24 of the most important questions about psychedelics, answered | Matthew Johnson: Full Interview

Key Concepts

Psychedelic: "Mind manifesting" compounds that profoundly affect one's sense of reality and self.
Classic Psychedelics: Psilocybin, LSD, DMT, mescaline; primarily activate serotonin 2A receptors.
Non-Specific Amplifiers: Psychedelics can amplify any human experience (euphoric or hellish), highly dependent on individual context.
Hallucinogen: A term often used but criticized for focusing on perceptual effects and implying true hallucinations, which are rare.
Entheogen: Refers to sacramental/spiritual use; criticized for defining a drug class by one specific use.
Serotonin 2A Receptor: The primary site of action for classic psychedelics in the brain.
Neuroplasticity: The brain's ability to form new connections and pathways, potentially enhanced by psychedelics, aiding long-term change.
Set and Setting: The mental state (set) and physical/social environment (setting) that profoundly influence a psychedelic experience.
Mystical Experience: A psychological construct describing feelings of unity, timelessness, spacelessness, and ineffability, often correlated with therapeutic outcomes.
Integration Phase: The period after a psychedelic session where participants process and derive meaning from their experience.
Heroic Dose: A high dose of a psychedelic (e.g., 30-40mg psilocybin) intended to induce profound experiences, often larger than recreational doses.
Trans-diagnostic Processes: Underlying commonalities across different psychiatric disorders that psychedelic treatments may address.
Psychedelic Exceptionalism: The dangerous belief that new rules apply to psychedelics due to their profound nature, leading to a disregard for clinical boundaries.
Metaphysical Neutrality: The principle that guides should not impose their own spiritual or philosophical interpretations on a patient's psychedelic experience.
Hard Problem of Consciousness: The philosophical question of why and how subjective experience (awareness) exists.

Introduction to Matthew Johnson and the Uniqueness of Psychedelics

Matthew Johnson, a professor of psychiatry and behavioral sciences at Johns Hopkins, has dedicated nearly two decades to studying psychedelic compounds. He highlights psychedelics as unique among drugs due to their profound, often life-altering impact from a single use, a phenomenon rarely observed with other drug classes like cannabis, stimulants, or opioids. Johnson's interest, sparked over 25 years ago, stems from the historical use of psychedelics by indigenous cultures, their explosion in Western culture in the 1960s, and their interdisciplinary nature, touching on domains from anthropology to neuroscience. He cites examples like Nobel laureate Kary Mullis attributing his PCR invention to psychedelic experiences and The Beatles' musical evolution pre- and post-LSD as evidence of their transformative potential.

Defining 'Psychedelic' and Related Terminology

The term "psychedelic" was coined by Humphry Osmond in a letter to Aldous Huxley, meaning "mind manifesting" from its linguistic roots. Johnson considers this an apt description, aligning with the concept of psychedelics as "non-specific amplifiers" that can intensify any human experience, from euphoric to hellish, depending on the individual's life context.

Johnson critiques alternative terms:

Hallucinogen: He dislikes this term because it focuses on perceptual effects (e.g., "wavy walls") which are often trivial and not the primary therapeutic mechanism. True hallucinations (believing something is real when it isn't) are rare; psychedelics typically induce visual illusions or pseudohallucinations where reality testing remains intact. In therapy, eye shades are used to minimize focus on these perceptual effects and encourage internal introspection.
Entheogen: Meaning "awakening the divine within," this term refers to sacramental or spiritual use. Johnson argues against using it to define a drug class, as many psychoactive substances (tobacco, coca leaves, opioids) have been used entheogenically. He prefers referring to the "entheogenic use" of a substance rather than defining the substance itself as entheogenic, especially since many recreational users do not report spiritual effects.

He clarifies that "psychedelic" broadly encompasses classic compounds like psilocybin (magic mushrooms), LSD, DMT (ayahuasca), and mescaline (peyote), which primarily affect the serotonin 2A receptor. However, he also includes drugs with different mechanisms, such as MDMA (releasing serotonin, more emotional/heart-focused) and ketamine/PCP (affecting the glutamate system), under the psychedelic umbrella. For Johnson, the unifying definition is their profound effect on one's sense of reality, including the sense of self, to an extreme degree not seen with stimulants, sedatives, or opioids.

The First Wave of Psychedelic Research (1950s-early 1970s)

The initial scientific interest in psychedelics surged in the 1950s, following Albert Hofmann's discovery of LSD's psychoactive properties. Sandoz, Hofmann's employer, liberally distributed LSD samples to physicians for research. Early work by Abram Hoffer and Humphry Osmond in Saskatchewan, Canada, was pivotal. They developed what is now known as "psychedelic therapy," realizing that with proper preparation and a comfortable environment, these drugs could induce meaningful, lucid, and transcendental experiences, rather than just mimicking psychosis as initially thought. The Spring Grove group in Maryland also conducted early research, particularly with cancer patients.

However, this era was also marked by significant ethical lapses. Some researchers administered massive doses (e.g., 800 micrograms of LSD) without warning, sometimes restraining patients, leading to psychotic-like reactions. Timothy Leary's controversial practices at Harvard, including researchers taking the drugs with participants, further complicated the field. The CIA's MKUltra program involved highly unethical experiments, administering LSD to unsuspecting American citizens without consent, often in exploitative settings, to observe effects. These abuses, combined with the drugs' association with the counterculture and anti-war movements of the late 1960s, led to a decades-long halt in research.

Legality of Psychedelics

Most psychedelics remain illegal globally, often classified in the most restrictive categories (e.g., Schedule 1 in the US, Schedule A in the UK), implying high abuse potential and no recognized medical use. However, there are nuances: some US states have decriminalized them, and Oregon has legalized psilocybin use in a therapeutic context with a guide.

Current research is exploring medical applications through FDA and DEA approval processes. Phase 3 clinical trials are underway, and Johnson anticipates that MDMA and psilocybin could be approved for medical use within 2-4 years, depending on trial results. If approved, they would be legal for medical use, similar to how cocaine, methamphetamine, and opioids are legal in specific medical settings, but would remain illegal for recreational use.

Main Effects of Psychedelics

Psychedelics induce a wide array of subjective changes in thoughts, cognition, feelings (often with extreme intensity and variability), self-identification, and perception of reality. These "deepest aspects" are believed to be most aligned with their therapeutic effects.

Remarkably, compared to their intense subjective impact, psychedelics have a relatively low physiological effect. They are "robustly safe at the physiological level," with minimal impact on heart rate or blood pressure for most individuals. Unlike other drug classes where overdose can lead to respiratory failure, organ damage, or cardiovascular events, there is no known lethal overdose amount for psilocybin or LSD for most people. The primary dangers stem from behavioral risks while intoxicated (e.g., wandering into traffic) or psychological distress. The profound subjective experiences, particularly the "mystical experience" (sense of oneness with the universe/humanity), are thought to reframe disorders like addiction or depression by shifting one's self-perception and priorities.

How Psychedelics Work in the Brain

Johnson emphasizes that the psychological experience and biological correlates are "two sides of the same coin." While there's a clear biological effect, the resulting life changes often resemble those from psychotherapy or major life events.

Biological Mechanism:

Receptor Activation: Psilocybin converts to psilocin, which activates the serotonin 2A receptor. While serotonin also binds to this receptor, psilocin induces a different neuronal response, propagating downstream effects.
Neurotransmitter Systems: Other neurotransmitter systems, like glutamate, become involved as a result of the initial serotonin 2A activation. Johnson likens serotonin 2A to the "first domino" in a complex chain reaction.
Brain Network Dynamics: A key level of analysis is the change in communication across the brain. Psychedelics cause a "massive increase in communication" between brain areas that normally operate in compartmentalized "silos." This increased correlation in activity across different regions is believed to underlie psychological insights, extraordinary experiences, and radically altered perspectives of self and reality.
Neuroplasticity: Animal research suggests increased neuroplasticity in the days following a psychedelic experience. This means brain cells become more flexible, forming new branches and connections, potentially priming individuals to learn new things and establish more optimal states, contributing to long-term behavioral change.

Distinction between Classic Psychedelics and MDMA:

Classic Psychedelics (e.g., psilocybin, LSD): Mimic serotonin, directly activating the 2A receptor. Johnson uses a baseball analogy: a "tie-dye baseball" (psychedelic) is thrown into the "catcher's mitt" (receptor), causing a different reaction than a "regular baseball" (serotonin).
MDMA: Works differently by causing neurons to release a "massive increase" of natural serotonin into the synaptic space, leading to a different effect on the system, typically less intense and more emotionally focused.

Evidence for Serotonin 2A's Role:

Antagonists: Compounds like ketanserin specifically block the serotonin 2A receptor. When administered, psilocybin has no effect in humans.
Animal Studies: Rats trained to discriminate psilocybin from saline injections lose this ability when their 2A receptors are blocked. Genetically modified "knockout" rodents lacking 2A receptors show no psychedelic effects.
Potency Correlation: There's a strong correlation between the potency of classic psychedelics (how much is needed for an effect) and their affinity (stickiness) for the serotonin 2A receptor.

While serotonin 2A is key, other receptor sites may add "coloring" to the experience. Other compounds like ketamine/PCP primarily affect the glutamate system, and salvinorin A activates the kappa opioid receptor. Ibogaine is "pharmacologically promiscuous," affecting multiple mechanisms, and is of interest for opioid addiction due to its normalizing effect on the reward system, though it carries cardiac risks (prolonged QT interval). Johnson is more interested in psilocybin and LSD for opioid addiction due to their lower physical toxicity.

Dangers and Risks of Psychedelics

Johnson clarifies that all medical interventions and psychoactive compounds carry risks, but the prevalence of harms from psychedelics is significantly lower than from many legal and illegal substances (e.g., tobacco, alcohol, which consistently rank highest in harm to self and others). Classic psychedelics like psilocybin and LSD are not addictive and are "freakishly physically safe," with no known lethal overdose for most people and no organ damage.

The primary risks are:

Exacerbating Mental Illness: Psychedelics can destabilize individuals with a predisposition to psychotic disorders like schizophrenia or bipolar disorder. Screening is crucial to identify and exclude such individuals. In thousands of clinical cases, no one who passed screening has developed schizophrenia from psychedelic use, but observational cases suggest vulnerable individuals can be pushed "over the edge" (e.g., Syd Barrett of Pink Floyd).
Bad Trips (Challenging Experiences): These involve anxiety, fear, and panic, potentially leading to dangerous behavior. Clinical protocols address this through preparation, emphasizing that fear is normal, and building strong rapport with guides who provide reassurance and a safe environment. Johnson debunks urban legends from the 1960s, such as staring into the sun or genetic damage, noting a lack of credible evidence. While bad trips can be horrific, most resolve without lasting harm if the person is in a safe, supported environment.

A major factor in minimizing risks is the presence of a sober, trusted guide and a safe environment where the individual can "let go" without external distractions or safety concerns.

"All-Arounders" and the Core of Psychiatric Disorders

Johnson refers to psychedelics as "all-arounders" (a term borrowed from Cheech & Chong) because their effects are highly unpredictable and cannot be reliably explained in simple terms like "uppers" (cocaine, caffeine) or "downers" (opioids, benzodiazepines). Psychedelics can induce experiences ranging from profound bliss and universal love to terrifying panic and feelings of permanent insanity, often within moments.

Given this unpredictability, the therapeutic approach emphasizes:

Surrender: Encouraging participants to accept whatever experience unfolds, rather than trying to control it.
Mindfulness: Observing the experience without judgment, even if it's difficult.
Acceptance: Treating every experience as a learning opportunity. This approach is crucial, as fighting a challenging experience can exacerbate it. Johnson notes that a lack of apprehension before a session indicates insufficient preparation, as the gravity of the experience warrants some "butterflies."

The Role of a Guide in a Psychedelic Session

Matthew Johnson has guided over 100 psychedelic sessions, finding it exceptionally rewarding. He prefers the term "guide" over "therapist" or "shaman" in this context, though he acknowledges the therapist role as psychedelics move into mainstream medicine. The guide's primary role is as a "safety net," establishing deep rapport and trust during preparation. During the session, the guide encourages the participant to "trust, let go, be open" and surrender to the experience, offering support and reassurance.

The vulnerability of participants during these sessions, where they may feel they are dying, necessitates strict adherence to clinical boundaries and ethics. Johnson warns against "psychedelic exceptionalism," the idea that the profound nature of these experiences justifies new, looser rules. Instead, he argues for even more tenacious adherence to ethical codes to prevent abuses like sexual misconduct. Safeguards include multiple guides, limited therapeutic touch with informed consent, and avoiding extensive bodywork.

Focus and Impact of Matthew Johnson's Research

Johnson's research focuses on characterizing psychedelic experiences, particularly the "mystical experience" – a validated psychological construct describing feelings of unity, timelessness, spacelessness, and ineffability, divorced from supernatural beliefs. His therapeutic studies consistently show a correlation: the more mystical the session, the greater the reduction in depression and anxiety for cancer patients, or the higher the success rate for smoking cessation. This suggests the psychological nature of the experience, not just receptor activation, is crucial, making psychedelic treatments more akin to psychotherapy than traditional psychiatric medications.

Key therapeutic areas of his research include:

Cancer-Related Depression and Anxiety: Dramatic, long-lasting reductions in symptoms after a single high-dose psilocybin session, often bringing patients into a non-disordered range.
Tobacco Smoking Cessation: A pilot study showed an 80% biologically verified smoke-free rate at six months, significantly outperforming existing treatments. This research has received the first US federal grant for classic psychedelic therapeutic use in half a century.
Meditation Practice: Psilocybin experiences can jumpstart meditation practices, leading to increased pro-social benefits and altruistic traits.

Johnson is "floored" by participants' reports, including combat veterans stating a psilocybin session was the "most intense experience of their life," surpassing combat. He notes that psychedelics often bring deep-seated psychological "baggage" and unresolved trauma to the surface, even when not the primary focus of the study. He quotes the Rolling Stones: "You may not get what you want, but you may get what you need," emphasizing the experience's ability to present what is psychologically necessary for the individual. Guides are trained to accept and validate all emotions, fostering an environment where crying or intense processing is welcomed, unlike typical recreational settings.

The Psychedelic Renaissance

The current "psychedelic renaissance" is driven by several interacting factors:

Mental Health Crisis and Stagnation: Society faces a severe mental health crisis, with traditional treatments for depression and addiction showing limited progress for decades. Antidepressants (SSRIs) offer modest benefits and often take weeks to work, while addiction treatments often rely on substitution therapies. Psychedelics offer a novel approach that appears to address the "roots" of these disorders.
Passage of Time: Enough time has passed since the research halt of the late 1960s/early 1970s, allowing for a re-evaluation. The initial scientific work was unfairly sacrificed due to psychedelics' association with the counterculture and societal changes that scared those in power. Johnson likens this to Thomas Kuhn's concept of a "paradigm shift," where new ideas are initially resisted by the "old guard" but eventually adopted by younger generations.
Societal Readiness: Society is now more prepared to accept a balanced view of psychedelics, recognizing their immense promise while acknowledging they are not panaceas.

Pitfalls of Psychedelic Medicine

Johnson identifies three critical pitfalls for the burgeoning field:

Abuse of Vulnerability: The profound intimacy and vulnerability of psychedelic sessions make them ripe for abuse, particularly sexual abuse. Safeguards are essential: multiple guides, limited and consented therapeutic touch, and strict adherence to established clinical boundaries and ethical codes. He warns against "psychedelic exceptionalism," the dangerous belief that the unique nature of these experiences justifies abandoning standard ethical practices.
Metaphysical Neutrality: Guides must remain neutral regarding patients' interpretations of their experiences (e.g., encountering God, ancestors, or other dimensions). The patient should drive the meaning-making process. Guides should avoid imposing religious icons or playing the role of guru or priest, instead encouraging patients to bring their own meaningful objects.
Loose Use of "Consciousness": The term "consciousness" is often used imprecisely. Johnson urges greater precision, distinguishing between:
- Phenomenal Consciousness (Hard Problem): The question of why subjective experience exists at all. Johnson believes psychedelics currently offer no scientific way to address this, though he remains open to future possibilities.
- Self-Identity: Psychedelics can profoundly alter the sense of self ("ego death"), offering insights into the brain mechanisms underlying self-concept.
- Access Consciousness: The process of bringing memories or thoughts into awareness. Psychedelics may inform this process. He cautions against the automatic leap that understanding how psychedelics work in the brain fundamentally explains consciousness itself.

Will Psychedelics Answer the Hard Problem of Consciousness?

The "hard problem of consciousness" refers to the seemingly unsolvable question of how and why subjective experience (awareness) exists. Johnson explains that scientific evidence for phenomenal consciousness is limited to one's own subjective feeling of being conscious, with no empirical way to prove it in others (e.g., "What is it like to be a bat?"). While many people report that psychedelics provide insights into the nature of consciousness, this subjective belief does not constitute scientific evidence. Johnson believes no current experiment can use psychedelics to crack this problem, but he remains open to the possibility. He stresses the importance of separating phenomenological exploration (what people report) from validating the "ground truth" of those experiences.

Medicines Used in Psychedelic Therapy Sessions

In the modern renaissance, the primary compounds used are:

Psilocybin: Administered as a pure, precisely dosed white powder in capsules (e.g., 30mg high dose), not whole mushrooms.
MDMA: A synthetic white powder given in capsules.
LSD: Historically used, now being researched for chronic pain, delivered dissolved in water.
Ketamine: Approved as an anesthetic for decades, lower doses are now FDA-approved for depression. Ketamine offers immediate antidepressant effects but they typically last only about a week, requiring repeated administration.

Johnson contrasts psilocybin with ketamine:

Onset/Duration: Ketamine's antidepressant effects are immediate but short-lived (about a week), while a single high dose of psilocybin has shown reductions in depressive symptoms lasting at least six months.
Therapeutic Approach: Ketamine is often given with instructions to ignore the psychedelic effects, while psilocybin therapy treats the experience itself as central to healing, encouraging introspection and insight.
Addiction/Safety: Ketamine can be addictive, whereas psilocybin is rarely addictive and is robustly safe physiologically, with no known lethal overdose or organ damage. Johnson believes psilocybin has significant advantages and may prove superior for long-term effects.

The "Heroic Dose" in Psychedelic Therapy

Therapeutic research often uses a "heroic dose" of psilocybin (e.g., 30-40 milligrams of pure psilocybin, equivalent to about five dried grams of mushrooms), which is typically larger than most recreational doses. While historically adjusted by body weight, recent data suggests a fixed dose is sufficient. Johnson also addresses microdosing (1/20th to 1/10th of a recreational dose), noting that despite popular buzz, rigorous studies have yet to conclusively demonstrate its claimed benefits for mood, creativity, or ADHD.

A Psychedelic Therapy Session

A session begins after several hours of preparation to build rapport. The environment is designed to be warm and inviting, resembling a living room rather than a hospital. The participant takes the capsule with water, and during the 20-60 minute onset period, engages in light discussion or looks at art books. Once effects begin, the participant lies down with eye shades and headphones playing music, encouraged to "trust, let go, be open." They are advised to embrace the "absorptive side of their mind," experiencing without judgment, and to surrender to whatever unfolds, even challenging experiences. Guides provide support, including physical touch like hand-holding, while maintaining strict boundaries. The 5-6 hour experience is followed by an "integration phase." The "set and setting" (e.g., warm environment vs. a "padded room") profoundly shapes the experience, with a welcoming context leading to more meaningful reactions. The ceremonial style is generic, avoiding specific religious traditions.

Experiences People Have in Their Sessions

Experiences vary widely, from rapid, overwhelming onset to a gradual creep. Participants are encouraged to surrender to the experience, even if it feels like being "eaten by a monster," and to explore its meaning. Examples include:

Feeling they've reached the "end of reality" and learning to "let go of things."
Witnessing the "birth of the Universe" or confronting an "infinite void" that is both empty and pregnant with meaning.
Bizarre experiences (e.g., focusing on "Foghorn Leghorn").
Reflecting on deceased family members, processing grief and guilt.
Experiencing "universal empathy" and being overwhelmed by global suffering.

The core instruction, "trust, let go, be open," means:

Trust: The process, the institution, the guides, and one's own resilience.
Let Go: Of preconceived notions, control, and flow with the experience.
Be Open: To follow the experience wherever it leads, knowing one is in a safe, contained environment.

The Integration Phase

The integration phase begins with the participant writing a narrative about their experience. This essay forms the basis for discussion the next day, where guides help unpack the meaning without imposing interpretations. Key aspects include:

Revealed Truth: Participants often feel they've learned something at a fundamental level, "in their bones," even if they intellectually knew it before (e.g., the agency to quit smoking, the ability to live life despite cancer).
Reminders: People are often reminded of forgotten aspects of themselves or life-affirming activities (e.g., a love for poetry).

Why Psychedelic Therapy Seems So Effective

Psychedelic therapy's effectiveness appears to stem from its ability to address the "roots of psychological problems" rather than just surface symptoms.

Ego Dissolution/Oneness: Experiences of "dissolving the ego" or "oneness" allow individuals to step outside their self-narrative, viewing themselves with compassion and breaking free from self-critical thought patterns.
Neuroplasticity: Animal research shows increased neuroplasticity (brain cells growing new branches and connections) in the days following psychedelic administration. This is hypothesized to occur in humans, making them more flexible and primed to learn new, healthier patterns.
Trans-diagnostic Potential: Psychedelics' efficacy across diverse conditions (depression, anxiety, multiple addictions) suggests they address "trans-diagnostic processes" – common underlying mechanisms across disorders. Johnson views many disorders as "addictions" to narrowed mental and behavioral repertoires, from substance abuse to self-persecutory thoughts. Psychedelics can "blow people out of that narrowed story."
Prevention: Beyond treating disorders, psychedelics may offer insights into what fosters mental health and how to implement preventative care. Even "healthy normals" often confront past traumas or "addictions" of various types during sessions.

The profound nature of these experiences means that one, two, or three sessions in the right setting may be sufficient to treat disorders, sometimes appearing like a "cure" by resolving deep-seated psychological issues. Johnson notes that while Big Pharma hasn't traditionally invested, they are likely "waiting in the wings" to acquire successful small start-ups, adapting to a business model focused on infrastructure and professional guidance rather than daily pill sales.