A 23-year-old male is brought by police officers from a social gathering due to combative behavior and altered mental status. The police say that phencyclidine was found on the premises. The patient is alone, and acquiring an accurate history proves difficult. However, you do learn that the patient is having visual hallucinations. Vital signs show a blood pressure of 155/95 mmHg, pulse is 103/min, respirations is 20/min, oxygen saturation of 99%. Airway, breathing, and circulation are intact. The patient appears violent, and is trying to remove his clothes. Multiple hospital staff are needed to restrain the patient in bed. A finger-stick glucose show 93 mg/dL. The team is unable to place an IV, and thus intramuscular midazolam is administered to achieve sedation; however, he is still agitated. What is the mechanism of action of the best alternative sedative drug for this patient?

Mu-opioid receptor partial agonist

Competitive opioid receptor antagonist

Alpha-2 and H1 receptor antagonist

Increases duration of chloride channel opening of GABA-A receptors

A 68-year-old man, accompanied by his wife, presents to his physician with cognitive decline and hallucinations. The patient’s wife tells that his cognitive impairment progressed gradually over the past 6 years, and first began with problems counting and attention. The hallucinations began approximately a year ago. The patient describes them as realistic and non-frightening; most often, he sees his cat accompanying him everywhere he goes. The patient’s wife also notes frequent episodes of staring spells in her husband and prolonged daytime napping. The blood pressure is 130/80 mm Hg with the orthostatic change to 110/60 mm Hg, heart rate is 75/min, respiratory rate is 13/min, and the temperature is 36.6°C (97.8°F). The patient is alert and responsive, but he is disoriented to time and place. He is pale and hypomimic. The cardiac, lung, and abdominal examinations are within normal limits for the patient’s age. The neurological examination is significant for a bilateral symmetrical cogwheel rigidity in the upper extremities. What would you most likely see on additional radiological investigations?

Decreased perfusion and dopaminergic activity in occipital lobes on PET

Multiple lacunar infarcts on MRI

Marked hippocampal atrophy on MRI

Hypoperfusion and hypometabolism in frontal lobes on SPECT

Pontine 'hot-cross bun' sign on MRI

Hallucinogen-related disorders for USMLE Step 2 CK: High-Yield Psychiatry Lessons

Hallucinogens - The Mind Benders

Classic Hallucinogens: Lysergic acid diethylamide (LSD), psilocybin, mescaline.
Mechanism of Action: Primarily serotonin 5-HT2A receptor agonists, altering perception and mood.
Intoxication Syndrome:
- Profound perceptual changes: visual illusions & hallucinations, synesthesia (e.g., "hearing colors").
- Psychic effects: depersonalization, derealization, anxiety, paranoia ("bad trip").
- Sympathomimetic signs: ↑ HR, ↑ BP, mydriasis.
Hallucinogen Persisting Perception Disorder (HPPD):
- Spontaneous, transient recurrences of perceptual disturbances ("flashbacks") causing significant distress or impairment.

⭐ Unlike intoxication, HPPD flashbacks occur without recent drug use and are a key diagnostic feature.

5-HT2A Receptor Characteristics and Signaling

Classic Hallucinogens - Serotonin's Wild Ride

Mechanism: Primarily agonists at serotonin 5-HT2A receptors, altering perception and mood.

Feature	Lysergic Acid Diethylamide (LSD)	Psilocybin (Magic Mushrooms)	Mescaline (Peyote Cactus)
Onset & Duration	Onset: 30-90 min; Duration: 6-12 hrs	Onset: 20-40 min; Duration: 4-6 hrs	Onset: 1-2 hrs; Duration: ~12 hrs
Intoxication	Visual hallucinations, synesthesia, delusions, pupillary dilation, tachycardia, tremors.	Similar to LSD but often more visual and less panic-inducing.	Vivid visual hallucinations, anxiety, tachycardia, diaphoresis, nausea/vomiting.
Unique Trait	📌 "Flashbacks" or Hallucinogen Persisting Perception Disorder (HPPD) can occur long after use.	Often described as more "natural" or "spiritual" experiences.	Strong association with nausea and vomiting during onset.

⭐ Exam Favorite: Hallucinogen Persisting Perception Disorder (HPPD) involves spontaneous, transient recurrences of visual disturbances reminiscent of acute intoxication. It's a diagnosis of exclusion and can be distressing, often triggered by stressors or other substance use.

PCP & Ketamine - Dissociative Disconnect

Mechanism: Non-competitive NMDA receptor antagonists; inhibit excitatory glutamate neurotransmission.
Clinical Presentation: Dissociative state with analgesia, amnesia, and a feeling of detachment. Key signs include aggression, impulsivity, ataxia, and nystagmus (horizontal, vertical, or rotary).
📌 Mnemonic (PCP): RED DANES - Rage, Erythema (red skin), Delusions, Amnesia, Nystagmus, Excitation, Skin dryness.
Management: Focus on supportive care in a low-stimulus environment.
- Agitation/Seizures: Benzodiazepines (e.g., lorazepam) are first-line.
- Severe Psychosis: Antipsychotics like haloperidol may be used cautiously.
- Monitor for rhabdomyolysis (CK levels) and hyperthermia.

⭐ Vertical or rotary nystagmus is highly suggestive of PCP intoxication.

Management - Calm, Cool, Collected

Initial approach focuses on supportive care and verbal de-escalation (“talking down”).
Place patient in a low-stimulus environment (quiet, dimly lit room) to minimize perceptual distortions.
Avoid physical restraints if possible, as they may increase agitation and risk of rhabdomyolysis.
For severe agitation or psychosis unresponsive to environmental management, pharmacotherapy is indicated.

⭐ In PCP intoxication, avoid antipsychotics like haloperidol. They lower the seizure threshold and have anticholinergic effects that can worsen hyperthermia.

High‑Yield Points - ⚡ Biggest Takeaways

LSD intoxication is marked by visual hallucinations and synesthesias; reality testing is typically intact.

Hallucinogen Persisting Perception Disorder (HPPD), or "flashbacks," is a key long-term risk with LSD.

PCP is notorious for causing nystagmus (rotary, vertical), aggression, and dissociation. Use benzodiazepines for management.

MDMA (Ecstasy) toxicity can precipitate serotonin syndrome and life-threatening hyponatremia from SIADH and excess water intake.

Unlike opioids or alcohol, classic hallucinogens have no significant withdrawal syndrome.

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Hallucinogen-related disorders