Day # 166: Hallucinogen Use Disorder (LSD, MDMA, Pscilocybin, Mescaline, & More)
- Marcus Hunt
- Sep 1
- 7 min read
Today we will discuss hallucinogens. In this post, we’ll cover the history, neurobiology, epidemiology, clinical presentation, and evidence-based treatment strategies for hallucinogen use disorder. Paradoxically, we will also explore current research on hallucinogens as treatments in psychiatry.
Today's Content Level: Intermediate to Advanced
Hallucinogens are a broad class of substances that alter perception, mood, and thought.
Most aren’t physically addictive — but they can still seriously disrupt lives and lead to dangerous behavior or psychiatric issues.
As a class, some are natural, others are synthetic. They include LSD, psilocybin (“magic mushrooms”), mescaline, DMT, and MDMA (ecstasy, molly).
Mechanism of Action
Classic Hallucinogens (LSD, psilocybin, mescaline, DMT)
Primarily 5-HT2A agonists → cortical serotonin flooding and increased glutamate release in the prefrontal cortex = altered sensory perception, emotion, cognition.
Variable effects on dopamine and norepinephrine receptors contribute to arousal, mood changes, and sympathetic stimulation.
MDMA
Acts primarily by reversing the serotonin transporter (SERT), flooding the synapse with serotonin.
It also increases dopamine and norepinephrine release.
Secondary effects include inhibiting the reuptake of serotonin, dopamine, and norepinephrine, and mild agonist activity at serotonin receptors.
Diagnostic Criteria 3
Diagnostic criteria for all substance use disorders are the same, characterized by a ≥ 12-month period of problematic substance use that leads to impairment or distress and requires ≥2 additional criteria. See Day #160: Introduction to Substance Use Disorders for complete diagnostic criteria and severity specifiers.
Genetics, environmental influences, and mental health comorbidities contribute to vulnerability.
Prevalence: ~10–15% of U.S. adults with lifetime hallucinogen use. 12-month use ~1%. Hallucinogen-related ED visits in the U.S. rose 54% from 2016 to 2022.
Demographics: Varies by drug, age, sex, and ethnicity. Most first-time users in late teens to early 20s. Slightly higher use in males.
Genetics: Not well defined; likely overlaps with general SUD risk. Stressful contexts, novelty-seeking traits, and co-occurring psychiatric conditions likely contribute to risk.
Comorbidities: Associated with mood, anxiety, personality, eating disorders, and other substance use, especially cannabis and stimulants. Can trigger or worsen psychotic or mood disorders.
History:
General SUD: Obtain a detailed history (onset, frequency, quantity, last use, forms and routes), prior treatment attempts, periods of sobriety, withdrawal symptoms, impact on daily functioning, social history with triggers, legal obligations, and co-occurring psychiatric or medical conditions. Ask about prescription misuse and illicit use. Ask about injection drug use, overdose history, co-use of other substances. Assess for other safety concerns related to use, including IV/IN use, sharing paraphernalia, needle licking, exchanging sex for drugs, body packing/stuffing, or impaired driving.
Hallucinogen specific: Historically, used for “mind expansion,” spirituality, music festivals. Most common presentations that lead to psychiatric care ->"Bad trip" (panic, paranoia); Persisting psychosis or mood changes; Hallucinogen persisting perception disorder (HPPD). Ask about timing, context (recreational, “spiritual”, self-treatment), frequency, dosage, and adverse effects (e.g., “bad trips” or disintegration of reality).
Physical Exam:
Exam may be normal
Mydriasis (big pupils)
Tachycardia, hypertension
Diaphoresis
Hyperreflexia, tremors
MDMA-specific: bruxism (jaw clenching), hyponatremia risk, serotonin syndrome risk
Labs/Diagnostics (during acute intoxication):
Urine drug screen does not reliably detect most hallucinogens (e.g., LSD, psilocybin, mescaline often missed). MDMA may show up on amphetamine screen.
Screen for co-ingestants (amphetamines, stimulants).
Check sodium, temperature, CPK if concerned for MDMA toxicity.
Drug-Specific Pearls
LSD (Lysergic acid diethylamide): Synthesized in 1938 by Albert Hofmann, derived from ergot fungus. LSD is one of the most potent hallucinogens. Even microgram doses produce vivid visual distortions, altered perception of time, and “ego dissolution.” Long-acting ~8-12 hours.
Psilocybin (“Magic Mushrooms”): Found in certain mushroom species, psilocybin has been used for centuries in indigenous rituals. It produces visual changes, euphoria, and mystical-type experiences. Relatively short-acting ~4–6 hours.
Mescaline (Peyote, San Pedro cactus): A naturally occurring hallucinogen with long-standing ceremonial use in Native American traditions. Less potent than other hallucinogens. Mescaline produces colorful visual hallucinations and altered states of consciousness lasting ~10–12 hours.
DMT (Dimethyltryptamine): Found in plants and in trace amounts endogenously, DMT is the active compound in ayahuasca. It is known for its extremely intense but short-lived hallucinations, often described as “breaking through” to another reality. Extremely short-acting (~20 min when smoked; longer with ayahuasca due to MAOI).
MDMA (3,4-methylenedioxymethamphetamine, “Ecstasy”/“Molly”): Technically an entactogen rather than a classic hallucinogen, MDMA combines stimulant and psychedelic properties. It induces empathy, sociability, and emotional openness, but carries risk of dehydration, hyponatremia, and neurotoxicity. Mechanism overlaps with SSRIs, amphetamines → risk for serotonin syndrome, especially in combinations.
Intoxication
Symptoms:
Perceptual distortion: colors, shapes, time.
Ego dissolution = temporary breakdown of a person's sense of self, leading to feelings of oneness with the universe and a loss of personal identity.
Emotional swings: emotions can vacillate between euphoria and terror, spiritual awe and paranoia.
Somatic: dizziness, nausea, dilated pupils, tremors.
“Bad trip”: anxiety, panic, paranoia, dissociation, psychosis or hallucinations.
MDMA-specific: intense empathy, emotional openness, energy, pleasant touch enhancement; physical agitation is possible.
Treatment:
Supportive care, calm environment, reassurance.
Monitor vital signs and temperature. Cool them down if hyperthermic. This is particularly relevant in MDMA intoxication. External cooling measures — ice packs to groin/axillae, cooling blankets, mist and fan, chilled IV fluids if severe.
Benzodiazepines: first-line for severe anxiety, panic, or agitation.
Antipsychotics: avoid antipsychotics unless absolutely needed — may paradoxically worsen anxiety, enhance sensory distortions, or extend the psychedelic experience.
MDMA Emergencies:
Manage hyperthermia, seizures, hyponatremia, or serotonin syndrome.
Always check CK, renal function, and electrolytes given risk of rhabdomyolysis and AKI.
Withdrawal
There is no stereotypical withdrawal syndrome for classic hallucinogens.
MDMA “comedown” may cause anhedonia, fatigue, depression, irritability, or sleep disturbance.
Hallucinogen Persisting Perception Disorder (HPPD): A rare complication of hallucinogen use marked by persistent visual disturbances (halos, afterimages, trails, visual snow, geometric shapes) that occur long after intoxication. Unlike brief “flashbacks,” HPPD can be chronic and disabling, lasting weeks to years, and is often anxiety-provoking.
Transition to Chronic Psychosis: There is an elevated risk of transition to chronic psychosis. Amonth those with brief drug-induced psychosis on hallucinogens, 26% went on to later be diagnosed with schizophrenia. Individuals with personal or family history of psychosis or schizophrenia should avoid hallucinogens—recent data shows a 3.5-fold increased schizophrenia risk following a hallucinogen-related ER visit.
Treatment of Hallucinogen Use Disorder 12
•Effective treatment requires a combination of medical, psychological, and social interventions. A multi-disciplinary team—often including psychiatrists, primary care providers, therapists, social workers, and peer support specialists collaborates to address all aspects of the disorder.
Determine the Appropriate Treatment Setting: Choosing the right level of care depends on substance use severity, comorbid conditions, and prior treatment history. See Day 60: Intro to SUD for a description of each level of care.
Psychosocial Interventions:
Individual and/or group therapy should be part of every SUD treatment approach. See Day 60: Intro to SUD for a discussion of interventions that include behavioral therapies, peer support & 12-step programs, and family support resources.
Medications:
There is no approved medication for hallucinogen use disorder.
Educate patients about rare but notable risks (e.g., HPPD and risk of chronic psychosis).
Address psychiatric comorbidities, especially psychotic and mood disorders.
HPPD: Supportive care and psychoeducation are first-line. Some evidence supports benzodiazepines, clonidine, lamotrigine, or naltrexone for symptom relief. Antipsychotics may worsen symptoms and are generally avoided (with the possible exception of aripiprazole according to small studies). SSRIs lack evidence for efficacy.
Chronic Psychosis: Antipsychotics.
Here’s where it gets fascinating: many of these substances — sometimes the stuff of bad trips and ER visits — are now undergoing clinical trials as treatments for psychiatric and substance use disorders. And they are promising!
Psilocybin: FDA “Breakthrough Therapy” designation for treatment-resistant depression and major depressive disorder. Also being studied for alcohol use disorder, tobacco use disorder, and other addictions, with early results showing reduced cravings and relapse.
MDMA: Phase 3 trials show strong efficacy for PTSD, especially in veterans, sexual assault survivors, and first responders. Trials also exploring use in social anxiety and couples therapy.
Ayahuasca/DMT: Studied in controlled settings for substance use disorders (alcohol, cocaine, tobacco), as well as major depression and eating disorders. Ritualistic/ceremonial use has shown some long-term reduction in addictive behaviors.
LSD: Investigated for cluster headaches, anxiety related to terminal illness, and historically for alcohol use disorder with surprisingly positive outcomes. Modern trials are revisiting these applications with renewed rigor.
Mescaline: Less studied in modern trials, but preliminary work suggests potential benefit for depression and alcohol misuse, with ongoing research into its unique empathogenic and hallucinogenic profile.
The mechanisms behind this are still being worked out — it likely involves 5-HT2A activation + altered network connectivity + deep emotional processing in controlled settings. But the takeaway is this:
Set, setting, and supervision matter.
The same drug that can ruin someone in the wrong context might actually heal them in the right one. Clinical psychedelic-assisted therapy is structured, guided, and regulated — not a rave or back-alley experiment.
The very drugs once demonized as dangerous are now some of the most exciting frontiers in psychiatry — a paradox worth keeping an eye on.
Conclusion
MOA: Think 5HT2A agonism → serotonin flooding → perception chaos
No withdrawal syndrome in most, but psychiatric fallout is real
MDMA toxicity = serotonin syndrome, seizures, hyponatremia
Supportive care + benzos are mainstays for intoxication
Treatment is primarily therapy-based, not med-based
Resources for today's post include:
Articles referenced above
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