Glossary

The primary serotonin receptor subtype responsible for the psychedelic effects of classical psychedelics (psilocybin, LSD, DMT). Located predominantly in cortical regions, particularly the prefrontal cortex.

A serotonin receptor subtype involved in mood regulation and anxiety. Activation produces anxiolytic and antidepressant effects. Many psychedelics have secondary activity at this receptor.

A substance that binds to a receptor and activates it, producing a biological response. Most classical psychedelics are serotonin 5-HT2A receptor agonists.

A substance that binds to a receptor but does not activate it, blocking the action of agonists. Ketanserin is a 5-HT2A antagonist used in research to block psychedelic effects.

A substance that binds to a receptor at a site different from the active site, altering the receptor's response to its primary ligand. Can be positive (enhancing) or negative (diminishing).

A 21-item self-report inventory measuring the severity of depression. One of the most widely used instruments in depression research, including psychedelic clinical trials.

A protein that supports neuron survival, growth, and synaptic plasticity. Ketamine rapidly increases BDNF levels, which is thought to contribute to its rapid antidepressant action. Psilocybin also upregulates BDNF.

An FDA designation to expedite development of drugs that show substantial improvement over existing treatments. Psilocybin received this designation for treatment-resistant depression in 2018 (COMPASS Pathways) and major depression in 2019 (Usona Institute).

A design where each participant receives both treatments (active and placebo) in sequence, serving as their own control. Reduces between-subject variability but requires adequate washout periods.

An observational study that follows a group of people over time to see how certain exposures or characteristics affect outcomes. Cannot establish causation as robustly as an RCT.

A detailed report of a single patient's clinical presentation, treatment, and outcome. Provides the lowest level of evidence but can identify novel observations and generate hypotheses for further research.

A standardized measure of effect size calculated as the difference between two group means divided by the pooled standard deviation. Values: 0.2 (small), 0.5 (medium), 0.8 (large).

A range of values within which the true population parameter is expected to fall with a certain level of confidence (typically 95%). Narrower intervals indicate more precise estimates.

Clinician-Administered PTSD Scale for DSM-5. The gold-standard assessment for PTSD severity, used as primary outcome in MDMA-PTSD clinical trials. A structured interview with 20 items scored 0-4.

A regulatory pathway allowing patients with serious conditions to access investigational drugs outside clinical trials when no comparable alternative exists. Switzerland has an active compassionate use program for psychedelic therapy.

The dopamine transporter responsible for clearing dopamine from the synapse. Some psychoactive substances (including MDMA at higher doses) interact with DAT, contributing to euphoric and stimulant effects.

A dopamine receptor subtype involved in reward, motivation, and motor control. Some psychedelics (particularly LSD) have significant D2 receptor affinity, contributing to their unique pharmacological profile.

A study design where neither participants nor researchers know who receives the active treatment or placebo. Challenging in psychedelic research because subjective effects make blinding difficult.

A brain network active during self-referential thinking, mind-wandering, and rumination. Psychedelics reduce DMN connectivity, which correlates with ego dissolution and may underlie their antidepressant effects.

The removal of criminal penalties for personal possession or use of a substance, while it may remain technically illegal. Several US cities and Oregon have decriminalized psilocybin. Distinct from legalization.

The half-maximal effective concentration: the concentration of a drug that produces 50% of its maximum possible effect. Used to compare the potency of different drugs.

A quantitative measure of the magnitude of a treatment effect, independent of sample size. Common measures include Cohen's d and Hedges' g. Psychedelic therapies often show large effect sizes (d > 0.8).

The subjective experience of losing one's sense of self or identity during a psychedelic experience. Associated with reduced activity in the default mode network and correlated with therapeutic outcomes.

A theory proposing that psychedelics increase the entropy (disorder/randomness) of brain activity, moving consciousness to a more flexible, less constrained state. Developed by Robin Carhart-Harris.

A regulatory pathway (also called 'compassionate use' in the US) that allows patients to receive investigational drugs outside of clinical trials under specific conditions approved by the FDA.

A clinician-administered assessment of depression severity. The 17-item version (HDRS-17) is most common. Used in many ketamine and psilocybin trials as a primary or secondary outcome measure.

A public health strategy that aims to minimize the negative consequences of substance use without requiring abstinence. In psychedelic contexts, includes testing substances, dosage education, safe environments, and trip sitters.

A term coined by Terence McKenna for a very high dose of psilocybin mushrooms (5+ grams dried), intended to produce a complete mystical experience. Not used in clinical settings due to safety concerns.

The half-maximal inhibitory concentration: the concentration of an inhibitor required to reduce a biological process by 50%. Key metric for measuring drug potency in inhibition assays.

A ligand that binds to the same receptor as an agonist but produces the opposite pharmacological effect by reducing the receptor's baseline (constitutive) activity.

An analysis strategy that includes all participants as originally allocated, regardless of whether they completed the treatment. Preserves randomization and provides a conservative estimate of treatment effect.

The process of making sense of and incorporating insights from a psychedelic experience into daily life. Typically involves therapy sessions after the dosing session to process the experience.

The inhibition constant (Ki) measures a ligand's binding affinity for a receptor. Lower Ki values indicate stronger binding. Expressed in nanomolar (nM) concentrations.

An opioid receptor subtype whose activation produces dysphoria, dissociation, and hallucinations. Salvinorin A (from Salvia divinorum) is a potent kappa-opioid agonist. Ibogaine also interacts with this receptor.

The primary opioid receptor mediating analgesia and euphoria. Relevant in psychedelic research because ibogaine's metabolite (noribogaine) has mu-opioid activity, which may help treat opioid addiction.

A statistical method that combines results from multiple independent studies to estimate an overall effect. Provides the highest level of evidence when based on high-quality RCTs.

Montgomery-Asberg Depression Rating Scale: a clinician-rated 10-item scale for depression severity. Commonly used in psilocybin and ketamine clinical trials. Scores range from 0-60.

A profound subjective experience characterized by unity, transcendence of time and space, noetic quality, and sacredness. Measured by the Mystical Experience Questionnaire (MEQ30). Strongly predicts therapeutic outcomes.

The practice of taking sub-perceptual doses (typically 1/10th to 1/20th of a full dose) of a psychedelic on a regular schedule. Often used for cognitive enhancement, mood improvement, and creativity. Evidence base is still limited.

Taking a full psychoactive dose of a psychedelic substance that produces significant perceptual, cognitive, and emotional changes. Standard approach in clinical psychedelic-assisted therapy.

N-methyl-D-aspartate receptor, a glutamate receptor subtype critical for synaptic plasticity and memory. Ketamine is an NMDA receptor antagonist, which underlies its rapid antidepressant effects.

The norepinephrine (noradrenaline) transporter responsible for reuptake. MDMA and some other psychoactive substances inhibit NET, contributing to sympathomimetic effects such as increased heart rate.

The number of patients who must receive a treatment for one additional patient to benefit. Lower NNT indicates a more effective treatment. For MDMA-PTSD, NNT is approximately 3.

The brain's ability to reorganize itself by forming new neural connections. Psychedelics promote structural and functional neuroplasticity, particularly through increased dendritic spine density and BDNF expression.

A study where both researchers and participants know which treatment is being administered. Common in early psychedelic research and compassionate use programs. Lower evidence grade than blinded RCTs.

A substance that binds to a receptor and activates it, but produces only a partial response compared to a full agonist, even at maximum occupancy. LSD displays partial agonism at some serotonin receptors.

A trial where the control group receives an inactive substance (placebo) to measure the true drug effect. In psychedelic trials, active placebos (e.g., low-dose niacin) are sometimes used because participants can easily detect a true placebo.

First-in-human studies testing safety, tolerability, pharmacokinetics, and dose range in a small group (20-80 participants). Establishes the maximum tolerated dose.

Studies that evaluate efficacy and side effects in a larger group (100-300 participants). Often includes dose-finding studies. Many psychedelic therapies are currently in Phase II.

Large-scale studies (300-3000+ participants) comparing the drug to existing treatments or placebo. Required for regulatory approval. MAPS Phase III MDMA-PTSD trials are a landmark example.

Post-marketing studies conducted after a drug is approved. Monitor long-term safety, effectiveness in broader populations, and rare side effects. Also called post-marketing surveillance.

The probability of obtaining results at least as extreme as the observed results, assuming the null hypothesis is true. A p-value < 0.05 is conventionally considered statistically significant.

An analysis that includes only participants who completed the study as planned, excluding dropouts and protocol violations. May overestimate treatment effects compared to intention-to-treat analysis.

Patient Health Questionnaire-9: a self-report measure of depression severity with 9 items scored 0-3. Total scores range from 0-27. Widely used as outcome measure in psilocybin depression trials.

A therapeutic approach using low to medium doses of psychedelics over multiple sessions to facilitate psychotherapy. Originated in Europe in the 1960s. Contrasts with the high-dose psychedelic therapy model.

A treatment model combining psychedelic substance administration with professional psychological support (preparation, dosing session, and integration). The standard clinical model includes preparatory sessions, 1-3 dosing sessions, and integration therapy.

The strength of the interaction between a ligand and its receptor. High affinity means the drug binds strongly at low concentrations, measured by the dissociation constant (Kd) or Ki value.

The gold standard of clinical research. Participants are randomly assigned to treatment or control groups. Randomization minimizes bias and enables causal inference about treatment effects.

RElaxed Beliefs Under pSychedelics: a model proposing that psychedelics relax high-level priors (beliefs/expectations) in the brain's predictive processing hierarchy, allowing suppressed information to reach consciousness.

US federal law (2018) allowing terminally ill patients to access investigational drugs that have completed Phase I testing without FDA approval. Potentially applicable to psychedelic therapies for end-of-life anxiety.

The serotonin transporter protein responsible for reuptake of serotonin from the synaptic cleft. MDMA primarily acts by inhibiting SERT and reversing its direction, flooding the synapse with serotonin.

A chaperone protein at the endoplasmic reticulum involved in neuroprotection and neuroplasticity. DMT and some other psychedelics bind to sigma-1 receptors, possibly contributing to their neuroprotective properties.

A comprehensive review that identifies, evaluates, and synthesizes all relevant studies on a specific research question using a predefined, reproducible methodology.

The two key determinants of a psychedelic experience: 'set' refers to the individual's mindset, expectations, and psychological state; 'setting' refers to the physical and social environment. Concept formalized by Timothy Leary.

The most restrictive drug classification in the US Controlled Substances Act. Substances deemed to have high abuse potential, no accepted medical use, and lack of accepted safety. Includes psilocybin, LSD, MDMA, and DMT.

US drug classification for substances with high abuse potential but accepted medical use. Includes cocaine, methamphetamine, and fentanyl. No psychedelic is currently Schedule II.

US drug classification for substances with moderate abuse potential and accepted medical use. Includes ketamine. If MDMA or psilocybin gain FDA approval, they might be rescheduled to Schedule III or lower.

A sober individual who remains present during a psychedelic experience to provide support, reassurance, and safety. In clinical settings, this role is fulfilled by trained therapists or guides.