18.2 Hallucinogens & Dissociatives: Classic Psychedelics, PCP, Ketamine & HPPD
Key Takeaways
- Classic psychedelics act as 5-HT2A receptor agonists, produce rapid tolerance, and do not cause physical dependence or a withdrawal syndrome.
- The first-line management of a difficult psychedelic experience is a calm low-stimulus environment with reassurance, with benzodiazepines reserved for persistent severe agitation and antipsychotics generally avoided.
- PCP intoxication is distinguished by vertical or rotary nystagmus, extreme agitation with analgesia, and violent behavior, and is managed with benzodiazepines in a low-stimulus setting.
- MDMA can cause life-threatening hyponatremia from excessive free-water intake plus SIADH, and serotonin syndrome when combined with MAOIs or serotonergic agents.
- Ketamine use disorder produces ulcerative cystitis with severe urinary frequency and reduced bladder capacity, which may be irreversible if use continues.
18.2 Hallucinogens & Dissociatives: Classic Psychedelics, PCP, Ketamine & HPPD
Quick Answer: Classic psychedelics (LSD, psilocybin, mescaline, DMT) are 5-HT2A agonists that produce rapid tolerance, no physical dependence and no withdrawal syndrome. A difficult experience is managed with reassurance in a calm, low-stimulus environment; benzodiazepines are reserved for persistent severe agitation and antipsychotics are generally avoided. PCP produces vertical or rotary nystagmus, extreme agitation with analgesia, and violence. MDMA causes hyponatremia and serotonin syndrome. Chronic ketamine causes ulcerative cystitis. HPPD is persistent visual disturbance after psychedelic use.
1. Classic Serotonergic Psychedelics
| Agent | Onset | Duration | Notes |
|---|---|---|---|
| LSD | 30 to 90 minutes | 8 to 12 hours | Active in microgram doses; extremely potent |
| Psilocybin | 20 to 40 minutes | 4 to 6 hours | Converted to psilocin; the subject of current clinical trials |
| Mescaline (peyote) | 45 to 90 minutes | 10 to 12 hours | Sacramental use by the Native American Church is federally protected |
| DMT | Seconds (smoked) | 15 to 30 minutes | In ayahuasca, combined with an MAOI (harmine), extending duration to hours |
| 2C compounds, NBOMe | Variable | Variable | NBOMe compounds are potent 5-HT2A agonists with a much narrower safety margin and reported deaths; often sold as LSD |
Pharmacologic facts worth memorizing:
- Tolerance develops within 3 to 4 consecutive days and is cross-tolerant among classic psychedelics, which structurally limits daily use.
- There is no withdrawal syndrome and no physical dependence.
- Classic psychedelics are physiologically well tolerated in healthy people; the danger is behavioral (trauma from impaired judgment) and psychiatric (precipitating or unmasking psychosis in vulnerable people).
Managing a difficult experience
- Environment first. Quiet, dim, low-stimulus room; minimal personnel; one consistent person.
- Talk-down. Reorient repeatedly to the fact that the experience is drug-induced, is time-limited, and will end.
- Benzodiazepines only if reassurance fails and agitation threatens safety.
- Avoid antipsychotics where possible: they can intensify dysphoria and, in an unknown ingestion, may worsen anticholinergic toxicity or lower the seizure threshold.
- Consider NBOMe or an adulterant if the physiology is more severe than expected — hyperthermia, seizure or marked sympathomimetic toxicity is not typical of LSD or psilocybin.
2. MDMA
| Complication | Mechanism | Management |
|---|---|---|
| Hyponatremia | SIADH plus large free-water intake during prolonged dancing | Fluid restriction; hypertonic saline for seizure or severe symptoms — a genuine emergency with several documented deaths |
| Hyperthermia | Serotonergic thermoregulatory disruption plus exertion in hot environments | Aggressive cooling, benzodiazepines |
| Serotonin syndrome | Massive serotonin release; potentiated by MAOIs, SSRIs, linezolid, tramadol, dextromethorphan | Stop serotonergic agents, benzodiazepines, cooling, cyproheptadine in severe cases |
| Rhabdomyolysis, DIC, hepatic injury | Downstream of hyperthermia | Supportive intensive care |
| Post-use dysphoria | Serotonin depletion in the days after use | Education; the "Tuesday blues" pattern |
Harm reduction teaching: hydrate but do not overdrink (about 500 mL per hour maximum while active), take breaks from dancing, avoid combining with serotonergic medications, and use drug-checking services where available, since supply is frequently adulterated with cathinones.
3. PCP and Dissociatives
| Feature | PCP | Ketamine |
|---|---|---|
| Mechanism | NMDA antagonist, also dopaminergic and sigma activity | NMDA antagonist |
| Duration | Hours to days; redistributes from fat | Under an hour recreationally |
| Signature signs | Vertical, horizontal or rotary nystagmus; extreme agitation with analgesia and apparent superhuman strength; hypertension; violence; may alternate with catatonia | Dissociation, "K-hole," transient hypertension and tachycardia |
| Emergency management | Benzodiazepines, low-stimulus environment, physical restraint only with concurrent chemical sedation, monitor for rhabdomyolysis and hyperthermia | Usually supportive |
| Chronic complication | Persistent psychosis, cognitive impairment | Ulcerative cystitis: urinary frequency, urgency, pain, hematuria, reduced bladder capacity, potentially irreversible contracture; also biliary dilation ("K-cramps") |
Exam anchor: vertical nystagmus in an agitated, violent, hypertensive patient who does not respond to pain is the classic PCP presentation. It is one of the few nearly pathognomonic findings in toxicology.
Ketamine's dual identity: intranasal esketamine is FDA-approved for treatment-resistant depression and is administered under a REMS with observation, while non-medical ketamine use carries dependence and urologic risk. Both facts are true and the APRN must be able to hold them together when counseling a patient who reports using ketamine "for depression" from a non-clinical source.
4. Hallucinogen Persisting Perception Disorder (HPPD)
- Definition: re-experiencing perceptual symptoms that occurred during intoxication — geometric hallucinations, trails behind moving objects, afterimages, halos, intensified colors, micropsia or macropsia — after the drug's effects have ended, causing distress or impairment.
- Reality testing is intact, which distinguishes HPPD from a psychotic disorder.
- Must not be attributable to another medical condition (seizure, migraine aura, retinal or optic pathology) or another mental disorder.
- Management: reassurance, avoidance of further hallucinogens and of cannabis and stimulants, which commonly exacerbate symptoms; limited evidence supports clonidine, lamotrigine or a benzodiazepine in severe distressing cases. Antipsychotics can worsen symptoms.
5. Other Hallucinogen-Adjacent Agents
| Agent | Mechanism | Key point |
|---|---|---|
| Salvia divinorum | Kappa-opioid agonist | Extremely brief, intense dissociation; not detected on routine screens |
| Dextromethorphan (high dose) | NMDA antagonist plus serotonergic activity | Serotonin syndrome risk; combination products contain acetaminophen, creating hepatotoxicity risk |
| Datura / jimsonweed | Antimuscarinic | "Blind as a bat, mad as a hatter" anticholinergic toxidrome; physostigmine in severe cases |
| Ibogaine | Multiple; used illicitly for opioid detoxification | QT prolongation and sudden cardiac death; not legal in the United States and not a safe detox method |
6. Use Disorder and Treatment
DSM-5-TR recognizes phencyclidine use disorder and other hallucinogen use disorder, and lists no withdrawal syndrome for classic hallucinogens. There is no approved pharmacotherapy. Treatment follows general principles: assess co-occurring psychiatric illness carefully (particularly psychosis risk), address the function the drug serves, use motivational and cognitive behavioral approaches, and counsel explicitly on adulteration risk in an unregulated supply.
A 20-year-old who took psilocybin two hours ago is frightened, tearful and convinced he is "losing his mind." Vital signs are normal and he is oriented. What is the appropriate first-line management?
A patient at a music festival who used MDMA is brought in with confusion and a generalized seizure. Serum sodium is 118 mEq/L. What is the mechanism and immediate priority?
A 26-year-old with heavy recreational ketamine use over two years reports urinary frequency every 20 minutes, urgency, suprapubic pain and intermittent hematuria. Urine culture is negative. What should the APRN recognize?