Misuse of Anticholinergic Medications: A Systematic Review

(1) Background: Over the last decade, misuse and diversion of medications has appeared to be increasingly concerning phenomena, including a range of different molecules. As current knowledge on the abuse of centrally acting anticholinergics is limited, the aim of the present study is to review the relevant published data, focusing on the following molecules: benztropine, biperiden, scopolamine, orphenadrine, and benzhexol/trihexyphenidyl (THP). (2) Methods: A systematic literature review was carried out using Pubmed, Scopus, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Research methods were registered on PROSPERO (CRD42021257293). (3) Results: A total of 48 articles, including case reports, surveys, and retrospective case series analyses, were included. Most articles focused on benzhexol/THP (n = 25), and benztropine (n = 4). The routes of administration were mostly oral, and macrodoses together concomitant illicit drugs, e.g., cocaine, have been recorded. Toxidromes included both physical (e.g., tachycardia, tachypnoea, dilatated pupils, dry skin, urinary retention, ataxia, etc.) and psychiatric symptoms (e.g., anxiety, agitation, delirium, etc.). Fatal outcomes were very rare but reported. (4) Conclusion: Results from the present study show that anticholinergic misusing issues are both widespread worldwide and popular. Considering the potential adverse effects associated, healthcare professionals should be vigilant and monitor eventual misusing issues.


Abiuse of Medications
The use of medications for purposes other than medical, such as recreational or enhancement purposes, refers to an increasingly reported phenomenon, known as "pharming", defining the non-medical use of prescription (e.g., pain relievers, tranquilizers, stimulants, sedatives, etc.) and over-the-counter (OTC) drugs (e.g., loperamide, promethazine, antitussive cough syrups, etc.), either on their own or in combination with other licit or illicit substances [1] and outside of accepted medical guidelines [2]. In the past decades, among prescription drugs recorded, several anticholinergic drugs, known anecdotally to be misused or already reported through literature by online drug user websites and fora, have emerged as abused and diverted [1][2][3].

Abuse of Anticholinergic Medications
The widespread use of anticholinergic agents has been mostly related to their use to alleviate extrapyramidal symptoms in patients receiving neuroleptics for psychosis since the 1960s. However, although the new generation of atypical neuroleptics available is relatively safe on this point of view, anticholinergics are still widely prescribed. Data regarding the prevalence of anticholinergic abuse in the general population are poor, and most prevalence studies refer to mentally ill subjects. Regarding the abuse of anticholinergics in the psychiatric population, it varies widely, going from levels of abuse as high as 34% [4] to only 6.5% [5]. Moreover, data might suffer from the possibility of underdiagnosis, as anticholinergic intoxication might often be mistaken for manifestations of primary psychiatric disorders or other organic diseases [3]. Data drawn from the Norwegian Prescription Database recorded the main consumers of anticholinergic antiparkinsonian drugs were patients using antipsychotic medication, outnumbering patients suffering from Parkinson's disease by more than 20 to 1. In this study, although the abuse of benzodiazepine tranquilizers was also recorded among patients using antipsychotics, there were no clear indications of abuse of anticholinergics, even among patients who were strongly suspected of abusing benzodiazepines [6]. A case series collecting a number of 40 abusers of anticholinergic drugs attending Oxford hospitals between 1980 and 1982 reported that 28 of them were psychiatric patients on treatment with neuroleptics [7]. Similarly, an American editorial alerted on the abuse of anticholinergic agents, routinely used in psychiatry to treat the extrapyramidal side effects of antipsychotic medications in Jacksonville, Florida, causing an increasing number of evaluations of subjects with chronic mental illnesses in the Emergency Departments on a daily basis [8]. Despite the above-mentioned studies, poor information is available on the abuse of anticholinergic agents, and in most cases, they are partial or limited to case reports/series.
Aims of the study: The current review aimed at: (i) systematically studying the current literature on the misuse of some anticholinergic drugs, including the following molecules: scopolamine, benztropine, biperiden, orphenadrine, and benzhexol/trihexyphenidyl (THP); (ii) describing patterns of anticholinergics' misuse and eventual related toxicity symptoms; and (iii) better understanding the psychotropic molecular mechanisms underlying their recreational use.
The systematic review was structured in accordance with the PRISMA [9,10] and PROSPERO [11] guidelines. Identified studies were assessed at the title/abstract and full-text screening against eligibility criteria.

Data Synthesis Strategy
Data were extracted by n = 3 investigators (AM, AM, GM/ Gianluca Mancusi, and MCS) supervised by SC and MP; doubtful cases were discussed by the professors GM (Giovanni Martinotti), MdG, and FS. The exclusion criteria were the following: (1) nonoriginal research (e.g., review, commentary, editorial, and book chapter); (2) non-fulltext articles (e.g., meeting abstract); (3) language other than English; (4) animal/in vitro studies; (5) articles not dealing with the misuse of anticholinergic drugs; (6) articles without anticholinergic drugs misuse symptoms reported. Removing duplicate articles (n = 294) from a total of 1338 papers (PubMed = 200; Scopus = 611; WoS = 527), 1042 records have been screened, and among these, some 850 were not relevant to the subject as they were not dealing with the misuse of anticholinergic drugs, including articles focusing on the misuse of antihistamine drugs with anticholinergic effects and the misuse of datura alkaloids, articles without anticholinergic drug misuse symptoms reported, a number of 99 were not written in English, and 22 were non-original articles (e.g., review, metanalysis, commentary, letter to the editor without data available, and book chapter). Of the 71 fulltext articles assessed for eligibility, 23 did not match the inclusion criteria for our review. Finally, 48 articles were included ( Figure 1). All these research methods were approved by PROSPERO (identification code CRD42021257293).

Biperiden
Two case reports dealt with biperiden misuse in two adult males [45,46]. One of them had no psychiatric comorbidity but had suffered withdrawal syndrome symptoms after discontinuation of the drug [45], while the other suffered from chronic psychosis [46]. The substance was taken orally in one case [45], while in the other intramuscularly at a dosage of 120 mg [46]. One case reported a mild confusional state with spatio-temporal disorientation and psychomotor agitation after the concomitant abuse of THP, cocaine, alcohol, and cannabis was recorded [45]. Elevated hepatic function tests have been reported [46].

Dicyclomine
Dicyclomine was addressed by two case reports [47,48], one involving a 30-yearold male [47] and the other an 18-year-old female [48]. In one case, the misuse was oral at a dose of 50-75 mg/day and concomitant with mefenamic acid [47]; in the other, the misuse was intramuscular [48]. Both studies described withdrawal symptoms with anxiety after drug discontinuation [47,48]; one case also reported depression, anorexia, and confusion [48]. Regarding physical symptoms, in both articles, palpitations, sweating, tachycardia, weakness, blurred vision, and dry skin were recorded [47,48]. Finally, both recorded the treatment done, which consisted of fluoxetine and clonazepam [47] and physostigmine [48].

Orphenadrine
Both studies describing the abuse of orphenadrine were case reports respectively related to a 26-year-old female diagnosed with psychosis [49] and a 24-year-old male with a diagnosis of SUD (amphetamines and cocaine abuse) [50]. In both cases, macrodoses have been reported, up to 1250-1500 mg [50], and symptomatology described included psychotic symptoms with visual hallucinations and mystic-megalomanic delusion, hypomania, agitation, and aggressivity. Physical symptoms included dry and warm skin, mydriasis, asymmetrical abdominal reflexes [49], dizziness, and tremor [50].

Tropicamide
Two articles were related to tropicamide abuse together with other substances, e.g., heroin, benzodiazepines, ecstasy, and cannabis, in three adult subjects [51,52]; interestingly, both described an intravenous route of administration and recorded the following psychiatric symptomatology: relief, euphoria and relaxation [51,52], and hallucinations and dissociation [44,45]. Regarding the treatments adopted, naloxone was administered when tropicamide had been used together with heroin [51]; diazepam and quetiapine were also recorded as long-term treatment [51,52].

Glycopyrronium Tosylate
Only an article reported on the misuse of glycopyrronium tosylate. It was a case report focusing on a 14-year-old female subject diagnosed with ADHD and acne vulgaris who topically took an excessive amount of glycopyrronium tosylate, showing myopia, dry mouth and anhidrosis, urinary hesitancy, and chronic constipation [53].

Oxybutynin
A case series reported on the oxybutynin misuse in two male subjects aged 27 and 45 years, both diagnosed with a SUD, who orally took 100-150 mg/day and 300-400 mg/day of the drug, respectively [54].

Procyclidine
A case report dealt with procyclidine abuse in a 36-year-old male subject diagnosed with an antisocial personality disorder, who orally took 40 mg of the drug together with physeptone ® (methadone) and alcohol, showing disinhibition, mania, and aggressiveness [56].

Unspecified Anticholinergic Drugs
Finally, a controlled prospective study reported on the abuse of unspecified anticholinergic drugs [57] in 21 subjects (M/F = 14/7) with a mean age of 33.6 ± 6.1, suffering from psychiatric diagnoses, e.g., mood disorder, schizophrenia, schizoaffective disorder, and schizophreniform disorder, and requiring an antipsychotic treatment, who reported effects of relaxation, elevated mood and energy, reduced concentration, visual and auditory hal-lucinations, confusion, and the physical symptoms such as dehydrated skin, tachycardia, blurred vision, and thirst.

Discussion
To the best of our knowledge, this work constitutes the first review investigating the diversion and abuse of anticholinergic drugs. These medications block the muscarinic acetylcholine receptor and are usually prescribed for their parasympatholytic effect. Indeed, the effects of inhibition of dopaminergic neurons are normally balanced by the excitatory actions of cholinergic neurons; thus, if dopamine receptors are blocked by antipsychotics, a relative excess of cholinergic activity is caused, resulting in extrapyramidal motor effects, which can be balanced by its block trough anticholinergic agents [58]. On the other hand, anticholinergic drugs also act as a potent indirect dopamine agonist in the limbic system, which can in part explain their misuse potential in both psychiatric and non-psychiatric patients [58,59]. Common anticholinergic agents, such as benztropine, benzhexol/THP, cyclobenzaprine, orphenadrine, and scopolamine, are used for the treatment of both primary and secondary parkinsonism, bradycardia, asthma and chronic obstructive pulmonary disease, dystonia, urinary incontinence, muscle cramps, nausea, and emesis. Moreover, these agents are also frequently seen in the medical setting as instruments of both accidental and intentional overdose [3]. In the present study, they were widely used to treat extrapyramidal motor symptoms caused by antipsychotic drugs or other molecules resulting with antidopaminergic effects [60] and then abused to reach a psychotropic effect, e.g., to abolish neuroleptic-induced anhedonia; conversely, patients might have hypothetically taken more than the recommended dose of anticholinergics in an attempt to treat the adverse effects resulting from the use of antipsychotics [60]. Although muscarinic acetylcholine receptors exist as five subtypes, each with specific characteristics and effects, e.g., M1 subtypes are located on central nervous system (CNS) neurons and sympathetic post-ganglionic cell bodies; M2 receptors are located in the myocardium, smooth muscle organs, and neuronal sites; the M3 muscarinic subtypes receptors are the most common on parasympathetic target tissues, such as in smooth muscle and glandular cells) [59]; finally, the majority of anticholinergic drugs available as medications are non-specific in terms of which receptor subtypes they target, then explaining the rich symptomatology associated with their diversion [61], specifically referring to the psychiatric symptoms resulting from their misuse. In fact, in cases of medication-induced delirium, health care professionals should take into account the possibility of anticholinergic drugs misuse. Indeed, anticholinergic drugs might be abused at clinically and epidemiologically significant levels for their psychotropic effects [3], e.g., to achieve a high or euphoria, to elevate energy and mood, to increase social interaction, or to induce an anticholinergic toxic syndrome, which may feature disorientation, hallucinations, paranoia, and confusion [12,24,28]. These clinical symptoms may configure forms of exogenous psychosis, also with chronic developments [62].
Our review confirmed previous literature identifying benzexhol/THP as the mostoften abused anticholinergic. This might be related to its greater psychotropic (e.g., stimulatory and euphorigenic) effects [3,4,12,58]. Benztropine and biperiden have also been shown to induce euphoria, owning an abuse potential, albeit less than those of benzexhol/THP [3]. However, benzexhol/THP, benztropine, and biperiden are among the wider available anticholinergics, with differences in the regional diffusion depending on regulatory issues, medicine supply, their promotion and prescription by health care providers, and access to them. These factors may have an influence and increase the base of possible users by encouraging the development of phenomena of abuse.
In most cases, due to its relevant symptomatology, anticholinergic intoxication is often seen and treated in emergency settings. In fact, toxicity symptoms might include dry mouth and mucosal surfaces, mydriasis, decreased bowel sounds, hot and flushed skin, urinary retention, constipation, and agitation, emerge within an hour of ingestion of an acute overdose, and were recorded by almost all studies retrieved. Moreover, tachycardia, hypertension, tachypnoea, and fever are in most cases described, although in severe overdose, hypotension, life-threatening arrhythmias (e.g., supraventricular tachycardias), severe heart blocks, and respiratory depression may occur. Neurological and psychiatric symptoms might include drowsiness, sedation, ataxia, amnesia, and finally coma; and paranoia, hallucinations, delirium, and confusion [1,3]. The diagnosis of anticholinergic intoxication is typically based on the clinical symptomatology presented; moreover, the intravenous use of an acetylcholinesterase inhibitor such as physostigmine can be used as both a diagnostic and a therapeutic intervention [12]. Here, toxicity symptoms are explainable through the pharmacological drug effects related to the antimuscarinic action of the index drug at each target tissue. However, the psychotropic, e.g., euphoric, stimulatory, and antidepressant effects of anticholinergic drugs should still be clarified. From the current findings, both the euphoric and toxic effects are dose-dependent, but it was not possible to understand the eventual threshold dosages related to each drug due to the possibility of personal variations and idiosyncratic reactions related to the use of concomitant drugs and unusual routes of administration [12]. Finally, the chronic use was here related to tolerance and withdrawal phenomena, possibly related to the reinforcing effect of abused drugs on the mesolimbic dopaminergic system, including the ventral tegmental area, the nucleus accumbens, and the prefrontal cortex [58]. Therefore, the rapid discontinuation of an anticholinergic drug was here associated with a withdrawal syndrome characterized by the symptoms including increased anxiety, insomnia, restlessness, sweating, irritability, headache, and tachycardia [16][17][18][25][26][27]30,45]. Moreover, apart from the physical symptomatology, when the drug is withdrawn, abusers might also experience a psychological dependence together with craving, which generally resolve in two weeks [25].
Studies here retrieved have shown that anticholinergic abusers are mostly young, male, single, and, when recorded, unemployed or marginalized, as previously described by the literature [31]. Moreover, anticholinergic drugs are often figured in polydrug abuse since they have been possibly used to potentiate the effects of other psychoactive substances, including alcohol, cocaine, benzodiazepines, and opioids [5,12,17,24,25,[28][29][30][31]34,35,[40][41][42]44,45,51,52,63]. Indeed, regarding the abuse of anticholinergic medications, three distinct groups of abusers have been previously described [64]: (i) individuals who consume a medication only for its psychotropic and mind-altering effects; (ii) individuals with a medical indication for the use of, e.g., an anticholinergic drug, who might eventually abuse or misuse it for its psychotropic effects; and finally, (iii) individuals who have an appropriate medical indication for the agent and use it according to medical guidelines. Moreover, misusers/abusers might also be recognized because they might exaggerate extrapyramidal symptoms, repeatedly request unnecessary dose increases, or perform doctor shopping practices. In the present review, although in two studies, patients faked extrapyramidal symptoms in order to obtain a prescription for the drug of interest [19,24], sources of the drugs were in all cases licit prescriptions and could then be included in the second group. Accordingly, the European Monitoring Center for Drugs and Drug Addictions (ECMDDA) [2] described the diversion of prescription medicines as one of the new main sources of medicines on the illicit market due to the unsanctioned supply of regulated pharmaceuticals from legal sources, either to the illicit drug market or to a user for whom the drugs were not intended. The EMCDDA also alerted on the increasing online availability of medicines, not only from online licit pharmacies, marketplaces, or suppliers.
Limitations: One of the limitations regarding the literature focusing on prescription drug misuse is both its heterogeneity and the issues in identifying misusing practices. In this regard, considering the United Nations Office on Drugs and Crime (UNODC) definition of misuse of medicines, it could be described as "the problematic consumption outside of acceptable medical practice or medical guidelines, when self-medicating at higher doses and for longer than is advisable, for intoxicating purposes and when risks and adverse consequences outweigh the benefit" [65][66][67]. However, the terminology used in the studies might be variable and inconsistent [3]; thus, in this study, we use misuse as referred to non-medical use, problem use, harmful use, recreational use, self-medication, or inappropriate use, which calls into question whether there is a consensus on the negative consequences (i.e., problem, harm) of their use. Moreover, given the novelty of the topic, the scarcity of articles focusing on the issue should be considered another limitation of the present study. For sure, the heterogeneity of studies recorded, mostly represented by case reports/case series of clinical assessments, interventions, and outcomes, was another important limitation. Moreover, the duration of the studies analyzed and the consequent absence of follow-up evaluations carried out at a distance of time was another limitation of studies retrieved.

Conclusions
Despite the limitations of the study, the abuse of prescription drugs and medications has rapidly risen, threatening to overtake illicit drugs as the most commonly abused substances. In the present challenging drug scenario, including prescription drugs and medications in general, anticholinergic drugs as substances of abuse should be monitored. Healthcare professionals should be vigilant and prevent possible medicines' misuse and diversion.