Summary
Dr. Matthew Johnson, a senior psilocybin researcher at Sheppard Pratt, discusses how psychedelics are classified, their mechanisms of action, therapeutic applications, and potential risks. The conversation covers clinical protocols for psilocybin-assisted therapy, the neuroscience of self-representation, and emerging research into psychedelics for depression, addiction, PTSD, and neurological injury. Dr. Johnson also addresses the current lack of evidence supporting microdosing while expressing optimism about high-dose therapeutic models.
Key Takeaways
- Psychedelics are defined by their ability to profoundly alter one’s sense of reality and self, spanning multiple pharmacological classes rather than a single drug type.
- Classic psychedelics (LSD, psilocybin, DMT, mescaline) work primarily as agonists at the serotonin 2A receptor, which distinguishes them from MDMA and ketamine.
- The primary therapeutic mechanism appears to be persistent changes in self-representation — dissolving rigid identity models such as “I am a depressed person” or “I am a smoker.”
- In clinical settings, roughly one-third of participants experience some degree of a “bad trip” even at high doses (around 30mg psilocybin) with optimal preparation.
- “Surrendering” to the psychedelic experience rather than resisting it is associated with better outcomes, including transcendental or mystical experiences linked to long-term positive results.
- Microdosing currently lacks peer-reviewed evidence of benefit; studies show no gains in creativity or cognition, and some show minor impairments in time perception.
- MDMA may be particularly well-suited for PTSD treatment because it produces fewer profoundly destabilizing experiences compared to classic psychedelics.
- Early rodent data and human anecdotes suggest psilocybin may promote neuroplasticity and potentially aid recovery from traumatic brain injury, though human evidence remains preliminary.
Detailed Notes
What Qualifies as a Psychedelic?
The term “psychedelic” is more cultural than pharmacological, spanning several distinct drug classes. The unifying feature is the ability to profoundly alter one’s sense of reality and sense of self.
Major classes include:
- Classic psychedelics / hallucinogens: LSD, psilocybin, DMT, mescaline — act as agonists or partial agonists at the serotonin 2A receptor
- Structurally divided into tryptamines (psilocybin, DMT) and phenethylamines (mescaline)
- NMDA antagonists: Ketamine, PCP, dextromethorphan — overlapping subjective effects with classic psychedelics
- MDMA: Stands in its own class; termed an “entactogen” (touching within) or “empathogen” for its ability to enhance emotional connection and empathy
How Classic Psychedelics Work
Psilocybin and LSD act on the serotonin 2A receptor, but serotonin itself is not psychedelic — the specific downstream signaling pathways triggered by these compounds differ from normal serotonin activity. The exact neuroscience remains under active investigation.
Dr. Johnson’s functional framing: psychedelics act as “prediction machine disruptors” — humans operate largely on top-down models of reality, and psychedelics dissolve those models. This includes challenging the model of the self.
A key perceptual effect is dis-habituation: the reversal of the normal tendency to stop noticing familiar stimuli, causing ordinary objects or sensations to feel profoundly significant.
Clinical Protocol for Psilocybin Therapy
Screening phase:
- Structured psychiatric interviews assessing for disqualifying conditions
- Key exclusions: psychotic disorders (schizophrenia), manic phase of bipolar disorder
- Cardiovascular screening for heart disease
Preparation phase:
- Building therapeutic rapport with session guides
- Didactic explanation of the range of possible experiences (from deeply beautiful to highly challenging)
- Goal: no surprises; all emotional responses are welcomed
Session day:
- Pure psilocybin administered in capsule form (not raw mushrooms)
- Therapeutic dose range: 20–30 mg psilocybin
- Minimal structured tasks to preserve a naturalistic therapeutic experience (fMRI environments and cognitive tasks reduce meaningfulness)
- Participants encouraged to surrender to the experience rather than resist it
- Medical oversight in place: if blood pressure rises significantly, nitroglycerin can be administered sublingually without affecting the psychedelic experience
Post-session integration:
- Processing of experiences with guides
- Reconsolidation of memories and identity shifts are central to lasting effects
Therapeutic Mechanisms: Self-Representation and Identity Change
The most consistent therapeutic mechanism across conditions appears to be changes in self-representation — how a person fundamentally holds their identity.
Examples:
- A smoker shifting from “I’m someone who can’t quit” to experiencing a clear sense of agency: “I can just decide not to smoke”
- Cancer patients realizing they are choosing to avoid activities they could enjoy
- These are described as “duh experiences” — logically known but now felt with new emotional gravity
This connects to a supercharged sense of personal agency, which differs from simply being told to think differently.
MDMA for PTSD
MDMA’s combined dopamine and serotonin release may make it better suited for trauma processing than classic psychedelics because:
- Lower likelihood of profoundly destabilizing or reality-shattering experiences
- Allows reprocessing of traumatic memories with lasting effects, consistent with memory reconsolidation science
- Research with MDMA for PTSD is active; psilocybin for PTSD treatment is also being developed
Risks and Dangers
Primary risks:
- Pre-existing psychotic disorders (schizophrenia, bipolar mania) — can be severely destabilized
- Bad trips — can occur in anyone, even psychologically healthy individuals, especially at high doses or in uncontrolled environments
At 30mg psilocybin with optimal preparation, approximately one-third of participants experience significant anxiety, fear, or a sense of losing their mind at some point during the session.
Key principle: trying to resist or control the experience increases the likelihood of a bad trip; surrender is associated with better outcomes, including mystical experiences tied to long-term positive results.
Psychedelics are not recommended for unsupervised use in dynamic environments (e.g., navigating city streets) due to altered perception and dis-habituation effects.
Microdosing: Current Evidence
Claims around microdosing psilocybin include:
- Improved focus (described as a better version of stimulants for ADHD)
- Improved mood (described as a better version of SSRIs)
What peer-reviewed studies actually show:
- No studies have demonstrated benefits in creativity, cognition, or sustained mood improvement
- Some studies show minor impairments in time estimation and production tasks
- Participants report feeling slightly high and mildly impaired
Important caveat: No studies have yet modeled the specific cycling protocols that microdosing advocates recommend (e.g., dosing every 3–4 days over several weeks). Dr. Johnson speculates the most plausible benefit, if any, would be a modest antidepressant effect via chronic low-level stimulation of the serotonin 2A receptor — similar in principle to SSRIs.
Neurological Injury and Neuroplasticity
Emerging area of interest: using psilocybin to potentially repair brain damage from repetitive head impacts (e.g., combat sports, contact sports).
Evidence base (early stage):
- Rodent studies from labs including David Olsen’s and Brian Roth’s show various forms of neuroplasticity with psychedelic compounds
- Human anecdotes from athletes reporting improved cognition and memory following psychedelic use
- Proposed mechanism: same neuroplastic effects possibly underlying psychiatric benefits
Planned research:
- Retired MMA athletes with history of repetitive head impacts and depression
- Primary aim: treat depression
- Exploratory aim: assess cognitive improvement and gray matter changes via MRI