Anticholinergic Misuse Extends Beyond Traditional Toxicology Boundaries
Misuse of centrally acting anticholinergic medications has moved well beyond isolated case reports. A systematic review published in Biomedicines assembled 48 articles spanning case reports, surveys, and retrospective case series to map how these drugs are being taken outside their intended use, which compounds are most often involved, and what kinds of toxic effects follow. The review focused on benztropine, biperiden, scopolamine, orphenadrine, and benzhexol/trihexyphenidyl (THP), all of which can produce rewarding central effects while also carrying a narrow safety margin when taken in excess.
The signal that emerges is not subtle. Misuse has been documented across multiple settings and appears to involve both deliberate dose escalation and diversion, often in people who are also using illicit substances. Oral ingestion was the predominant route, but the clinical picture was shaped less by route alone than by the size of the exposure and the frequent overlap with other psychoactive drugs. In practical terms, this is exactly the kind of pattern that can obscure diagnosis in emergency care, where anticholinergic toxicity may be mistaken for primary psychiatric agitation, stimulant intoxication, or delirium from another cause.
Benzhexol and Benztropine Dominate the Published Record
Among the 48 included articles, benzhexol/THP accounted for the largest share, with 25 studies, while benztropine appeared in 4. That distribution is clinically meaningful because it points to a recurring misuse pattern centered on drugs with established central nervous system activity, not only peripherally acting antimuscarinic effects. THP and benztropine are both capable of producing euphoria, altered perception, and disinhibition in some users, while simultaneously driving the classic anticholinergic toxidrome when taken in macrodoses.
Macrodosing was a recurring theme. The review recorded large doses taken together with other illicit drugs, including cocaine, a combination that can amplify autonomic instability and complicate bedside assessment. Cocaine-related sympathetic activation can overlap with the anticholinergic syndrome’s tachycardia, agitation, and hyperthermia risk, creating a mixed toxidrome that demands careful medication history-taking rather than assumption-based treatment. In that setting, physical findings such as dry skin, dilated pupils, urinary retention, and ataxia become especially important clues.
The toxidrome was not purely neurologic
The toxic effects extended well beyond confusion or sedation.
Patients described in the literature developed physical signs such as tachycardia, tachypnoea, mydriasis, dry skin, urinary retention, and ataxia, alongside psychiatric manifestations including anxiety, agitation, and delirium. That combination reflects the pharmacology of muscarinic blockade across both peripheral and central pathways. In the brain, acetylcholine supports attention, arousal, and memory; when those circuits are disrupted, agitation can evolve into frank delirium. In the periphery, glandular suppression, impaired detrusor contraction, and reduced gastrointestinal motility create the familiar anticholinergic exam findings that often distinguish this syndrome from other forms of intoxication.
Polysubstance Use Complicates Recognition at the Bedside
The co-occurrence of anticholinergic misuse with cocaine and other illicit drugs raises the stakes for acute care. Mixed intoxication can blur the clinical picture, especially when patients present with behavioral disturbance rather than a clear overdose history. In these cases, anticholinergic toxicity may be underrecognized until urinary retention, abnormal pupils, or escalating delirium forces reconsideration of the differential diagnosis.
This is where toxicology knowledge becomes operational. Centrally acting anticholinergics are not benign adjuncts; they are medications with cognitive effects that can become reinforcing at higher doses and dangerous when combined with other substances. A patient who arrives anxious and agitated after taking THP or benztropine may not volunteer the exposure, and the clinical team may only later discover that the presentation is consistent with a deliberate misuse pattern rather than an accidental side effect. The review’s dataset supports exactly that concern: misuse is not restricted to one country, one drug, or one route.
Fatal outcomes were rare, but they did occur. Even without frequent death, the presence of severe toxicity matters because anticholinergic delirium can require prolonged observation, repeated reassessment, and treatment for complications such as urinary retention or cardiovascular instability. The rarity of fatality should not be mistaken for low clinical relevance; recurrent toxicity can still generate substantial emergency department utilization and significant patient harm.
Signals for Clinicians, Poison Centers, and Prescribers
The review points to a straightforward clinical responsibility: keep anticholinergic misuse on the radar when evaluating unexplained delirium, agitation, or mixed intoxication. Because these medications are often prescribed for neurologic or extrapyramidal symptoms, opportunities for diversion or intentional overuse may arise in routine outpatient care. Prescribers who use benztropine, THP, or similar agents should remain alert to requests for early refills, escalating dose demands, or reports of lost medication, especially when the patient has a substance use history.
A second responsibility lies in bedside pattern recognition. Dry skin, mydriasis, urinary retention, tachycardia, and delirium together suggest a pharmacologic syndrome rather than a primary psychiatric disorder. The diagnosis becomes more likely when the presentation includes oral macrodoses or concurrent stimulant use. Toxicology consultation, medication reconciliation, and targeted questioning about nonprescribed use can change management quickly, particularly when patients are too delirious to offer a reliable account.
The literature base is not built on randomized trials or large prospective cohorts, and that limits any attempt to quantify incidence or comparative risk across individual drugs. Still, the aggregate evidence is strong enough to show a consistent pattern of misuse, a recognizable toxidrome, and rare but real severe outcomes. In a setting where centrally acting anticholinergics remain available and sometimes underappreciated, vigilance is not optional; it is part of routine toxicologic care.