THC and Hallucinogens

Principles of Toxicity

Serotoninergic agents are a broad category of compounds that share structural similarities with serotonin (5-hydroxytryptamine [5-HT]) or enhance serotonergic tone within the body, predominantly by their action at the 5-HT _2A serotonin receptor subtype. These agents include various lysergic acid derivatives (lysergamides) and tryptamines (indolealkylamines). Serotonin-like agents produce changes in thought, mood, perception, and consciousness. Orientation to person, place, and time is usually preserved, but severe intoxication may cause delirium, disorientation, and altered levels of consciousness. Patients may present to the emergency department (ED) because of an acute panic reaction, excessive ingestion, or accidental exposure (e.g., children or adults who have ingested the drug unknowingly). Unlike opioids, there is no addictive component in psychedelics and no euphoria-dysphoria cycle, as occurs with sympathomimetic drugs such as cocaine. The rapid development of tolerance also limits the effect of repeated doses.

Lysergamides

Lysergic acid diethylamide (LSD), or acid, is a potent psychedelic drug. Doses of 1 to 1.5 μg/kg produce psychedelic effects. The typical dose taken for an “acid trip” is approximately 25 to 100 μg. LSD is sold as a tablet (microdot), liquid, powder, gelatin square (or “windowpane”), and blotter acid. Sheets of blotting paper are sprayed with LSD, dried, and perforated into small squares. Graphics are incorporated onto the blotting paper in designs that include cartoon characters (e.g., Felix the Cat, Bart Simpson) and geometric designs ( Fig. 145.1 ). Each sheet is composed of hundreds of squares that are placed sublingually or eaten whole. Massive ingestions are rare. Drug paraphernalia recently sold and touted as “LSD” does not actually contain lysergic acid diethylamide but synthetic cannabinoids.

In addition to synthetic LSD, several plants contain lysergic acid amide (LSA) similar in structure and action to LSD. These plants include the Hawaiian baby wood rose ( Argyreia nervosa ), Hawaiian wood rose ( Merremia tuberosa ), morning glory ( Ipomoea violacea ), and ololiuqui ( Rivea corymbosa ). Intoxication may result after ingestion of the seeds, extract, or tea.

Tryptamines

Tryptamines may be synthetic or natural compounds. For centuries, Native Central and South Americans have used tryptamine-containing beverages such as ayahuasca in their religious ceremonies. This beverage is brewed from a combination of plants containing dimethyltryptamine (DMT) and 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT), as well as harmine alkaloids with monoamine oxidase inhibitor effects that increase the bioavailability of orally ingested DMT. Ayahuasca has gained recent popularity in Europe and North America.

Psilocybin and psilocin are naturally occurring tryptamines found in some species of Psilocybe ( Fig. 145.2 ), Panaeolus, and Conocybe mushrooms. Psilocybin remains active when the mushrooms are dried or cooked. Street psilocybin sold as pills or capsules is frequently substituted with phencyclidine (PCP) or LSD. Naturally occurring tryptamines are also found in the parotid glands of the Bufo toad species. The venom of the Sonoran Desert or Colorado River toad ( Bufo alvarius ) contains 5-MeO-DMT. Smoking of the dried venom results in psychoactive effects.

Designer tryptamines such as α-methyltryptamine, diisopropyltryptamine, and diisopropyl-5-methoxytryptamine (street named foxy or foxy methoxy) have been synthesized and are orally active. The effects of these synthetic derivatives are similar to those of naturally occurring tryptamines.

Clinical Features

In Western society, psychoactive agents are taken for internal mental exploration or, more commonly, for recreation. Effects include loss of boundaries between the user and environment, the sensation that colors and sounds are distorted and intensified, the sensation that perceptions are occurring via unusual pathways such as synesthesia, and the perception that usual objects appear novel, fascinating, or awe-inspiring. Users are usually aware that they are under the influence of the drug. A sense of euphoria is common, but it may alternate with an intense dysphoric experience that is accompanied by paranoia (e.g., illusions of dying or being born).

Acute panic reaction is a common adverse reaction to psychedelics. Paranoid delusions and fear of impending death can also occur. Behavior may be agitated or withdrawn. Sympathomimetic effects include mydriasis, tachycardia, hypertension, and in severe cases, hyperthermia. Mydriasis seems to parallel the intensity of the trip. The individual’s altered perceptions may result in lack of awareness of dangers in the environment, resulting in injury. Psychosis after LSD trips has been reported, and schizophrenia (overt or borderline) may worsen. Transient depression sometimes occurs after LSD use. Flashbacks, or posthallucinogen perceptual disorder, are transient episodes of altered consciousness that occur months or years after LSD ingestion. Hyperactivity may also be seen, with marked auditory and visual hallucinations. Massive ingestions may result in coma and decreased responsiveness to painful stimuli. Fixed and dilated pupils, diaphoresis, vomiting, hyperthermia, rhabdomyolysis, coagulopathy, and seizures may result.

Euphoria and a distortion of reality usually occur after ingestion of one to five Psilocybe cubensis mushroom caps. In contrast to peyote (discussed later), vomiting is unusual. Larger doses (5–20 P. cubensis mushrooms) produce colorful visual hallucinations. Few adverse reactions occur, and the incidence of bad trips or panic reactions is lower than with LSD. Rarely, seizures, coma, and hyperthermia have been reported after psilocybin use.

Differential Diagnoses

Alcohol, other drugs and mixed ingestion are a possible source of the patient’s symptoms, especially with coma or marked physiologic changes. Cocaine, PCP, amphetamines, and anticholinergic agents should be considered. Acute psychosis and schizophrenic breaks may also appear similar to a psychedelic reaction. Finally, nontoxicologic diagnoses are crucial to rule out, including central nervous system infection, intracranial mass or bleed, and partial complex seizures.

Diagnostic Testing

Often, patients are in a panic or are brought in by a worried companion who may be aware of the use of hallucinogenic substances. A focus on history, especially from collateral information sources, and physical exam are important to make the diagnosis. Most patients require no laboratory testing, but a basic metabolic profile, serum ethanol, and serum glucose levels may be helpful in patients with unclear ingestions, co-ingestants, or underlying psychiatric disorders. Toxicology screening and specific testing for psychedelics is not available in a timely fashion in most clinical settings, and rarely changes management.

Management

Reassurance and supportive care are the cornerstones of management. If patients are a danger to themselves or others, they may need to be sedated with benzodiazepines (see below) or physically restrained temporarily to permit sedation. There is no specific antagonist to the effects of serotonergic agents. Empathetic reassurance in a calm, quiet environment with decreased external stimuli is an effective therapeutic modality. The drug effects typically last for hours, but most patients return to baseline after the acute effects.

Benzodiazepines are the mainstay of treatment for hallucinogenic drug-induced agitation. Diazepam, lorazepam, and midazolam have all been successfully used in this setting. Diazepam can be administered via the intravenous (IV) route in increments of 5 to 10 mg every 5 minutes in adults until sedation is achieved. Diazepam has a rapid onset of action, is easily titratable, and has active metabolites for a sustained effect. Lorazepam, 1 to 2 mg IV every 5 minutes is also an acceptable option. Additional doses of lorazepam or diazepam should be titrated to effect, until the patient is calm and relaxed. There is no true maximum dose of these medications. For an adult patient in whom IV access is not possible because of agitation, intramuscular (IM) midazolam, 5 to 10 mg, can be administered to facilitate subsequent interventions. In all patients, titration of the benzodiazepine is important. The emergency clinician should observe the effects of one dose (usually 5 minutes) before an additional dose is given. After sedation is achieved, the patient should be closely observed to ensure that respiratory status is stable when the peak sedation effect is achieved.

The vast majority of patients with hallucinogen-induced agitation respond clinically to adequate doses of benzodiazepines. Butyrophenone antipsychotic agents, such as haloperidol and droperidol, are rapidly effective and generally safe for drug-induced psychosis or agitation states from other drugs, including cocaine, amphetamines, and phencyclidine (also discussed in Chapter 144, Chapter 150 ). Haloperidol, given 2 to 5 mg IM, may be repeated every 20 to 30 minutes with consideration of other agents after a total of 10 mg. Although not approved for IV use, this route is widely used but may be considered in the psychotic or severely agitated patient with stable vital signs with cardiac monitoring in 5-mg doses to a maximum dose of 15 mg. The recommended sedative dose for droperidol is 2.5 to 5 mg IM. Of note, droperidol has a black box warning from the U.S. Food and Drug Administration (FDA) for QT prolongation and potentially torsade de pointes. However, most reported cases of butyrophenone-induced dysrhythmias have been in individuals receiving large doses for prolonged periods, such as hours to days, or in elderly populations (older than 60 years). These medications lack the respiratory depression potentially caused by other agents and may be beneficial in some cases when rapid sedation is required. For these reasons, the butyrophenones remain effective agents for treatment of more severe hallucinogenic-induced agitation in carefully selected patients.

Disposition

The majority of patients with anxiety or panic reactions can be verbally deescalated, with little clinical intervention. Acutely toxic patients who respond to sedation and do not have complications can be discharged after the acute toxicity stage resolves. We recommend discharging them accompanied by a non-intoxicated, responsible family member or friend. Patients who persist with confused or paranoid behavior should be observed until their mental status returns to baseline. Patients with altered mental status that does not normalize after 8 to 12 hours of observation in the ED, or who present after a massive ingestion with medical complications, require admission to a monitored setting for serial reassessments. Patients with self-destructive behavior or in need of addiction counselling may benefit from psychiatric intervention.

Principles of Toxicity

Dissociative hallucinogens describe a cohort of agents that result in symptoms that include dissociation from the environment that frequently have analgesic and amnestic properties. The agents in the category of dissociative hallucinogens have effects on multiple receptors that result in their unique properties, but the common thread among this group is their activity at the N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor is found on neurons and normally functions as an ion channel that is activated by glutamate or glycine but modulated by various other substances that bind to the receptor. When open, it allows cations to flow into the nerve cell and propagate an impulse. The NMDA receptor in the brain is thought to play an important role in neuronal plasticity and memory. Phencyclidine (PCP) and ketamine are the two main agents included in the class of dissociative hallucinogens, although dextromethorphan and methoxetamine have emerged as drugs of abuse and have some similar symptoms of toxicity. All of these are similar in chemical structure and pharmacologic effects and at least part of their activity is on the NMDA receptor and more specifically as channel blocking agents. Despite being simple molecules, PCP, ketamine, dextromethorphan, and methoxetamine have complex pharmacology that includes activity on the NMDA receptor, dopamine-norepinephrine-serotonin reuptake pump, sigma opioid receptor, and cholinergic receptors. The combination of these pharmacologic effects, duration of the effects, and amount of agent used all contribute to the ultimate presentation and management of these patients.