The experience: a guided walk-through

What a ketamine session, or a psilocybin or MDMA trial session, may feel like from the week before to the week after, told in four voices you can switch between. A written preparation session for people who would like to know more before the real one. Current to November 5, 2026.

Read it as

All four voices shown, one after another, at every stage.

A preparation session you can read

Before a ketamine course, and before a psilocybin or MDMA trial session, the care team sits down with you and walks through what the hours of a dosing session may feel like. This page is that conversation in written form, so you can read it at your own pace, more than once, and bring your questions to the real one.

It follows one session from the week before to the week after. Each stage opens with a short box, What happens, that states what the trials and the FDA labels actually report. The same facts are then told through four different voices, which you choose with the buttons above. The facts do not change between voices. What changes is the frame.

Ketamine is the treatment most people reading this will actually receive, so it is the spine of the page. Psilocybin and MDMA appear where trial participants’ reports add something, because the preparation used in those trials is where most of this material comes from. Neither is FDA-approved. Psilocybin is legally available only in a trial or in a state-licensed program (Oregon, Colorado); MDMA only in a trial.

How to use the four lenses

People arrive at this treatment from very different places. Some want the receptor diagram; some want to know exactly what the nurse will do; some have read William James or sat on a meditation cushion; some have listened to a lot of Terence McKenna. The lenses let you read the same walk-through in the voice that will actually land. You can switch at any point, or show all four at once to compare.

Pharmacology

Receptors, circuits and numbers from the trials. Modelled on how the NIMH, Johns Hopkins and Imperial College groups write. Every number here is cited.

Clinical

What your care team does and why, in the language of ketamine-assisted psychotherapy training and the Hopkins and MAPS session guidelines. Practical, second person.

Contemplative

The inner experience treated as its own kind of knowledge: William James’s four marks of a mystical state, Stanislav Grof’s map, Bill Richards’s “trust, let go, be open.” Perspective, clearly labelled.

Visionary

The big-picture storytellers: McKenna, Paul Stamets, Michael Pollan. Held loosely, for people who find that voice encouraging. Perspective, not evidence.

Two honest cautions

The contemplative and visionary lenses are there because some people are helped by them, not because they are proven. Where a lens makes a claim the trials do not support, the page says so in that lens. And no lens on this page is advice to take anything on your own: the psilocybin and MDMA material describes what screened, prepared, monitored trial participants report, under conditions that are a large part of why those trials have been as safe as they have^1,2.

Who this is for, and what it is not

This page is for you if

You are starting ketamine or esketamine treatment with a clinician and want to know what the session itself may feel like.
You are enrolled in, or being screened for, a psilocybin or MDMA clinical trial, or a state-licensed psilocybin program, and have been told to prepare.
You are a family member or support person who will be driving someone home and want to understand what they have just been through.

This page is not

A guide to taking any of these substances on your own. Psilocybin and MDMA remain Schedule I under federal law; ketamine is a controlled (Schedule III) prescription anesthetic.
A substitute for the preparation session with your own care team, which will be tailored to your history and medications.
A promise about what you will feel. The range of experiences in the trials is wide, and “not much” is a common and legitimate outcome (see the last stage).

If you are in crisis

Nothing on this page should be read while waiting for help. In the United States call or text 988, or go to the nearest emergency department³. Tell your treating clinician before any session if suicidal thoughts have increased.

Stage 1 · The week before

Preparation

What happens

The modern psychedelic trials, and the ketamine-assisted psychotherapy protocols, put one or more preparation meetings before the first dose: screening, your history, your medications, what the day will look like, and what you hope to get from it^1,4,5,6.
In the Hopkins guidelines the purpose of preparation is explicit: the most likely harm is overwhelming distress during the session, and rapport with the people who will sit with you is one of the main safeguards against it¹.
How you arrive matters. Across 14 studies, people who came in open, accepting and willing to surrender to the experience were more likely to have positive, meaningful sessions; people who arrived preoccupied, apprehensive or confused were more likely to have a difficult one⁷.
For ketamine the practical items are on the patient checklist: fasting schedule, medication review, music chosen and downloaded, a ride home, the rest of the day free.

Pharmacology lens

Apart from the dose, which the clinic sets, the predictor of how a session goes that you can most influence is your state on the way in. The review that pooled the predictor studies found openness, absorption and a willingness to surrender on the positive side, and apprehension and preoccupation on the negative side; sex was not a robust predictor, and prior experience slightly blunted intensity⁷. The Imperial group argues this sensitivity to context is pharmacological: serotonin-2A agonism, and the plasticity that follows, make the drug effect unusually dependent on what is going on around and inside you⁸. Ketamine is a different drug (an NMDA-receptor blocker, not a serotonin agonist⁹), and the same claim is less tested for it, but two randomized ketamine trials have tested additions to the setting: one found that music, an eye mask and a mindfulness exercise made the experience richer without changing the antidepressant effect¹⁰, and the other found that music changed neither the experience nor the outcome¹¹.

“Set and setting” is a 1960s term for what placebo researchers call expectancy and context; the two literatures describe the same thing from different directions¹².

Clinical lens

Your preparation visit is a working meeting, not a formality. Bring your full medication list, including anything over the counter, and say what you are afraid of. Your clinician will go through the fasting rule, the drive home, and what the room and the monitoring will look like, and will agree a signal with you (a raised hand) that means “I need you” or “please pause.”

Then do the part only you can do. Write one intention in a sentence: something you want to understand, or to be able to do, held loosely. The MAPS manual and the ketamine-assisted psychotherapy practices frame the intention as a direction to face, not a result to demand^13,6. Choose your music and listen to a few minutes of it beforehand so it is familiar. Decide who you will talk to afterwards. Sleep. Skip alcohol the night before. If a difficult feeling is already close to the surface this week, tell the team; that is exactly the kind of thing preparation exists to hear¹.

Contemplative lens

Contemplative traditions have a word for the week before: it is the retreat before the retreat. The practical preparation above is also an inner one. The instruction Bill Richards gave his volunteers at Spring Grove and later at Hopkins, and gives in his book, is three words: trust, let go, be open¹⁴. Trust the people in the room and the fact that your body keeps working on its own. Let go of steering. Be open to whatever comes, including boredom and nausea.

William James, who experimented on himself with nitrous oxide and wrote one of the first serious psychologies of such states, described ordinary waking consciousness as one type among several, “parted from it by the filmiest of screens”¹⁵. Preparation, in this lens, is deciding ahead of time that you are willing to look through the screen for an afternoon, and arranging your life so that nothing else needs you while you do. This is a frame, not a finding.

Visionary lens

Terence McKenna’s preparation advice was brutally simple: silence, darkness, and (in our paraphrase) a willingness to be astonished¹⁶. The clinic’s version is a tamer cousin, an eye mask and headphones in a quiet room, and one randomized trial that tested it found it made sessions feel richer without making them work better¹⁰. What McKenna got right is the attitude: you are not going to a procedure, you are going to meet something. What he got dangerously wrong is the dose and the solitude; the sessions he described were at or above the highest trial dose, taken by unscreened people with no one in the room, and this page describes the opposite of that^16,1.

Michael Pollan, preparing for his own guided sessions, reports advice from his guides that amounts, in our paraphrase, to treating the day as an appointment with yourself and expecting the important part to come afterwards¹⁷. This is reportage and personal experience, not a trial result.

Stage 2 · Arriving, the first twenty minutes

The room, the chair, the vitals

What happens

Ketamine clinics check blood pressure, pulse and oxygen before starting, because blood pressure rises during the infusion and peaks at around 40 minutes with esketamine; it is checked again then¹⁸.
An IV infusion of 0.5 mg/kg runs over about 40 minutes; esketamine is a nasal spray you give yourself under observation; intramuscular and oral forms exist. Whichever route, you are observed for at least two hours after esketamine by label, and for a similar period after IV ketamine by common practice^18,19.
In the psilocybin trials the drug is a capsule taken in a living-room-like space with two monitors, a couch, eyeshades and headphones; the session is scheduled for about eight hours, and sits inside a protocol of psychological support before, during and after the dosing day^20,21,1,22.
Eye mask and headphones are optional in both settings; in the ketamine trial that assigned a mindfulness exercise, music and an eye mask together, 4 of the 19 people in that group who gave written feedback reported discomfort, mostly about the fixed music they could not choose, which is why the authors recommend offering the additions as optional¹⁰.

Pharmacology lens

The physiology of the first minutes is cardiovascular, not psychological. Ketamine and esketamine raise blood pressure and heart rate through sympathetic activation; the esketamine label puts the peak at about 40 minutes, which is also the time of peak plasma concentration, and the Montreal trial found curated music trimmed the systolic rise by about 7 mmHg²³. This is why the cuff goes on before anything else, and why an aneurysm rules the treatment out and a high reading before dosing means the session waits¹⁸.

Psilocybin in a capsule has a slower pharmacokinetic ramp than an IV drug, which is the pharmacological reason the first half hour of a psilocybin session is usually uneventful and the first few minutes of an infusion are not. Both settings are designed around the same principle from the Hopkins guidelines: a safe physical environment, reduced external stimulation, and continuous interpersonal support¹.

Clinical lens

You will be shown to a reclining chair or a couch. A nurse will put on a blood-pressure cuff and a pulse-oximeter clip and will take a baseline set of vitals; with IV ketamine a small cannula goes in the back of the hand or the forearm. Your clinician will go over the signal you agreed on, confirm you have nothing further to eat or drink, and ask how you are. Say how you are, honestly. “Nervous” is the normal answer and the team would rather know.

Then you settle: blanket, music started, eye mask on if you want it. The MAPS and KAP protocols describe this moment the same way: the therapist’s job now is to be present and quiet, not to run the session^13,6. Nothing is required of you. The infusion starts, or the capsule is swallowed, and for a few minutes nothing happens at all.

Contemplative lens

Most traditions that work with altered states ritualize the threshold: the door, the removal of shoes, the bell. The clinic has its own thresholds, the cuff, the cannula, the eye mask, and they do the same job. They mark that ordinary time is being set aside. It can help to treat them that way rather than as medical fuss.

The last of James’s four marks of a mystical state is passivity: the sense that something is being done to you rather than by you, even if you prepared for it¹⁵. The chair is where passivity begins. You have made all the decisions you need to make. For the next hour or so, the only task is to let the experience be what it is. Whether James’s categories apply to a drug-induced state is a philosophical argument, not a settled fact; they are offered here as a vocabulary.

Visionary lens

Paul Stamets likes to point out that a mushroom is only the fruiting body; the organism is the mycelium underneath, a web you never see²⁴. The first twenty minutes are the mycelial part of a session: nothing visible, everything being set up. Pollan describes his guides saying very little once the session began, having given their instructions beforehand¹⁷. If the hospital room feels unglamorous compared with the stories you have read, notice that the unglamorous room is part of what has kept the trials safe¹. The metaphor is Stamets’s; the safety claim is the Hopkins guidelines’.

Stage 3 · Onset

Something is different

What happens

With IV ketamine the first changes come within minutes. In the pooled NIMH side-effect data the single most common report was feeling “strange, weird or loopy”; most effects peaked within the first hour²⁵.
The esketamine label lists what is being described: dissociative or perceptual changes including distortion of time and space, illusions, feeling detached from one’s surroundings (derealization) or from oneself (depersonalization), plus dizziness, nausea, sedation, vertigo and reduced sensation¹⁸. The time distortion is measurable: under psilocybin, twelve volunteers became measurably worse at reproducing intervals longer than about two and a half seconds²⁶.
With psilocybin the onset is gradual rather than sudden. The Hopkins volunteers were told to close their eyes and direct attention inward²⁰; session guides commonly describe the earliest effects as bodily (warmth, heaviness, sometimes queasiness) and visual (light and colour behind the eye mask), and nausea is among the most common adverse events in the trials²⁷.
Nausea occurs with both drugs; in the large psilocybin trial headache, nausea and dizziness were the most common adverse events^27,18.

Pharmacology lens

Ketamine blocks the NMDA receptor, a glutamate receptor, and at antidepressant doses that produces the dissociative state that anesthetists have known since the drug entered clinical use in 1970: a disconnection of sensory input from the sense of self, with the body still working on its own⁹. On resting-state imaging in healthy volunteers scanned the day after a ketamine infusion, connectivity between the default mode network and a dorsal prefrontal region that is overconnected in depression was reduced, a change the authors tie to the timing of the antidepressant effect rather than to the acute state²⁸. Psilocybin, by contrast, is a serotonin-2A agonist, and the Imperial fMRI work found the surprising result that it decreased activity in the brain’s hub regions and loosened the coupling between medial prefrontal and posterior cingulate cortex, with the size of the decrease predicting how intense the experience felt²⁹.

Two different receptors, a similar first impression: the usual tight coordination of the brain’s networks relaxes. The subjective result is that familiar things (the chair, your hands, the music) start to feel slightly unfamiliar. The timing is the main practical difference: minutes for an infusion, with the peak inside the first hour²⁵; a slower climb for a capsule.

Clinical lens

The first thing most people notice with ketamine is a sense of heaviness or lightness in the limbs, then a feeling of distance, as if the room has moved a few feet away. The music may seem to come from inside your head. Time becomes hard to judge. This is the dissociation the label describes, and it is expected, not a sign that something is wrong¹⁸. Your nurse is watching the monitor and will check your blood pressure at around the 40-minute mark; you do not need to track any of it.

If you feel queasy, say so; anti-nausea medication is usually on hand and a slower infusion rate helps. If the eye mask or the music starts to grate, take them off. The ketamine trial that assigned these found that a few people were uncomfortable with them, mostly over music they could not choose, which is why they are optional¹⁰. Otherwise, the instruction from the protocols cited here is the same: do not try to make anything happen, and do not try to stop anything from happening^13,1.

Contemplative lens

James’s first mark is ineffability: the state resists description, and people reach for images rather than statements¹⁵. Onset is where language starts to slip. Notice it and do not fight it; you will have the whole afternoon and the next week to find words.

Grof, who sat with thousands of LSD sessions in Prague and Maryland, described the first layer of experience as biographical, ordinary memories and feelings surfacing with unusual vividness, before anything stranger³⁰. Whether or not his map is right (it has never been tested the way a drug is tested), the practical advice that came with it is sound and matches the modern protocols: meet what comes with curiosity, and if it is a feeling, feel it rather than analyse it.

Visionary lens

Pollan’s book made famous an image the Imperial researchers used to explain their imaging results: the mind as a ski slope, where years of thinking carve the same deep tracks, and the drug as a fresh snowfall that lets you go a different way for a while^17,31. Onset is the first flakes. The science behind the image is a theory, not a measurement, and the researchers who proposed it say so³¹; it is included here because it may give some people a calmer way to hold the first strange minutes than “my brain is malfunctioning.”

A visionary-lens version of the same advice: attend to the body first. Translated into clinic terms: if you are cold, ask for a blanket; if you are nauseated, say so. The practical part of that advice is simply good nursing.

Stage 4 · The peak

The hour that is hard to describe

What happens

With esketamine, 61% to 84% of people in the trials had measurable dissociative or perceptual changes; the state is transient and confined to the day of dosing¹⁸. With IV ketamine, the altered state is measured at the end of the 40-minute infusion, close to its strongest, and most effects have resolved by two hours^32,25.
What the label describes: distortion of time and space, illusions, feeling detached from surroundings or from oneself¹⁸. Recreational users interviewed in one study, at street doses usually higher than clinic doses, named melting into the surroundings, visual hallucinations, out-of-body experiences and giggliness as the appealing effects, and call the deep end a “K-hole”³³.
In the Montreal ketamine trial the altered state often included mystical-type experience: a sense of unity, of sacredness, of insight, measured by the same questionnaire used in psilocybin research; it was common with or without music and was linked to improvement session by session¹¹. A small earlier study in cocaine dependence, using a different mysticism scale, pointed the same way³⁴.
With psilocybin at the doses used in trials, 72% of healthy volunteers in the Hopkins dose study had a mystical-type experience and 39% had extreme fear or anxiety at some point; the two were not mutually exclusive²¹. The intensity rises with dose; the difficult parts barely do³⁵.
Ego dissolution, the sense that the boundary between you and everything else has thinned or gone, is a distinct and measurable feature of the psychedelic peak, strongly correlated with the “unity” items of the mystical-experience scale³⁶.

Pharmacology lens

Pharmacologically the peak is the top of the concentration curve: the end of the infusion for IV ketamine and around 40 minutes for esketamine^18,19; for an oral psilocybin dose it is usually described as the second and third hour, a timing the trials on this page assume rather than report. Phenomenologically it is where the questionnaires come in. Dissociation is scored with the CADSS (the Clinician-Administered Dissociative States Scale); mystical-type experience with the 30-item MEQ, validated in 184 people given psilocybin in laboratory sessions and defined so that a “complete” mystical experience means high scores on all four of its factors (unity and sacredness, positive mood, transcendence of time and space, ineffability)³⁷; ego dissolution with an eight-item inventory³⁶.

Whether the peak matters for the antidepressant effect is the live scientific argument. For ketamine, one NIMH analysis found that more dissociation at 40 minutes predicted more improvement at 230 minutes and at day 7³², a systematic review found that association in only 2 of 5 studies that looked³⁸, and the NIMH group’s own perspective concludes the literature does not show dissociation is necessary³⁹. A small Columbia study found that mystical-type experience, not dissociation, mediated ketamine’s effect on motivation in cocaine dependence³⁴. For psilocybin the evidence that the experience matters is stronger: mystical-type scores predict persisting change after controlling for how intense the drug felt³⁷, and in the Imperial depression trial “oceanic boundlessness” predicted lower depression scores at five weeks, “dread of ego dissolution” predicted higher ones, and visual effects predicted nothing⁴⁰. Yaden and Griffiths argue the experience is necessary; Olson argues the plasticity may be separable from it, mostly from animal data; both positions are in the source list^41,42. The idea that the ketamine state itself could be the treatment is older than any of this: a Leningrad group ran “ketamine psychedelic therapy” for alcoholism through the 1980s and 1990s and reported far higher abstinence than usual care, in a comparison that was neither blinded nor randomized by modern standards⁴³.

On imaging, the psilocybin peak corresponds to the moment of least constraint: hub regions quieter, long-range coupling reduced, a larger repertoire of network states, which the entropic-brain and REBUS models interpret as a temporary relaxing of the brain’s high-level predictions about itself and the world^29,44,31. Ego dissolution specifically tracked reduced connectivity between the medial temporal lobe and higher cortex and a breaking-up of the salience network⁴⁵. These are models fitted to small imaging studies, and they are presented by their authors as theories.

Clinical lens

You are now in the part of the session that no description quite prepares you for, and that is fine, because nothing is asked of you here. Your body is monitored. You are not unconscious; you can hear and respond, and the hand signal still works. If you want to talk, you can; in our experience most people find talking effortful at this point and prefer to go inward.

Three things your care team will have told you, and will say again if needed. First, you do not have to make sense of anything now; collect experiences to talk about afterwards instead of analysing them¹. Second, strange body sensations (floating, heaviness, no clear sense of where your hands are) are the drug, not an emergency¹⁸. Third, the peak passes on its own: with IV ketamine the strongest effects are over within an hour or so of the infusion ending²⁵, and with psilocybin the session is scheduled for the day precisely so that no one has to hurry²⁰.

Some people have an experience here that feels enormous: unity, light, a sense of being held, grief that moves through. Some people have an hour of odd geometry and a numb mouth. Both kinds of session occur in the trials, and improvement did not depend on whether the setting was arranged to make the experience richer^11,10. The team will not grade your experience, and neither should you.

Contemplative lens

This is the hour James was writing about. His four marks are all here if the state goes deep: it is ineffable, it is noetic (it carries a sense of knowing, of insight into depths the ordinary mind does not reach), it is transient, and it is passive¹⁵. The modern mystical-experience questionnaire, built partly from James’s and Walter Stace’s descriptions, measures the same features, which is why the Hopkins researchers can say that most people given a high dose of psilocybin under supportive conditions have a “complete” mystical experience by that measure^37,46. Whether the measured thing and the thing James meant are the same is a question the questionnaire cannot answer.

Grof’s map puts the deepest part of a session in what he called the perinatal and transpersonal levels: experiences of confinement and struggle, of death and rebirth, of boundless unity³⁰. The 1962 Good Friday experiment, in which divinity students were given psilocybin during a service, is the ancestor of all this; its long-term follow-up found most of them still counted it among the high points of their lives, while also documenting how poorly it was blinded⁴⁷. The contemplative reading of the peak is simple: whatever arises, it is yours, it is passing, and the instruction remains trust, let go, be open¹⁴. None of this is evidence of anything beyond the experience itself, and it does not need to be.

Visionary lens

McKenna said the experience at this depth is like meeting an intelligence that is not yours¹⁶. Pollan, more cautiously, reports from his own session that the self he thought was essential turned out to be optional for an afternoon, and that this was less frightening than it sounds¹⁷. Stamets would remind you that the organism you are, like a forest, is a network, and that networks can reorganize²⁴. These are three ways of pointing at what the questionnaire calls ego dissolution and unity³⁶.

The visionary writers are good at one thing here and bad at another. They are good at giving permission: it is all right for this to be strange, large and beyond language, and in our experience some people who have read them arrive less frightened. They are bad at proportion. McKenna’s stories come from doses at or beyond the top of the trial range and from sessions with no one in the room; within the dose range the trials have tested, the intensity and the mystical-type quality of a session rise with dose while the difficult parts rise far less, and no one has measured what happens above that range under supervision^16,35,21. Take the permission; leave the proportions to the clinic.

Stage 5 · When it gets hard

Fear, grief and the feeling of dying

What happens

Difficult passages are common and expected. In the Hopkins dose study, 39% of volunteers had extreme anxiety or fear at some point at the higher doses; a month later the group as a whole still rated those sessions as having substantial personal and spiritual significance²¹. In a survey of nearly 2,000 people describing their single worst psilocybin experience, 84% said they nonetheless benefited, and greater difficulty went with greater later gains in well-being².
The difficult side has a shape. The Challenging Experience Questionnaire names seven: grief, fear, a sense of dying, a sense of going insane, isolation, physical distress and paranoia⁴⁸.
With ketamine, the difficult equivalents are a frightening degree of unreality, nausea, or a confused, dream-like emergence reaction on coming round; after anesthetic doses the Ketalar label reports emergence reactions in about 12% of patients, generally lasting a few hours, and says they may be reduced by minimizing noise, touch and light during recovery^49,18.
What makes difficult experiences dangerous is largely the dose and the setting. In the survey, physical risk went with higher doses, longer and more difficult experiences, and the absence of comfort and social support; in screened, prepared and monitored trial participants, risky behaviour and enduring distress are described as extremely low^2,1.

Pharmacology lens

The pharmacology of a hard passage is not different from the pharmacology of a good one; the same relaxation of top-down control that lets grief move can also let fear in. What the data show is that difficulty is weakly dose-dependent at trial doses³⁵, that it is predicted both by traits (low openness) and by the state you arrive in (preoccupied, apprehensive or confused rather than surrendered)⁷, and that its relation to outcome is mixed: in the Imperial depression trial, “oceanic boundlessness” during the 25 mg session predicted lower depression scores at five weeks, whereas “dread of ego dissolution” predicted higher ones, and the authors recommend reducing anxiety during sessions⁴⁰. The survey data point the other way on difficulty itself, with difficulty positively and duration negatively associated with later well-being². A hard passage is neither a requirement nor a verdict.

For ketamine, the dissociation that frightens some people is the same measurement that correlated with better antidepressant response in one NIMH dataset³². That is a correlation in a secondary analysis, not a reason to seek a frightening session, but it is some reassurance that a frightening session is not a bad sign. The 12% emergence-reaction figure on the Ketalar label refers to anesthetic doses, several times higher than antidepressant doses, and is included here as the upper bound⁴⁹.

Clinical lens

Here is what happens if it gets hard. You raise your hand or say a word, and the person sitting with you comes closer, says your name, reminds you where you are and what you have taken, and reminds you that it passes. They may take your hand if you agreed to that in preparation. They will not try to talk you out of what you are feeling, and they will not drag you back to the surface, because in the Hopkins and MAPS protocols the instruction is to help you turn toward the difficult thing rather than away from it, with support^1,13. If the problem is physical, nausea, a racing heart, a feeling of not being able to breathe, they will check your vitals and treat it. With IV ketamine the infusion can be slowed or paused.

Two things to remember on the way in. The team has sat with many people through this hour; your worst five minutes are not new to them. And the feeling of dying, which is on the list of challenging experiences for a reason, is a feeling, not a vital sign⁴⁸. Your body is monitored throughout. If you can, breathe slowly and let the music carry you until it shifts; it shifts.

Contemplative lens

Most contemplative traditions that use these states expect the hard passage and give it a name: the dark night, the bardo, the descent. Grof called the deepest version of it the experience of ego death, and insisted, from his own sessions, that it was usually the doorway to the most healing part of the day³⁰. Modern data give that claim only partial support: in a large survey, difficulty within a safe setting went with later benefit², but in the Imperial depression trial anxiety during the session predicted a worse five-week outcome⁴⁰. What the data do not support is the idea that you should seek the hard passage, or that a session without one has failed.

Richards’s instruction is at its most useful here. Trust: the people, the monitoring, the passing of time. Let go: of steering, of understanding, of being the one who is coping well. Be open: if it is grief, grieve; if it is fear, let the fear be there and keep breathing¹⁴. James noted that these states are transient, rarely sustained for long¹⁵; so is the hard part.

Visionary lens

The visionary writers have a line for this that is worth keeping and a habit that is worth dropping. The line, which McKenna repeated in many forms, is that the way through is toward the frightening thing, not away from it; his cosmic gloss on that (nature loves courage, in his phrase) can be left with him¹⁶. The habit is treating a terrifying session as a badge. Pollan, who had his own frightening hour and wrote about it, is clearer: he got through it because a guide was sitting a foot away, and he does not recommend the version without one¹⁷.

In Stamets’s idiom, decay and growth are the same process seen from different ends²⁴. If what comes is grief, it may be clearing ground. That is a metaphor. The clinical facts are that difficult passages are common, usually manageable with support, and rarely followed by lasting harm in a screened and monitored setting^21,1.

Stage 6 · Coming back

The landing

What happens

With IV ketamine most side effects have resolved by two hours after the infusion²⁵; with esketamine you are observed for at least two hours and assessed before leaving¹⁸. With psilocybin the descent is gradual over the afternoon; the Hopkins sessions are scheduled as eight-hour days, and you leave when the monitors are satisfied the effects have worn off^20,1.
Common on landing: dizziness, unsteadiness, a feeling of being drunk, nausea, tiredness, and with ketamine sometimes an emergence reaction, a confused or dream-like state that at anesthetic doses can last a few hours, which the label says is reduced by a quiet, dim room^18,49.
You may not drive until the next day after a restful sleep; this is a label requirement for esketamine, the ketamine label says no driving for 24 hours, and it is standard practice for every route^18,49.
The Montreal program builds a 20-to-30-minute debrief into the end of each infusion visit, with weekly psychotherapy alongside⁵⁰; a multi-clinic KAP series instead keeps the day short and schedules separate integration visits after the first two doses and after every two doses thereafter⁵¹.

Pharmacology lens

Ketamine leaves the brain quickly (the label gives a distribution half-life of 10 to 15 minutes and a redistribution half-life of about 2.5 hours) and is rapidly converted to norketamine and hydroxynorketamine metabolites, which is why the dissociation clears within a couple of hours while, in the trials, the antidepressant effect was measurable from about two hours onward and largest at 24 hours^49,9,19. The experience and the antidepressant effect therefore have different time courses, which is part of the evidence that they may be separable³⁹. In animal studies the synaptic changes thought to underlie the effect begin within hours and the new spines are needed to maintain, not to start, the behavioural improvement^52,53.

The landing itself is pharmacokinetic. Plasma levels fall, the NMDA blockade lifts, and the sense of self reassembles, sometimes with a short period of confusion that the anesthetic literature calls emergence⁴⁹. Low light and a quiet voice reduce it.

Clinical lens

Coming back is slower than going in. Take the eye mask off when you want to, not when the music stops. You will be given water and something light to eat when you are ready; your vitals will be checked again. Expect to feel wobbly on standing and to be walked to the bathroom. Do not judge anything you are feeling in the first half hour; the dream-like, slightly confused state the label describes is the drug leaving, not a verdict on the session⁴⁹.

Say a little about what happened if you want to, in a sentence or two, to the person who sat with you. Some programs do a short structured debrief now⁵⁰; many keep it light and save the real conversation for the integration visit, because the day-of memory is patchy and the meaning often arrives later. Then your ride takes you home. No driving, no important decisions, no email, and if you can, no screens for the rest of the day.

Contemplative lens

The return is another of James’s marks made concrete: transiency. The state does not last, and he observed that what persists is not the state but a changed relation to ordinary life¹⁵. In retreat traditions the first hour after is treated as still part of the practice, which is good advice here: keep the quiet going as long as you reasonably can.

Grof described the end of a session as the point at which the material that surfaced begins to settle into the biography, and he kept his clients in the session room until that settling had begun³⁰. The modern version is the debrief, or simply a quiet ride home with someone who does not need you to explain anything.

Visionary lens

Pollan writes that the landing was when he first understood that the session was not the point; the point was what he would do with it¹⁷. Even McKenna, who was far more interested in the journey than the return, framed the point of it as bringing something back¹⁶. The visionary literature is at its most useful on the way down, because it broadly agrees that the afternoon is a beginning. Everything from here on is the part that the trials actually measure.

Stage 7 · That evening and the next day

The afterglow, and the other possibilities

What happens

In the NIMH ketamine trial, depression ratings had already improved versus placebo by 110 minutes and the difference from placebo was largest at 24 hours, when 71% of those treated met response criteria; in a third of people the improvement lasted at least a week after a single infusion¹⁹.
An “afterglow” of lifted mood, openness and reduced defensiveness in the weeks after a psychedelic session was described in the early clinical literature and is one of the proposed windows for psychotherapy; its duration has never been measured prospectively⁵⁴.
Not everyone has it. Tiredness, flatness, tearfulness and vivid dreams are common reports the evening after (clinical observation, not a trial measure). In the largest psilocybin trial the common adverse events were headache, nausea and dizziness, and suicidal thoughts, suicidal behaviour and self-injury occurred in every dose group, including the 1 mg comparison group, which is why programs ask you to report any increase²⁷.
Driving and anything hazardous wait until the next day after a restful sleep¹⁸.

Pharmacology lens

The 24-hour point is where ketamine’s antidepressant effect is largest in the trials, with an effect size versus placebo of 1.46 at that time in the NIMH study, falling to 0.68 at one week¹⁹. The hypothesized substrate is a burst of synaptic plasticity: glutamate release, BDNF signalling, and new dendritic spines in prefrontal cortex, which in mice appear within about a day, after the behavioural effect has already begun, and are needed to keep the effect going rather than to start it^53,52. The serotonergic psychedelics produce a similar burst of structural plasticity in cell culture and animals via overlapping pathways⁵⁵, and in mice reopened a developmental window for social learning for a period proportional to each drug’s acute duration, from days to weeks⁵⁶. None of this has been directly shown in people; it is the best current account of why the days after may be a good time to practise something new.

The afterglow concept predates all of this and is a clinical observation rather than a measurement; Majić and colleagues review the evidence linking it to outcome without treating it as settled⁵⁴.

Clinical lens

Keep the evening simple. Eat, drink water, avoid alcohol, and go to bed early. If you can, before sleep, write for ten minutes: not an interpretation, just what you remember, in whatever order. Memory of the session fades quickly and the notes are for the integration visit.

Tomorrow you may feel markedly better, which is what the trials measure at 24 hours¹⁹; or flat and tired; or unusually open and easily moved; or no different. All four are within the normal range. The Montreal program and the KAP series both expect that the real work happens in the days that follow, in the conversations and the small changes you decide to make, rather than in the session itself^50,6. If anything frightening persists past the next morning, or if suicidal thoughts increase, call the clinic or 988³.

Contemplative lens

The afterglow has an old name in contemplative practice: it is the period after retreat when the mind is quiet and ordinary things look unusually clear. The traditions broadly agree that this is the time to act gently, not to make large declarations. James’s observation that mystical states leave the person with a changed sense of what matters, rather than new facts, is a good description of what many people report the next day¹⁵.

Grof held that the days after a session were when the inner healing process he believed in did most of its work, and protecting those days follows from that view³⁰. The idea of an inner healer has not been tested and cannot be; the advice to protect the day after is harmless and sensible.

Visionary lens

Pollan’s most quoted observation about the days after is that the insights can sound banal when written down (love matters; be kind), and that their banality is beside the point, because they are now felt¹⁷. Expect that. In Stamets’s idiom again, the visible growth comes long after the rain²⁴. And the ski-slope image completes itself here: new tracks are only made if you ski somewhere different in the days when the snow is still fresh^17,31. A metaphor for a hypothesis, offered as encouragement.

Stage 8 · The week after

Integration

What happens

Integration is the word every protocol uses for what happens between sessions: making sense of the experience and turning it into something that lasts. A 2022 concept analysis found many definitions and practices and offered a synthesis along those lines⁵⁷.
In the trials it is a scheduled part of treatment: roughly 11 hours of psychotherapy around two psilocybin sessions at Hopkins; three preparatory and nine integrative sessions around three MDMA sessions in the phase 3 trial^4,5. In ketamine programs it ranges from a debrief at each visit plus weekly psychotherapy, to integration visits after every two doses^50,51.
With a single ketamine infusion, about two-thirds of responders had lost the response within a week¹⁹, which is why courses are given as a series and why the week after is treated as a window rather than a result.
What the experience predicts: in the 12-month psilocybin follow-up, the meaning and mystical quality of the session predicted later well-being but did not predict the improvement in depression⁵⁸. The two can come apart. In the Hopkins cancer trial the reductions in anxiety and depression held at six months⁵⁹; in the long-term follow-up of the NYU cancer trial they held at three to four and a half years, when 71% to 100% of the 15 participants still rated the session among the most meaningful experiences of their lives⁶⁰.

Pharmacology lens

Integration has a pharmacological rationale in the plasticity hypothesis: the days after dosing are proposed to be a period of heightened synaptic and, in mice, behavioural plasticity, so learning that happens then may be retained preferentially^53,56,61. That proposal is coherent and under active study; direct evidence that psychotherapy delivered in that window outperforms psychotherapy delivered at another time does not yet exist in humans, and the trials that compared ketamine with and without added experiential elements did not find a difference in depression outcome^11,10.

The honest summary: for ketamine, the additions during dosing (music, mindfulness, an eye mask) are reasonably supported for making the session more meaningful for many and less comfortable for a few, integration itself has not been tested separately, and neither is proven to improve the core antidepressant effect; for psilocybin and MDMA, it has always been part of the package that was tested, so its separate contribution is unknown^4,5.

Clinical lens

Your integration visit, whether it is a 20-minute debrief or an hour with a therapist, is where the notes from the evening after come in. Say what happened, in order, including the boring and the embarrassing parts. Your clinician or therapist will listen for two things: anything that needs follow-up (a persisting fear, a memory that surfaced, a change in suicidal thinking), and anything that points to a small, concrete change worth trying this week, a conversation, a walk, a boundary, a phone call⁵⁷.

Between visits: keep the notes going, keep the sleep regular, and resist two temptations. One is to overinterpret: a vivid image is not an instruction. The other is to decide the session was a failure because the next week was ordinary. Whether the antidepressant effect of ketamine depends on what the session was like is unsettled; enriching the session did not change the depression outcome in the trials that tried it^11,10, and the next infusion is usually within days. If you are in a psilocybin or MDMA trial, the integration schedule is fixed by the protocol and is part of the treatment, not an optional extra⁵.

Contemplative lens

Integration is the oldest idea on this page. Most traditions that induce unusual states follow them with a period of return in which the community, a teacher or a practice helps the person carry what they found back into ordinary life; without it the state is a story rather than a change. James’s test of a religious experience was pragmatic: by its fruits, not its roots¹⁵. That is a good test for a session. The question is not whether the experience was real or profound, but what you do differently in the weeks after.

Richards’s version is that the session gives you material and the weeks give you a life to put it in¹⁴. Grof thought the material would keep working on its own³⁰; the modern programs assume it needs help, and schedule it⁴.

Visionary lens

Pollan ends his book by saying that the most useful thing the experience gave him was not an insight but a reminder that his habitual mind was one option among several, and that he could, with effort, choose another¹⁷. That is integration in one sentence. In Stamets’s idiom it is tending the mycelium: most of what matters is underground and slow²⁴. McKenna, for once, is the least useful voice here; he was far more interested in the experience than in the week after, and the week after is where the trials say the work is^16,4.

Stage 9 · If not much happened

The ordinary session

What happens

Many sessions are undramatic: some heaviness, odd geometry, a numb mouth, an hour that passed. In the two randomized ketamine trials that added music, mindfulness or an eye mask, depression improved as much without them as with them^11,10; one of the two nonetheless found that more mystical-type sessions went with more improvement¹¹, so the question is open rather than settled.
In the psilocybin dose study, the lowest dose produced significant effects and the lower doses were less often mystical; the design assumed a range of experiences and found one²¹.
The relationship between the experience and the outcome is an open scientific question for ketamine, with the literature so far not supporting the idea that dissociation is necessary, and most trials never having looked^39,38, and a live debate for psilocybin^41,42.
In the 12-month psilocybin follow-up, people whose sessions felt most meaningful reported more well-being a year later, but their depression had not improved more than anyone else’s⁵⁸.

Pharmacology lens

Pharmacologically an undramatic session is still a full dose. With ketamine, the NMDA blockade, the glutamate surge and the downstream plasticity signalling are properties of the drug at 0.5 mg/kg, not of your experience of it^9,53. The data on whether subjective intensity predicts response are mixed and, where positive, are correlations in secondary analyses^32,38,39. The right pharmacological attitude to a quiet session is to wait for the 24-hour and one-week ratings, which are the outcome the trials used¹⁹.

Clinical lens

If your session was ordinary, say so at the integration visit without apology. It is one of the most common things clinicians hear, and it changes nothing about the plan: the next infusion is scheduled, the depression ratings are what the team is tracking, and the experience is not being graded¹¹. If you had been hoping for something larger, that hope is worth a sentence too, because the state you arrive in next time is one of the better-documented things that shapes the session⁷, and disappointment carried in is a poor starting state.

Practical things that make the next session more likely to be comfortable, with no promise that it will be more profound: music you chose yourself, a lighter meal at the allowed time, an intention held even more loosely, and the eye mask on only if you liked it.

Contemplative lens

The contemplative traditions are entirely used to the ordinary session; most hours on a cushion are ordinary too. James was careful to say that mystical states are rare, brief and not under the will’s control¹⁵; it follows that their absence proves nothing about the person. Grof’s view was that a series of sessions unfolds over time, so a quiet one is not a verdict; that may be true and cannot be checked³⁰. The one thing to resist is the idea that you failed at letting go. Letting go is not a performance; a quiet hour in a safe room, having let the drug do what it does, is the thing itself.

Visionary lens

This is where the visionary literature is least helpful, because it mostly describes the spectacular. Read it as fiction about a place you did not visit this time, and note that Pollan, who did have the spectacular version, concluded that whatever lasting benefit he got came from the weeks afterward¹⁷. In Stamets’s idiom, the mycelium does not fruit every season²⁴. The trials would say your depression score next week is the number that matters^19,11.

What on this page is evidence, and what is perspective

The lenses deliberately mix registers, so here is the key.

Claim	Status	Where it comes from
What the session feels like with ketamine and esketamine (dissociation, perceptual change, timing, side effects)	Well documented	FDA labels; pooled NIMH side-effect data; the MUSIK and Kheirkhah trials^18,25,11,10
What psilocybin sessions feel like at trial doses, including fear and mystical-type experience	Well documented in healthy volunteers and patients	Hopkins dose and follow-up studies; Imperial trial; validated questionnaires^21,62,40,37
Set, setting and preparation shape the experience	Supported	Predictor review; Hopkins safety guidelines; the ketamine sensory trials^7,1,10
The experience is necessary for the antidepressant effect	Not shown for ketamine; debated for psilocybin	NIMH perspective and systematic review; Yaden and Griffiths versus Olson^39,38,41,42
Difficult experiences predict later benefit	Mixed	Survey data say yes; the one open-label psilocybin trial that tested it found session anxiety predicted a worse outcome; ketamine dissociation is a separate question^2,40,32
Default mode network, entropy, REBUS, pivotal mental states, the “snow” image	Theories, with some imaging support	Imperial College papers; presented by their authors as models^29,44,31,61
A plasticity window after dosing in which learning sticks	Shown in animals; hypothesis in people	Mouse and cell studies^52,55,56
Integration improves outcomes	Untested as a separate ingredient	Always part of the package in trials^4,5,57
James’s four marks; Grof’s map and inner healer; Richards’s instruction	Perspective	Books; one is from 1902^15,30,14
McKenna, Stamets, Pollan	Perspective	Speculative writing, mycology, journalism^16,24,17

Words you will hear

Dissociation: A sense of detachment from your surroundings (derealization) or from yourself (depersonalization), with changes in how time, space and your body feel. The expected effect of ketamine at treatment doses, measured on a scale called the CADSS¹⁸.
Set and setting: Your state of mind (set) and the physical and social environment (setting). A 1960s term for what shapes a drug experience beyond the drug¹².
Mystical-type experience: A questionnaire-defined experience of unity, sacredness, insight, positive mood, transcendence of time and space, and ineffability; “complete” when every dimension scores at least 60% of its maximum³⁷.
Ego dissolution: The sense that the boundary between you and everything else has thinned or disappeared; measured by its own inventory and closely tied to the “unity” part of the above³⁶.
Challenging experience: The difficult side: grief, fear, a sense of dying or going insane, isolation, physical distress, paranoia. Common, usually benign with screening, preparation and support, and rarely followed by lasting harm in a monitored setting^48,1.
Afterglow: A period of lifted mood and openness in the days and weeks after a session, described in the early clinical literature and never measured prospectively⁵⁴.
Integration: Making sense of the experience afterwards and turning it into lasting change, through conversation, writing and small actions⁵⁷.
Default mode network: A set of brain regions most active when the mind is at rest and turned inward; quieter under psilocybin, and less tightly coupled under both psilocybin and ketamine^29,28.
REBUS: “Relaxed beliefs under psychedelics”: the theory that the drugs loosen the brain’s strongly held predictions so they can be revised³¹.

Bring to your preparation visit

From this page

Questions

Which lens did you read, and which parts raised questions?
What are you most afraid might happen during the session?
What would you want the person sitting with you to do if it gets hard?
Have suicidal thoughts changed recently?

From the ketamine page

Practical

The before / during / after checklist: fasting, medications, music, ride home.
Your intention, in one sentence, held loosely.
A notebook for the evening after.

For trial participants

Ask the study team

Psilocybin and MDMA remain Schedule I in the United States and are available only inside a registered trial or a state-licensed program; ask how many preparation and integration sessions are in the protocol, and with whom.
Who will be in the room, and what the hand signal is.
What happens if you have a difficult experience, and whom to call afterwards.

Part 2 of this project, a preparation-and-integration companion you can talk to, is being designed; it will use the same four lenses and the same sources, and it will not replace any of the conversations above.

Get in touch

If you are considering ketamine treatment, or are in a trial and want a second opinion on preparation, our program provides consultations and will tell you honestly if another treatment is a better fit. We provide ketamine and esketamine treatment; we do not provide psilocybin or MDMA, which are available only inside clinical trials or, for psilocybin, state-licensed programs outside South Carolina.

Prisma Health Neuromodulation Program

For consultations, referrals, or questions about ketamine treatment.

(864) 455-8813

Behavioral Health and Wellness Pavilion
725 Grove Road, Greenville, SC 29605
Adam Hart, MD — Medical Director

Sources

Every number on this page is linked to one of the sources below, numbered in order of first citation. PubMed entries were generated from the NCBI record on November 4, 2026 and re-checked after an adversarial review on November 5, 2026; FDA labels, books and manuals are dated in the entry. Entries marked as books, perspective or theory are not clinical evidence and are cited so you can see where a voice comes from.

Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008;22(6):603-20. PubMed 18593734. Johns Hopkins safety guidelines for hallucinogen research: the most likely risk is overwhelming distress during drug action; safeguards are exclusion of people with personal or family history of psychosis, rapport with the session monitors before the session, careful preparation, a safe physical environment and interpersonal support from at least two monitors; persisting adverse reactions are rare under these conditions.
Carbonaro TM, Bradstreet MP, Barrett FS, et al. Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. J Psychopharmacol. 2016;30(12):1268-1278. PubMed 27578767. Online survey of 1,993 people about their single most difficult psilocybin experience, mostly outside clinical settings: 39% rated it among the five most challenging experiences of their lives; 11% put themselves or others at risk of physical harm; 7.6% of those more than a year out had sought treatment for enduring symptoms; 84% nonetheless said they benefited; difficulty was associated with later increases in well-being, duration with decreases; the incidence of risky behaviour or enduring distress is described as extremely low when psilocybin is given in laboratory studies to screened, prepared and supported participants.
988 Suicide & Crisis Lifeline (call or text 988; 988lifeline.org), United States, available 24 hours a day.
Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(5):481-489. PubMed 33146667. Johns Hopkins randomized waiting-list trial in major depression, 27 adults: two psilocybin sessions (20 then 30 mg/70 kg) inside approximately 11 hours of supportive psychotherapy.
Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033. PubMed 33972795. Phase 3 trial of MDMA-assisted therapy for severe PTSD, 90 participants: manualized therapy with three preparatory and nine integrative sessions around three dosing sessions; CAPS-5 improved more with MDMA (d = 0.91).
Dore J, Turnipseed B, Dwyer S, et al. Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy. J Psychoactive Drugs. 2019;51(2):189-198. PubMed 30917760. First descriptive series of ketamine-assisted psychotherapy (KAP), 235 patients in three private practices: preparation, the dosing session (sublingual or intramuscular, therapist present) and integration treated as one process; uncontrolled.
Aday JS, Davis AK, Mitzkovitz CM, et al. Predicting Reactions to Psychedelic Drugs: A Systematic Review of States and Traits Related to Acute Drug Effects. ACS Pharmacol Transl Sci. 2021;4(2):424-435. PubMed 33860172. Systematic review of 14 studies: people high in absorption, openness and acceptance, and in a state of surrender, were more likely to have positive and mystical-type experiences; those low in openness or surrender, or preoccupied, apprehensive or confused beforehand, were more likely to have acute adverse reactions.
Carhart-Harris RL, Roseman L, Haijen E, et al. Psychedelics and the essential importance of context. J Psychopharmacol. 2018;32(7):725-731. PubMed 29446697. Opinion piece from the Imperial group on set and setting (“context”): 5-HT2A agonism and associated plasticity are argued to make psychedelic effects exceptionally sensitive to context; the quality of the acute experience predicts later outcomes.
Zanos P, Moaddel R, Morris PJ, et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol Rev. 2018;70(3):621-660. PubMed 29945898. Review of ketamine pharmacology: anesthetic and dissociative actions generally attributed to NMDA-receptor blockade, with lower-affinity actions at other targets; rapid metabolism to norketamine and hydroxynorketamine metabolites, which have antidepressant effects in animals.
Kheirkhah M, McDonald N, Aepfelbacher J, et al. Mindfulness, music, visual occlusion in ketamine therapy for depression: do they change outcomes? A qualitative and quantitative analysis of a randomized controlled trial. Front Psychiatry. 2025;16:1642025. PubMed 40964432. 43 people with unipolar depression randomized to ketamine with a guided mindfulness exercise, music and an eye mask (22) or ketamine alone (21): depression improved to a similar degree in both groups; the sensory group more often described deeper engagement, relief from sadness, awe and spiritual insight; 4 of 19 who gave written feedback in the sensory group reported discomfort, mostly about the fixed music (versus 1 of 17 controls; figures from the full text, verified for the ketamine patient page on October 27, 2026), so the authors recommend offering these additions as optional.
Greenway KT, Garel N, Dinh-Williams LL, et al. The Music for Subanesthetic Infusions of Ketamine randomised clinical trial: ketamine as a psychedelic treatment for highly refractory depression. Br J Psychiatry. 2026;228(5):437-445. PubMed 40528492. MUSIK secondary analysis: depression, anxiety and suicidality improved similarly with or without music; mystical-type experiences (Mystical Experience Questionnaire) and emotional breakthroughs were common in both groups and were related to improvement session by session.
Hartogsohn I. Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology. J Psychopharmacol. 2016;30(12):1259-1267. PubMed 27852960. Historical and conceptual analysis of “set and setting” (the term dates to the 1960s) and its overlap with placebo-response theory: expectancy, preparation and beliefs shape the response to psychoactive drugs.
Mithoefer MC. A Manual for MDMA-Assisted Psychotherapy in the Treatment of Posttraumatic Stress Disorder, version 8.1. Santa Cruz, CA: Multidisciplinary Association for Psychedelic Studies (MAPS); 2017. maps.org/treatment-manual. The therapy manual used in the phase 3 trials (preparatory sessions, two therapists, music, eyeshades, a non-directive stance, integration sessions). Describes a treatment protocol that remains investigational.
Richards WA. Sacred Knowledge: Psychedelics and Religious Experiences. New York: Columbia University Press; 2015. By the Johns Hopkins session guide and co-author of the safety guidelines; source of the “trust, let go, be open” instruction used in Hopkins sessions. Memoir and reflection, not a trial.
James W. The Varieties of Religious Experience: A Study in Human Nature. Lectures XVI–XVII, “Mysticism.” New York: Longmans, Green; 1902 (public domain). Proposes four marks of mystical states: ineffability, noetic quality, transiency and passivity; describes his own nitrous-oxide experiments. Philosophy and psychology of religion, not clinical evidence.
McKenna T. Food of the Gods: The Search for the Original Tree of Knowledge. New York: Bantam; 1992, and The Archaic Revival. San Francisco: HarperSanFrancisco; 1991. Speculative natural history and lectures; the “heroic dose” taken alone in silent darkness, the “stoned ape” idea and the mushroom as teacher. Not evidence; the doses described are at or above the highest doses used in any trial and were taken without screening or supervision.
Pollan M. How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence. New York: Penguin Press; 2018. Journalism: reports the Hopkins, NYU and Imperial research and the author’s own guided sessions; the fresh-snow-over-old-ski-tracks image for relaxed habits of mind is reported there from the Imperial researchers.
U.S. Food and Drug Administration. SPRAVATO (esketamine) nasal spray prescribing information, NDA 211243, revised 01/2025. Section 5.2: the most common psychological effects were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization, in 61% to 84% of treated patients by the Clinician-Administered Dissociative States Scale; patients must be monitored for at least 2 hours. Section 6.1: in clinical trials dissociation was transient and occurred on the day of dosing. Sections 2.1 and 5.7: blood pressure peaks at approximately 40 minutes (the time of peak plasma concentration) and is re-measured then. Section 5.9: do not drive until the next day after a restful sleep. Section 6: common adverse reactions include dissociation, dizziness, nausea, sedation, vertigo and reduced sensation.
Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-64. PubMed 16894061. NIMH crossover trial, 18 subjects (17 treated with ketamine): 0.5 mg/kg intravenous infusion; ratings at 40, 80, 110 and 230 minutes and days 1, 2, 3 and 7; depression improved versus placebo within 110 minutes; 71% met response and 29% remission the day after the infusion; 35% held response for a week.
Griffiths RR, Richards WA, McCann U, et al. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl). 2006;187(3):268-83; discussion 284-92. PubMed 16826400. Johns Hopkins double-blind study, 30 hallucinogen-naive adults, psilocybin 30 mg/70 kg versus methylphenidate: 8-hour sessions with eyes closed and attention directed inward; psilocybin produced perceptual changes, labile moods including anxiety, and mystical-type experience; at 2 months volunteers rated the experience as having substantial personal meaning.
Griffiths RR, Johnson MW, Richards WA, et al. Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology (Berl). 2011;218(4):649-65. PubMed 21674151. Dose study, 18 adults, psilocybin 0, 5, 10, 20 and 30 mg/70 kg in 8-hour sessions with eyeshades: at the two highest doses, extreme anxiety or fear at some point in 39% of volunteers and mystical-type experience in 72%; effects rose with dose; ratings at 14 months were undiminished.
Raison CL, Sanacora G, Woolley J, et al. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA. 2023;330(9):843-853. PubMed 37651119. Phase 2 trial at 11 U.S. sites, 104 people with major depression: a single 25 mg psilocybin dose versus niacin, both with psychological support (preparation, a monitored dosing day, integration).
Greenway KT, Garel N, Dinh-Williams LL, et al. Music as an Intervention to Improve the Hemodynamic Response of Ketamine in Depression: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(2):e2354719. PubMed 38315489. MUSIK randomized trial, Montreal: 32 people with treatment-resistant depression, six 40-minute infusions of 0.5 mg/kg (181 infusions), curated music versus no music; music reduced the systolic blood-pressure rise during infusions by 7.4 mmHg (95% CI 2.9 to 12.0), a figure taken from the full text and verified for the ketamine patient page on October 27, 2026.
Stamets P. Mycelium Running: How Mushrooms Can Help Save the World. Berkeley: Ten Speed Press; 2005. Mycology and environmental advocacy; the image of mycelial networks as the forest’s communication web. Not a pharmacology source.
Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, et al. Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression. J Affect Disord. 2020;263:568-575. PubMed 31791675. Pooled side-effect data from 188 participants in five NIMH ketamine studies (163 with treatment-resistant major depressive disorder or bipolar depression): the most common side effect was feeling “strange, weird or loopy”; most side effects peaked within an hour of the infusion and had resolved completely by two hours; no serious drug-related adverse events and no increase in ketamine craving.
Wittmann M, Carter O, Hasler F, et al. Effects of psilocybin on time perception and temporal control of behaviour in humans. J Psychopharmacol. 2007;21(1):50-64. PubMed 16714323. Twelve healthy volunteers, placebo versus medium and high doses of psilocybin: impaired reproduction of intervals longer than about 2.5 seconds, slower preferred tapping and reports of disturbed “time sense,” depersonalization and derealization.
Goodwin GM, Aaronson ST, Alvarez O, et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med. 2022;387(18):1637-1648. PubMed 36322843. COMP360 phase 2b, 233 people with treatment-resistant depression: a single 25 mg, 10 mg or 1 mg dose with psychological support; the 25 mg dose reduced depression at 3 weeks; adverse events included headache, nausea and dizziness; suicidal ideation and self-injury occurred in all groups.
Scheidegger M, Walter M, Lehmann M, et al. Ketamine decreases resting state functional network connectivity in healthy subjects: implications for antidepressant drug action. PLoS One. 2012;7(9):e44799. PubMed 23049758. Placebo-controlled crossover fMRI study in healthy subjects: ketamine decreased functional connectivity of the default mode network to a dorsal prefrontal region that is hyperconnected in depression.
Carhart-Harris RL, Erritzoe D, Williams T, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A. 2012;109(6):2138-43. PubMed 22308440. Imperial College fMRI study, 30 healthy volunteers: intravenous psilocybin decreased blood flow and signal in hub regions (thalamus, anterior and posterior cingulate), decreased coupling between the medial prefrontal and posterior cingulate cortex, and the size of the decrease predicted the intensity of the experience.
Grof S. Psychology of the Future: Lessons from Modern Consciousness Research. Albany: SUNY Press; 2000. Grof’s map of the LSD session (biographical, “perinatal” and “transpersonal” levels) and his idea of an inner healing intelligence, drawn from thousands of supervised sessions in Prague and Maryland in the 1950s–1970s. A clinical hypothesis from that era, not an established or tested model.
Carhart-Harris RL, Friston KJ. REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics. Pharmacol Rev. 2019;71(3):316-344. PubMed 31221820. REBUS (“relaxed beliefs under psychedelics”): psychedelics are proposed to relax the precision of high-level beliefs or priors, letting bottom-up information revise them, including the overweighted priors thought to underlie depression and other conditions; a theoretical model.
Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects?. J Affect Disord. 2014;159:56-61. PubMed 24679390. 108 inpatients with treatment-resistant unipolar or bipolar depression: dissociation (CADSS) at 40 minutes correlated with percent improvement in depression at 230 minutes (r = −0.35) and day 7 (r = −0.41); psychotic-like symptoms, manic symptoms and blood-pressure changes did not; secondary analysis.
Muetzelfeldt L, Kamboj SK, Rees H, et al. Journey through the K-hole: phenomenological aspects of ketamine use. Drug Alcohol Depend. 2008;95(3):219-29. PubMed 18355990. Structured interviews with 90 recreational ketamine users (frequent, infrequent and ex-users; use verified by hair analysis), at street doses that are usually higher than clinic doses: the most appealing effects for two-thirds were “melting into the surrounding,” visual hallucinations, out-of-body experiences and giggliness; memory loss was the most commonly unappealing effect.
Dakwar E, Anerella C, Hart CL, et al. Therapeutic infusions of ketamine: do the psychoactive effects matter?. Drug Alcohol Depend. 2014;136:153-7. PubMed 24480515. Eight cocaine-dependent inpatients, lorazepam versus ketamine 0.41 and 0.71 mg/kg: mystical-type experience (Hood scale), not dissociation (CADSS), mediated ketamine’s effect on motivation to quit 24 hours later.
Hirschfeld T, Schmidt TT. Dose-response relationships of psilocybin-induced subjective experiences in humans. J Psychopharmacol. 2021;35(4):384-397. PubMed 33663259. Meta-regression of psilocybin questionnaire data: dose correlated with perceptual alteration and positively experienced ego dissolution; measures of challenging experience were barely modulated by dose.
Nour MM, Evans L, Nutt D, et al. Ego-Dissolution and Psychedelics: Validation of the Ego-Dissolution Inventory (EDI). Front Hum Neurosci. 2016;10:269. PubMed 27378878. Ego-Dissolution Inventory validated in 691 people reporting 1,828 drug experiences: ego dissolution loaded on one factor, correlated strongly with the unitive items of the mystical experience questionnaire (rho = 0.735), and was specific to psychedelics rather than cocaine or alcohol.
Barrett FS, Johnson MW, Griffiths RR. Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J Psychopharmacol. 2015;29(11):1182-90. PubMed 26442957. Validation of the 30-item Mystical Experience Questionnaire in 184 psilocybin sessions (at least 20 mg/70 kg): scores predicted persisting change in attitudes, behavior and well-being after controlling for the rated intensity of drug effects; defines a “complete mystical experience.”
Mathai DS, Meyer MJ, Storch EA, et al. The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review. J Affect Disord. 2020;264:123-129. PubMed 32056741. Systematic review, 8 single-dose studies in major depression: 2 of 5 CADSS studies and 1 of 6 BPRS studies found a correlation between the altered state and depression change; most studies did not examine it.
Ballard ED, Zarate CA Jr. The role of dissociation in ketamine's antidepressant effects. Nat Commun. 2020;11(1):6431. PubMed 33353946. NIMH perspective: the literature does not support the conclusion that dissociation is necessary for the antidepressant response to ketamine.
Roseman L, Nutt DJ, Carhart-Harris RL. Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Front Pharmacol. 2017;8:974. PubMed 29387009. Imperial College open-label trial, 20 people with treatment-resistant depression: “oceanic boundlessness” (mystical-type) during the 25 mg session predicted lower depression scores at 5 weeks and “dread of ego dissolution” (anxiety) predicted higher ones; perceptual (visual) effects did not; the authors recommend enhancing mystical-type experience and reducing anxiety.
Yaden DB, Griffiths RR. The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol Transl Sci. 2021;4(2):568-572. PubMed 33861219. Position paper (Yaden and Griffiths): the subjective effects of psychedelics are necessary for their enduring benefits and account for most of the benefit.
Olson DE. The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol Transl Sci. 2021;4(2):563-567. PubMed 33861218. The counter-position to Yaden and Griffiths: the plasticity-promoting actions may be separable from the experience; largely argued from animal data.
Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J Psychoactive Drugs. 1997;29(2):165-83. PubMed 9250944. Leningrad, 1980s–1990s: “ketamine psychedelic therapy” for alcoholism, 111 patients versus 100 controls, abstinence beyond one year in 65.8% versus 24%; not blinded, not randomized by modern standards; the largest early programme to use ketamine’s altered state as the treatment.
Carhart-Harris RL, Leech R, Hellyer PJ, et al. The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Front Hum Neurosci. 2014;8:20. PubMed 24550805. The “entropic brain” hypothesis: the psychedelic state shows a larger repertoire of brain-network configurations than normal waking consciousness, which is argued to operate just below a critical point; a theory, informed by imaging data.
Lebedev AV, Lövdén M, Rosenthal G, et al. Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin. Hum Brain Mapp. 2015;36(8):3137-53. PubMed 26010878. fMRI study, 15 healthy subjects: ego dissolution under psilocybin was associated with reduced connectivity between the medial temporal lobe and high-level cortical regions and with “disintegration” of the salience network.
Barrett FS, Griffiths RR. Classic Hallucinogens and Mystical Experiences: Phenomenology and Neural Correlates. Curr Top Behav Neurosci. 2018;36:393-430. PubMed 28401522. Review: under double-blind conditions psilocybin can occasion complete mystical experiences in the majority of people studied, dose-dependently; proposes a neural model based on the default mode network.
Doblin R. Pahnke’s “Good Friday experiment”: a long-term follow-up and methodological critique. J Transpersonal Psychol. 1991;23(1):1–28. Follow-up of the 1962 Harvard divinity-student experiment (psilocybin versus placebo during a Good Friday service) and a critique of its blinding and reporting; the modern Hopkins studies were designed to improve on it.
Barrett FS, Bradstreet MP, Leoutsakos JS, et al. The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms. J Psychopharmacol. 2016;30(12):1279-1295. PubMed 27856683. The Challenging Experience Questionnaire: seven factors (grief, fear, death, insanity, isolation, physical distress, paranoia) describe the difficult side of psilocybin experiences; factor scores were associated with how difficult, meaningful and spiritually significant the experience was rated.
U.S. Food and Drug Administration (DailyMed). KETALAR (ketamine hydrochloride) injection prescribing information, Par Health, revised 03/2026. Section 5.2, Emergence Reactions, describing recovery from anesthetic doses: emergence delirium in approximately 12% of patients, generally lasting a few hours, ranging from pleasant dream-like states and vivid imagery to hallucinations and delirium; reduced by minimizing verbal, tactile and visual stimulation during recovery. Section 12.3: distribution half-life 10 to 15 minutes, redistribution half-life about 2.5 hours. Patient counseling: no driving or hazardous activity within 24 hours.
Garel N, Drury J, Thibault Lévesque J, et al. The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression. Front Psychiatry. 2023;14:1268832. PubMed 37795512. The Montreal model of ketamine for severe treatment-resistant depression: a 20-to-30-minute debrief built into each infusion visit and weekly psychotherapy alongside the course (details from the full text, verified for the ketamine patient page on October 27, 2026).
Yermus R, Bottos J, Bryson N, et al. Ketamine-Assisted Psychotherapy Provides Lasting and Effective Results in the Treatment of Depression, Anxiety, and Post-Traumatic Stress Disorder at 3 and 6 Months: Findings from a Large Retrospective Effectiveness Study. Psychedelic Med (New Rochelle). 2024;2(2):87-95. PubMed 40051583. Retrospective multi-clinic KAP series: psychotherapy-only integration visits scheduled after the first two doses and after every two doses thereafter; uncontrolled.
Moda-Sava RN, Murdock MH, Parekh PK, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364(6436). PubMed 30975859. Article eaat8078. Mouse imaging study: antidepressant-dose ketamine restored dendritic spines that stress had eliminated in prefrontal cortex; new spines were required for the long-term maintenance of the behavioural effect but not for its initial onset.
Duman RS, Aghajanian GK, Sanacora G, et al. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-49. PubMed 26937618. Review: chronic stress disrupts synapses in mood-regulating circuits; rapid-acting agents such as ketamine reverse these synaptic deficits within hours in animals, on the same time scale as the improvement in mood.
Majić T, Schmidt TT, Gallinat J. Peak experiences and the afterglow phenomenon: when and how do therapeutic effects of hallucinogens depend on psychedelic experiences?. J Psychopharmacol. 2015;29(3):241-53. PubMed 25670401. Review of the “peak experience” and “afterglow” concepts: reviews the “afterglow” of elevated mood and openness after a session described in the early clinical literature, and summarizes the evidence linking subjective experience to therapeutic success.
Ly C, Greb AC, Cameron LP, et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018;23(11):3170-3182. PubMed 29898390. Cell-culture and animal study: serotonergic psychedelics, like ketamine, increase neurite growth, spine formation and synapse number via TrkB, mTOR and 5-HT2A signalling.
Nardou R, Sawyer E, Song YJ, et al. Psychedelics reopen the social reward learning critical period. Nature. 2023;618(7966):790-798. PubMed 37316665. Mouse study: psychedelics (and MDMA and ketamine) reopened a critical period for social reward learning for days to weeks, in proportion to the duration of their acute effects.
Bathje GJ, Majeski E, Kudowor M. Psychedelic integration: An analysis of the concept and its practice. Front Psychol. 2022;13:824077. PubMed 35992410. Concept analysis of “psychedelic integration”: many definitions and practices; offers a synthesized definition (a process of making sense of an experience and translating it into lasting change) and a summary of integration practices.
Gukasyan N, Davis AK, Barrett FS, et al. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. J Psychopharmacol. 2022;36(2):151-158. PubMed 35166158. 12-month follow-up of the same trial, 24 participants: response 75% and remission 58% at 12 months; ratings of personal meaning, spiritual experience and mystical experience after sessions predicted well-being at 12 months but did not predict improvement in depression.
Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181-1197. PubMed 27909165. 51 patients with life-threatening cancer and depression or anxiety, high dose (22 or 30 mg/70 kg) versus a very low dose in crossover: large decreases in depression and anxiety and increases in life meaning and optimism, sustained at 6 months; mystical-type experience on the session day mediated the effect.
Agin-Liebes GI, Malone T, Yalch MM, et al. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. J Psychopharmacol. 2020;34(2):155-166. PubMed 31916890. Long-term follow-up of the NYU cancer trial, 15 participants at 3.2 and 4.5 years: reductions in anxiety, depression and hopelessness sustained; 71% to 100% attributed positive life changes to the experience and rated it among the most meaningful of their lives.
Brouwer A, Carhart-Harris RL. Pivotal mental states. J Psychopharmacol. 2021;35(4):319-352. PubMed 33174492. The “pivotal mental state”: a proposed hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation, reliably induced by serotonin-2A agonists; a hypothesis.
Griffiths R, Richards W, Johnson M, et al. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol. 2008;22(6):621-32. PubMed 18593735. 14-month follow-up of the same volunteers: 58% and 67% rated the psilocybin session among the five most personally meaningful and the five most spiritually significant experiences of their lives; 64% said it increased well-being; 58% met criteria for a “complete” mystical experience.

Last reviewed: November 5, 2026 · Adam Hart, MD · Greenville, SC. This page is educational and does not substitute for the preparation session with your own clinician or study team.