
For some patients, particularly those with trauma and treatment-resistant depression who can access proper therapeutic support, it could be transformative. For others, it will be ineffective or inappropriate. The challenge is developing systems to identify who belongs in which category and ensuring equitable access to those who could benefit.
What psychedelics cannot do:
Fix structural inequities and social determinants of health
Replace the need for ongoing therapeutic work
Cure conditions that require chronic management
Work for everyone or in isolation from comprehensive care
Bypass the need for preparation, support, and integration
AN ANCIENT FUTURE
We find ourselves at a remarkable juncture. Substances used for millennia in Indigenous healing practices, investigated briefly in the 1950s and 1960s, then suppressed for half a century, are revealing themselves to be among the most promising tools we have for treating some of medicine’s most intractable challenges.
The neurobiological mechanisms are becoming clear: psychedelics appear to work not by simple neurotransmitter modulation but by directly promoting structural neuroplasticity, spurring the growth of neurons atrophied by chronic stress, reopening critical periods of enhanced learning, and creating windows of opportunity where, with appropriate therapeutic support, patients can break free from rigid, maladaptive patterns.
The clinical evidence, while still developing, is compelling. Response rates for treatment-resistant depression exceeding 60%. Sustained PTSD symptom relief in 71% of participants. Dramatic reductions in end-of-life anxiety. Meaningful improvement in addiction, where conventional treatments often fail.
Yet challenges abound. We’re still learning how to design trials that capture psychedelics’ unique properties while meeting regulatory standards. We’re grappling with questions about the role of subjective experience, the nature of consciousness itself, and what it means to medicalize states that Indigenous peoples have long considered sacred.
We face urgent ethical imperatives around equity, access, and Indigenous rights. The risk is real that we’ll create expensive treatments accessible only to the privileged while exploiting the knowledge of communities who preserved these medicines. How we navigate these challenges will determine whether psychedelics fulfill their promise or become another example of medical innovation that exacerbates rather than reduces health disparities.
The science is clear on one point: these compounds work through mechanisms fundamentally different from existing treatments. They don’t just alleviate symptoms; they appear to target root causes—the structural brain changes underlying psychiatric disorders. They don’t require daily dosing for months; they create windows of enhanced plasticity where healing can occur.
Perhaps most intriguingly, psychedelics are forcing us to reconsider our assumptions about consciousness, healing, and the nature of psychiatric treatment. The idea that mystical experiences might have therapeutic value, that temporarily dissolving the ego might allow psychological reorganization, that set and setting profoundly shape outcomes, these notions challenge the mechanistic frameworks dominating modern medicine.
We’re witnessing the beginning of what may be a paradigm shift in psychiatry. Not simply adding new drugs to our pharmacopoeia, but fundamentally rethinking how we understand and treat mental illness. The path forward requires rigorous science, thoughtful regulation, ethical engagement with Indigenous communities, and humility about how much we still don’t understand.
The Indigenous peoples who stewarded these medicines for centuries never saw them as mere drugs. They understood them as teachers, as doorways to healing that worked through transformation rather than suppression. As Western medicine finally catches up to this ancient knowledge, our challenge is to integrate the rigor of modern neuroscience with the wisdom of traditional practices, creating treatments that are both effective and ethical, both accessible and sustainable.
The psychedelic renaissance should be about moving forward with knowledge that we briefly glimpsed in the 1960s, then lost, and are now rediscovering with tools our predecessors couldn’t have imagined. Brain imaging revealing changes in default mode network connectivity. Molecular biology elucidating intracellular receptor signaling. Genomics identifying the proteins mediating neuroplastic responses.
Incredibly, we’re standing at the threshold of genuinely new approaches to healing the mind. What happens next depends on whether we can combine scientific rigor with ethical wisdom, technological capability with social responsibility, and innovation with justice.
The patient across from me wants to know if she should try ketamine.
My answer: “Let’s talk about what that would actually involve. Not just the sessions themselves, but the preparation before, the integration after, the lifestyle foundation we’d build alongside it. Let’s talk about realistic expectations, like what ketamine can and can’t do, who it helps, and who it doesn’t. Let’s make sure you have the support systems in place to use the neuroplastic window it creates. And let’s acknowledge that this is one tool among many, not a magic bullet.”
Because that’s where we actually are: at the beginning of something potentially revolutionary, armed with genuine scientific insights and promising clinical data, but still figuring out how to deliver these treatments safely, equitably, and effectively in the real world.
The stakes couldn’t be higher. The opportunity is immense. And the work of translating research into accessible, ethical practice is just beginning.
Jay Motley, M.D., is a physician and founder of MindWell Health in the upstate of South Carolina.
