Drug: Psychedelica in de geestelijke gezondheidszorg

What It Is

Psychedelics in mental health are a small group of very different drugs, studied under close supervision and alongside therapy, for conditions that current treatments often fail. The compounds differ sharply in how they work. The classic psychedelics, such as psilocybin, act through the serotonin 5-HT2A system. MDMA lowers fear by releasing serotonin. Ketamine and its refined form esketamine work on a separate system, and esketamine is the one member with an approved medical use.

The Main Compounds

1Classic psychedelics: psilocybin, LSD, DMT

These act mainly by switching on the serotonin 5-HT2A receptor, which changes how the cortex signals and is thought to loosen rigid, self-focused patterns of thought. Blocking that one receptor blocks the experience, which is how researchers know it is central. The best trial evidence here is for depression, including treatment-resistant depression, and for the distress of a life-threatening illness.

2MDMA: the trauma compound

MDMA works chiefly by releasing serotonin along with dopamine and noradrenaline, a different mechanism from the 5-HT2A receptor activation of the classic psychedelics. The effect is reduced fear and a greater sense of trust and connection, used to help people stay with traumatic memories during therapy. Its studied use is in post-traumatic stress disorder.

3Ketamine and esketamine: the dissociatives

Ketamine and its enantiomer esketamine are dissociatives, not classic psychedelics. They act on the NMDA glutamate receptor and produce dissociation. Esketamine nasal spray is approved for treatment-resistant depression and is given in a certified clinic, which makes this the one compound in the wider group with a settled regulatory position.

What It Does

Psilocybin in depression is the strongest, most consistent evidence in the field. In the largest controlled trial, a single 25 mg dose with therapy improved treatment-resistant depression by 6.6 points more than a low comparison dose at three weeks. That gain had faded by twelve weeks. A separate trial in major depression found a large short-term benefit against a waiting list, a comparison that inflates the size.

In people facing a life-threatening cancer, a single psilocybin session with support eased depression and anxiety, and most were still improved around six months on. MDMA-assisted therapy for post-traumatic stress showed a moderate-to-large benefit over placebo therapy across two phase 3 trials. Not every comparison favored the drugs. Tested head-to-head against a standard antidepressant, psilocybin did not clearly beat it on the main measure.

One limit affects all of these results: the blinding fails. These drugs produce unmistakable subjective effects, so in a trial almost everyone can tell whether they got the active drug or the placebo. A systematic review found the problem pervasive: in psilocybin studies, participants and raters identified who got the drug more than 90 percent of the time. Expectation can lift scores, and it is very hard to separate from the drug. It does not mean the benefit is absent.

It means the measured size of the effect is likely inflated, and the true effect is not yet established.

The Research & Studies

Everything here is based on the research we have collected and checked, sorted into groups and ordered with the strongest evidence first. Click any claim to open the studies behind it.

Mood & stress

Esketamine nasal spray, the one approved option here, beat placebo by about 4 points at four weeksModerate

In plain terms

Esketamine nasal spray, taken with an antidepressant, improved depression by about 4 points more than a placebo spray at four weeks on the MADRS depression scale, which runs from 0 to 60, a modest edge. It is the one compound in this area with regulatory approval, and it is a dissociative drug, not a classic psychedelic.

In detail

In the TRANSFORM-2 phase 3 trial, 227 adults with treatment-resistant depression started a new oral antidepressant and were randomized to esketamine nasal spray or placebo spray. MADRS improved by a difference of least-square means of 4.0 points favoring esketamine at day 28 (SE 1.69). An earlier phase 2 dose-finding trial showed a similar adjunctive benefit. On this evidence esketamine (Spravato) received regulatory approval for treatment-resistant depression, given under medical supervision because of dissociation and transient blood-pressure rises.

The studies · 2

Popova et al., efficacy and safety of flexibly dosed esketamine nasal spray in treatment-resistant depression · Am J Psychiatry 2019;176:428-438

Daly et al., efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression · JAMA Psychiatry 2018;75:139-148

Microdosing matched placebo, with no clear benefit for well-being in the largest self-blinded trialModerate · no effect

In plain terms

In the largest placebo-controlled test of microdosing, the people who microdosed felt better, but so did the placebo group, and the two did not differ. The apparent gains tracked with people guessing which they had taken.

In detail

This self-blinding citizen-science study had 191 participants build placebo control into their own microdosing routine over four weeks without clinical supervision, making it the largest placebo-controlled trial of psychedelics to date. All psychological outcomes improved from baseline in the microdose group, but the placebo group improved too, with no significant between-group differences. Small acute and post-acute differences (emotional state, drug intensity, mood, energy, creativity, and anxiety) were explained by participants breaking blind and correctly identifying whether they had taken a microdose or placebo.

The study · 1

Szigeti et al., self-blinding citizen science to explore psychedelic microdosing · eLife 2021;10:e62878

One 25 mg psilocybin dose eased treatment-resistant depression 6.6 points more than a low dose at three weeksEmerging

In plain terms

Eén enkele hoge dosis psilocybine, gegeven met therapie, verlichtte therapieresistente depressie meer dan een piepkleine vergelijkingsdosis na drie weken. De verbetering was na twaalf weken weer weggeëbd, en bijwerkingen waren gebruikelijk.

In detail

This phase 2b trial (COMP360) randomized 233 people with treatment-resistant depression to a single 25 mg, 10 mg, or 1 mg dose of synthetic psilocybin alongside psychological support. Mean MADRS change at three weeks was -12.0 (25 mg), -7.9 (10 mg), and -5.4 (1 mg). The 25 mg versus 1 mg difference was -6.6 (95% CI -10.2 to -2.9, P<0.001); the 10 mg versus 1 mg difference was not significant. Response and remission at three weeks favored 25 mg, but the advantage was not sustained at twelve weeks. Adverse events occurred in 179 of 233 participants (77%), including headache, nausea, and dizziness, and suicidal behavior was reported in some participants.

The study · 1

Goodwin et al., single-dose psilocybin for a treatment-resistant episode of major depression · N Engl J Med 2022;387:1637-1648

Two psilocybin sessions with therapy cut major-depression scores sharply, with 54% in remission at four weeksEmerging

In plain terms

Two psilocybin sessions with therapy produced a large short-term improvement in major depression, with about half of a small group in remission a month later.

In detail

This Johns Hopkins trial randomized 27 adults with major depressive disorder (24 completed; mean age 40; 67% women) to immediate psilocybin therapy or a delayed-treatment waiting list. Two psilocybin sessions with supportive therapy produced large reductions on the GRID-HAMD (Cohen d 2.5 at week 5 and 2.6 at week 8). At week 4, 71% met response (>=50% reduction) and 54% met remission (score <=7). The comparison was against a waiting list, which does not control for time, attention, or expectation.

The study · 1

Davis et al., effects of psilocybin-assisted therapy on major depressive disorder, a randomized clinical trial · JAMA Psychiatry 2021;78:481-489

Psilocybin did not clearly beat a standard antidepressant on the main depression measure at six weeksEmerging · no effect

In plain terms

When psilocybin was tested head-to-head against a standard antidepressant, the two came out about even on the main measure of depression. Some secondary measures leaned toward psilocybin, but the study was too small to decide.

In detail

This double-blind phase 2 trial randomized 59 people with depression to psilocybin (two 25 mg doses three weeks apart) or six weeks of daily escitalopram, both with psychological support. The primary outcome, change in QIDS-SR-16 at six weeks, showed no significant between-group difference (-2.0 points, 95% CI -5.0 to 0.9, P=0.17). Secondary measures such as QIDS-SR-16 response (70% vs 48%) and remission (57% vs 28%) favored psilocybin, but the trial was not powered for them and had no placebo-only arm.

The study · 1

Carhart-Harris et al., trial of psilocybin versus escitalopram for depression · N Engl J Med 2021;384:1402-1411

A single psilocybin session eased cancer-related distress, with 60 to 80% still improved at about six monthsEmerging

In plain terms

For people facing life-threatening cancer, a single psilocybin session with support eased depression and anxiety, and most were still better roughly six months later.

In detail

A Johns Hopkins crossover trial (51 patients) and an NYU crossover trial (29 patients) each gave people with cancer-related depression and anxiety a single moderate-to-high psilocybin dose with psychological support, compared with a very low dose or an active control. Both produced immediate, substantial, and sustained decreases in depressed mood and anxiety alongside increases in quality of life and sense of meaning; at roughly six months, 60 to 80% of participants still showed clinically significant improvement.

The studies · 2

Griffiths et al., psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer · J Psychopharmacol 2016;30:1181-1197

Ross et al., rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer · J Psychopharmacol 2016;30:1165-1180

Anxiety And Stress

MDMA-assisted therapy lowered PTSD severity more than therapy alone across two phase 3 trialsEmerging

In plain terms

In two large trials, MDMA given alongside structured therapy lowered PTSD symptoms more than the same therapy with a placebo. The effect was moderate to large.

In detail

The MAPP1 trial (n=90) randomized people with severe PTSD to MDMA or placebo, each with three preparatory and nine integrative therapy sessions. CAPS-5 severity fell by a mean 24.4 points with MDMA versus 13.9 with placebo (P<0.0001, d 0.91). The confirmatory MAPP2 trial (n=104, moderate to severe PTSD) again favored MDMA-assisted therapy on CAPS-5 (P<0.001, d 0.7). Both were well tolerated with no deaths or serious drug-related adverse events reported.

The studies · 2

Mitchell et al., MDMA-assisted therapy for severe PTSD, a randomized double-blind placebo-controlled phase 3 study · Nat Med 2021;27:1025-1033

Mitchell et al., MDMA-assisted therapy for moderate to severe PTSD, a randomized placebo-controlled phase 3 trial · Nat Med 2023;29:2473-2480

Evidence And Methods

Patients can tell what they got more than 90% of the time, and the FDA declined MDMA for PTSD in 2024Emerging · mixed

In plain terms

Because these drugs produce obvious effects, people in the studies can usually tell whether they got the active drug, which makes the benefit hard to separate from expectation. Partly for this reason, the FDA did not approve MDMA therapy for PTSD in 2024 and asked for another trial.

In detail

A systematic review of blinding integrity in psychedelic RCTs found that only 29.5% of trials even assessed blinding, while 57.1% named it as a limitation. Where it was measured, functional unblinding was substantial: psilocybin, LSD, and ayahuasca studies frequently reported blinding failure above 90% among both participants and raters, and inert-placebo MDMA trials exceeded 85%. A 2026 reassessment of the MDMA-for-PTSD program reached the same conclusion, that difficulties in blinding and expectation effects limit how firmly the benefit can be attributed to the drug. In 2024 the FDA declined to approve MDMA-assisted therapy for PTSD and requested an additional trial, citing trial-design, blinding, and conduct concerns.

The studies · 2

Blinding integrity in psychedelic randomized clinical trials, a systematic review · JAMA Psychiatry 2026

From therapeutic promise to evidentiary discipline, reassessing MDMA-assisted psychotherapy for PTSD · J Trauma Stress 2026

How it works

Classic psychedelics act on the 5-HT2A serotonin receptor, MDMA releases serotonin, ketamine blocks NMDAEmerging · mixed

In plain terms

The classic psychedelics act on one serotonin receptor (5-HT2A). MDMA floods the brain with serotonin instead, and ketamine acts on a different system entirely, so grouping them together is loose.

In detail

Comprehensive pharmacology reviews establish that the subjective effects of classic psychedelics depend on agonism at the serotonin 5-HT2A receptor: blocking that receptor blocks the experience. This is thought to increase the flexibility of cortical activity and reduce the grip of rigid, self-referential thinking, a mechanism of interest for depression and end-of-life distress. MDMA is an entactogen that chiefly releases serotonin (and dopamine and noradrenaline), not acting as a 5-HT2A agonist, producing empathy and reduced fear that are used to support trauma processing. Ketamine and its enantiomer esketamine are dissociatives that antagonize the NMDA glutamate receptor, a distinct pathway with rapid antidepressant effects.

The study · 1

Nichols, psychedelics, a comprehensive pharmacology review · Pharmacol Rev 2016;68:264-355

How It Works

The classic psychedelics work through a single receptor. Their benefit depends on activating serotonin's 5-HT2A receptor. Doing so raises the flexibility of activity across the cortex. The therapeutic idea follows. With that flexibility, a person can revisit thoughts, memories, and feelings from a fresh vantage point. The shift can outlast the drug.

MDMA works by a different mechanism than the 5-HT2A receptor. It releases a surge of serotonin that lowers fear and raises trust, so a person can stay with traumatic material long enough to work on it. Ketamine and esketamine act on the NMDA glutamate receptor instead. They lift mood fast, which is why they are used when a quick effect matters.

How the View Has Swung

For decades the received view held that psychedelics were dangerous drugs with no medical value. The trial evidence no longer supports that dismissal. A newer view goes the other way, calling these compounds close to a cure. The FDA's response to MDMA is the clearest check on it. Despite the positive phase 3 evidence, regulators declined to approve MDMA-assisted therapy for PTSD in 2024 and asked for another trial. Both the old dismissal and the newer overstatement go beyond what the data show.

Where the Law Stands

Esketamine is the exception the law already allows, prescribed under supervision. For everything else the picture is restrictive. In the United States the classic psychedelics (psilocybin, LSD, and DMT) and MDMA are Schedule I federally. That category, set in the early 1970s, is the most restricted the law has. Using them outside authorized research or approved treatment is illegal. Oregon and Colorado have built state-regulated frameworks for supervised adult psilocybin use, legal under state law but not under the federal classification. Everywhere else these compounds stay investigational, reachable only inside clinical trials and expanded-access programs.

Who Should Take Extra Care

A personal or family history of bipolar disorder or psychosis matters most, because these drugs can trigger mania or, in vulnerable people, psychosis. Anyone taking lithium, an MAOI, or a serotonergic antidepressant risks a real drug interaction, detailed in the cautions below. Heart-valve trouble is a concern mainly with frequent, repeated dosing. Someone currently very unsettled, or without support, is the most likely to have a difficult experience.

The Chinese Medicine View

Chinese medicine has a long-standing frame for altered states of mind, and it leans toward caution. The Heart is said to house the Shen, the spirit or consciousness. Clear thought, steady emotion, and restful sleep are read as signs of a settled Shen. A mind flooded, disoriented, or thrown into fear or agitation is a disturbed Shen. The classical tradition works to calm and anchor it.

The bias of the medicine tends toward grounding: steadying the Shen, harmonizing the Heart and Liver, settling a scattered mind through stillness, breath, and regular routine. Read this way, an intense, mind-altering experience deliberately stirs the Shen. The tradition would meet that with great care, especially in someone already depleted, agitated, or unsettled, and above all without skilled support and a calm setting. The old texts did not foresee modern trials; this is only how the tradition reads such states. This lines up with the clinical evidence: preparation, support, and a stable state shape the outcome. The wider preventive tradition of Yang Sheng, nourishing life, would put grounding practices first.

Cautions For This Practice

Everything to be aware of is here, in one place. This practice suits most healthy people; a few situations call for real care.

In unsupervised use, 11% recalling a bad trip put themselves or others at risk of physical harm

An online survey asked people (78% male, mean age around 30) about the single most psychologically difficult experience of their life with psilocybin mushrooms. Eleven percent reported putting themselves or others at risk of physical harm, 2.6% behaved aggressively, and 2.7% sought medical help; of those whose experience was more than a year earlier, 7.6% had sought treatment for enduring symptoms. Difficulty, dose, and the absence of physical comfort and social support all raised the likelihood of risk. Despite the difficulty, 84% still reported benefiting from the experience overall.Carbonaro et al., survey study of challenging experiences after ingesting psilocybin mushrooms

Psychedelics triggered mania in 5.8% to 30% of people and can provoke psychosis in the vulnerable

The meta-analysis pooled controlled trials and naturalistic studies. Rates of dysphoria, hypomania, or mania ran from 5.8% in controlled psilocybin-assisted therapy trials for depression up to 30% in naturalistic use among people with bipolar spectrum conditions. The pooled rate of subsequent transition to a bipolar diagnosis was 4% (95% CI 2 to 8%, N=7478), with little evidence of a hallucinogen-specific signal. A separate narrative review of psychedelics and schizophrenia spectrum disorders concludes they may trigger psychosis in vulnerable individuals, while noting the magnitude of that risk is inadequately quantified.Psychedelic-induced hypomania and mania, a systematic review and meta-analysisThe intersection between psychedelics and schizophrenia spectrum disorders, reevaluating risk and therapeutic potential

Repeated dosing touches the 5-HT2B receptor tied to heart-valve damage, a risk not yet measured

Valvular heart disease from drugs such as fenfluramine and certain dopamine agonists is driven by activation of the serotonin 5-HT2B receptor on heart valves. A pharmacology analysis found that LSD, psilocybin metabolites, and MDMA are partial agonists at 5-HT2B, with potencies generally lower than established valvulopathogens but not without potential risk. No animal or clinical study appropriately designed to measure valve outcomes from repeated or microdosed use has been done, so this remains a mechanistic concern, not a measured rate.Tagen et al., the risk of chronic psychedelic and MDMA microdosing for valvular heart disease

Mixing a classic psychedelic with lithium brought on seizures in 47% of reported cases

Researchers analyzed self-reported online accounts of combining a classic psychedelic with a mood stabilizer. Of 62 lithium-plus-psychedelic reports, 47% involved seizures, an additional 18% involved a bad trip, and 39% involved a need for medical attention; of 34 lamotrigine-plus-psychedelic reports, none involved seizures. The authors conclude the combination may pose a significant seizure risk for people taking lithium.Nayak et al., classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures

A minority develop lasting visual disturbances (HPPD) after use, uncommon but long documented

Hallucinogen persisting perception disorder is a documented condition in which visual phenomena such as trails, halos, or afterimages persist after psychedelic use, sometimes for a long time. A review covering 50 years of reports found the condition is real but its rate cannot be reliably estimated from the scattered case literature; it is more often described with repeated or heavy use than with a single supervised session.Halpern and Pope, hallucinogen persisting perception disorder, what do we know after 50 years

These are not everyday-safe drugs, and this is not a guide to using them

This page is education about the research, the law, and the risks. It carries no dosing, no sourcing, and no instructions for use. Most use outside an approved-treatment or research setting is illegal in most places, and unsupervised use carries psychological and medical risk. The clinical results come from screened patients in prepared sessions with trained support, which is a very different situation from taking a substance alone.

Interactions with other medicines

Serotonin-based antidepressants (SSRIs and SNRIs) can blunt the effect of classic psychedelics, and combining serotonergic drugs, including MDMA, with an MAOI antidepressant can push serotonin to dangerous levels. Combining a classic psychedelic with lithium has been linked to seizures, covered in the research above. Anyone on psychiatric medication is in a situation where these interactions can be dangerous, and a prescribing clinician is the right person to consult.

Set, setting, and supervision

The research repeatedly points to the same thing: preparation, a calm and safe environment, and skilled support shape how an experience goes. In the survey evidence above, difficulty and risk rose at higher doses and when support and physical comfort were absent. The phrase the field uses is set, setting, and supervision, and it separates the studied conditions from unsupervised use.

Psychedelics are a promising area of research, and they are potent drugs whose risks depend heavily on the person, the dose, and the setting. The stance here is to inform: read the evidence at its true strength, take the risks seriously, and, for anything touching your own care or medication, talk it through with a qualified clinician.

Common Questions

Does microdosing work?

The best test to date says the benefit does not survive a placebo control. In the largest placebo-controlled study, people taking small, regular doses improved on every psychological measure. The placebo group improved just as much, and the two did not differ. The small gaps that did appear tracked with people correctly guessing whether they were on the drug. Much of the effect is expectation.

Why did the FDA decline MDMA-assisted therapy in 2024?

The trials did show benefit. The decline was about how much of it to trust. Regulators cited the same blinding problem described above, then added concerns specific to this program: how the trials were run, and whether the improvement lasted. The 2024 decision was a judgment about the strength of the evidence.

Go Deeper

The lowest-risk place to start is the free, self-directed one. Meditation and mindfulness works on the same rumination the 5-HT2A drugs aim at, and it carries none of the risk.

• Psilocybin: the strongest single case, studied in depression and in end-of-life distress.
• MDMA: the trauma compound, and the 2024 FDA decision in full.
• Ketamine and esketamine: the approved relative, acting on the glutamate system.
• Ayahuasca: studied mainly for depression, with a serious serotonin-syndrome risk from its MAO-inhibitor action.
• Ibogaine: studied for interrupting opioid and other substance use, carrying a documented risk of fatal heart-rhythm disturbance.
• Depression: what actually helps and Anxiety: the conditions this research targets, with the treatments that have the longest track record.
• Purpose and meaning: where the end-of-life distress work ultimately points.