Perioperative Considerations for Patients Exposed to Hallucinogens

Abstract

Hallucinogen exposure in patients in the perioperative period presents challenges for anesthesiologists and other anesthesia providers. Acute and chronic exposure to these substances can cause physiological impacts that can affect the function of anesthetic and analgesic medications used during perioperative care. The objective of this narrative review is to educate readers on the wide array of hallucinogens and psychedelics that may influence the perioperative management of patients exposed to these substances. A narrative review of the literature surrounding hallucinogens and psychedelics was completed. Hallucinogens and psychedelics are quite varied in their mechanisms of action and therefore present a variety of perioperative implications and perioperative considerations. Many of these substances increase serotonin levels or act directly at serotonergic receptors. However, there are other relevant actions that may include varied mechanisms from NMDA receptor antagonism to stimulation of muscarinic receptors. With hallucinogen exposure rates on the rise, understanding the effects of hallucinogens is important for optimizing management and reducing risks perioperatively for patients with acute or chronic exposure.

Introduction

Hallucinogen use in the general population is growing and becoming more common, with estimated lifetime prevalence rates of approximately 9%. [1]. In 2021 8% of young adults reported using hallucinogens, up from 5% in 2016 and 3% in 2011 [2]. Recent estimates suggest that hallucinogen use increased over 40% from 2015-2020 for people over the age of 12 in the United States with over 7.1 million people using hallucinogens in the previous year as of 2020 (Figure 1) [3]. There is certainly a renewed interest in the therapeutic benefits of drugs commonly classified as hallucinogens [4]. The recent local decriminalization of some hallucinogens such as psilocybin and other entheogenic plants in the United States will likely increase interest, availability and therefore non-medical use [3, 5, 6].

Figure 1. Hallucinogen Use Graph in Patient > 12 Years of Age from 2015 to 2019.

Increase in Hallucinogen Use. Percent of people in the United States reporting using hallucinogens from 2015-2019. The percentage of the population using hallucinogens remains low. However, there continues to be a gradual rise in use of hallucinogens from 4.7 million in 2015 to 6 million in 2019 and this increase is likely to continue. Adapted from [3].

Given the high prevalence of hallucinogen exposure, it is important for health care providers and anesthesiologists to recognize clinical symptoms of chronic and acute hallucinogen use in surgical patients. Effective and safe perioperative management of these patients relies on understanding anesthetic implications of hallucinogen use, as side effects and pharmacological interactions have an impact on patient outcomes. Herein we will review the pharmacology of substances in this class as well as clinical considerations during the perioperative period.

Clinicians often rely on the detection of substances to guide clinical care. Rapid urine drug screen tests are the foundation of determining the presence or absence of many drugs in patients presenting to the hospital. However, perioperative providers may not be aware of the limitations of these urine screens. These tests are useful for detecting amphetamines, 3,4-methylenedioxy-methamphetamine (MDMA), ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), tetrahydrocannabinol (THC), and opioids [7, 8]. However, there is no rapid clinical test to validate the presence or absence of many hallucinogens. Furthermore, it is difficult to determine the presence of many of the novel synthetic compounds as the structures are changing rapidly [9].

Given the lack of detection of many hallucinogens, the clinical suspicion of acute intoxicated with hallucinogens must be based on history and clinical assessment of signs and symptoms related to the effects of these substances. This is even more important given the number of drugs that are not a part of the standard screening panel and the rapidly increasing presence of novel unknown compounds. Similar to recently published guidelines on medical cannabis in the perioperative period [10], a verbal screening of all perioperative patients for the use of hallucinogens is reasonable given the increased prevalence of hallucinogen use.

Hallucinogens

The dominant effects of drugs in this group are an altered perception of time and space or a dissociation from the environment and its perceived physiologic stimuli. These effects can include hallucinations as well as altered or enhanced imagination and magnified or blunted sensory perception that can include tactile, temperature, visual, taste, auditory and gustatory perceptual derangements (Table 1). Ingestion of this class of drugs activates the sympathetic nervous system resulting in tachycardia, hypertension, dilated pupils, and increased body temperature [11, 12]. The effects typically last approximately 12 hours [11, 12]. One side effect of hallucinogens can be serotonin syndrome. It should be considered in patients with hallucinogen exposure and signs of autonomic instability, increased temperature, and neuromuscular changes [13, 14]. Another rare but noteworthy side effect to hallucinogens is the hallucinogen persisting perception disorder (HPPD), which is a repeated hallucinogenic experience that may mimic a prior intoxication despite no additional use of the substance [15].

Table 1.

Classification of Hallucinogens with Summary of Action and Side Effects

Sub-Categories	Example	Principle Mechanism of Action	Other actions	Specific adverse effects	Shared common adverse effects
Psychedelics (LSD-like)	Lysergic acid diethylamide or LSD (Lysergamines (Indolealkylamines))	5HT2a receptor partial agonist	Increase Glutamate, May increase release of serotonin and inhibit reuptake, Bind adrenergic, dopaminergic, and histamine receptors and inhibit transporters	Thermoregulatory instability, cardiovascular instability, Nystagmus, exhaustion	Serotonin syndrome Nausea and vomiting Hallucinations Mydriasis Confusion Agitation Anxiety Hyperreflexia Hypertension Tachycardia Hyperthermia Drowsiness
	Dimethyltryptamine and derivatives (mushroom origin psylocibin and psilocin and ayahuasca related) (Tryptamines)	5HT2 receptor agonist	Increase Glutamate, May increase release of serotonin and inhibit reuptake, Bind adrenergic, dopaminergic, and histamine receptors and inhibit transporters Ultrapotent Serotonin agonists	Prolonged delusions, rhabdomyolysis, nausea/vomiting, diarrhea, serotonin syndrome; botanical tryptamines may be mixed with monoamine oxidase inhibitors (MAO-I) to increase duration of action
	Synthetic NBOMe derivatives (Phenylalkylamines Phenethylamines and derivatives)			Seizures, Serotonin syndrome violent behavior, rhabdomyolysis, excited delirium
	Mescaline (Phenethylamines and derivatives)		Increase release and inhibit reuptake of serotonin; limited dopaminergic activity	Seizures, Serotonin Syndrome, nausea, vomiting
Dissociative (ketamine-like)	Ketamine and PCP and early derivatives	NMDA receptor antagonists	Dopamine transporter inhibitor, muscarinic agonists, 5HT2 agonists, altered monoamine metabolism	Catatonic stupor, amnesia, analgesia	Nausea, diaphoresis, hypertension, tachycardia, agitation, disorientation, slurred speech, confusion, nystagmus, amnesia, hallucination, ataxia, muscle rigidity, rhabdomyolysis, kidney and bladder dysfunction, memory deficit
Deliriants (Scopolamine-like)	Scopolamine and diphenhydramine (Tropane alkaloids and derivatives)	Muscarinic and histamine antagonist		Delirium, dizziness, blurred vision,	Tachycardia, agitation, dry mouth, dry skin, mydriasis, photophobia, constipation, urinary retention

The hallucinogens can be categorized based on the principal perceived mental or physiologic effects (Table 1)[16–20]. The categories based on dominant effect are altered perception (the psychedelics or LSD-like drugs), dissociation from the environment (dissociative drugs or ketamine-like drugs) and production of delirium (the deliriant drugs or scopolamine-like drugs) [16–20].

The differences in the generalized pharmacologic effects of the hallucinogens largely fall along the same lines as the classification based on the dominant mental and physiologic effects. Many psychedelic substances act primarily as 5-HT_2A receptor agonists [21]. However, they also have activity at numerous receptor types including adrenergic, dopaminergic, histaminergic, and even muscarinic receptors, as well as variable effects at neurotransmitter transporters [22]. The dissociative class acts primarily as NMDA inhibitors. However just like the psychedelics, this class can also have variable dopamine transporter inhibition, 5-HT₂ agonism, and altered monoamine metabolism [23–25]. Lastly, the substances in the deliriant class act as muscarinic and histamine antagonists [26].

There are many drugs that can produce hallucinations as secondary effects and will not be addressed here; these include opioids or drugs that produce effects through the opioid receptors, cannabinoids, and many depressants. We herein focus on substances that have a primary effect of producing hallucinations or dissociation. In addressing the hallucinogens, the antimuscarinic and antihistaminergic, so called “deliriants,” have been included in the table as they are considered hallucinogens and are familiar and routinely encountered by anesthesia providers [26]. These drugs predominantly produce undesirable effects that, although they may be psychedelic in nature, are unpleasant and resemble psychosis or delirium. Therefore, repeated use is infrequent and substance use disorders for these compounds is rare. Additionally, these drugs and similar derivatives are commonly used in multimodal anesthesia, and anesthesiologists are well acquainted with their effects in the perioperative period. Nevertheless, it is good to recall that these drugs can produce unpleasant and hallucinogenic effects that should be considered during their use.

Psychedelics:

Generally, this diverse class of substances can cause a myriad of symptoms including a distorted sense of time, magnified sensory experiences, hallucinations, tachycardia, and nausea [27]. Temporary anxiety, increased blood pressure, and headaches are also common features of substances in this class [28]. As is common with other hallucinogens, substances within the class of psychedelics present a risk of serotonin syndrome[13]. Furthermore, substances within this class are often considered to cause less severe physiologic changes compared to other substances of abuse [29]. These substances do not traditionally manifest symptoms of dependence and withdrawal [29],[30]. This is shown by a number of early experiments showing that classic psychedelics lack reinforcing properties, which supports the conclusion that these drugs do not cause dependence or addiction [31].

Anatomically, inhibition of the amygdala creates many of the psychological clinical effects of psychedelics and explains its potential benefit in clinical conditions such as depression and anxiety [28],[32, 33]. In fact, multiple psychedelics have been studied as therapeutics for depression, anxiety, and other psychiatric conditions. For example, LSD has also been shown to produce meaningful improvements in mood symptoms in specific patient populations, such as patients with substance use disorder or cancer diagnoses [34],[35]. Psilocybin, in the class of tryptamines, has more recently undergone clinical studies for treatment of alcohol dependence, cancer related anxiety, tobacco use disorder, and obsessive-compulsive disorder [36, 37]. Ayahuasca, also in the tryptamine class, has been studied as a potential therapy for substance dependence and PTSD [38].

LSD (Lysergic Acid Diethylamide)

LSD is a substance without taste or odor, and it is derived from ergot, a rye fungus [39]. Ergot alkaloids with LSD-like effects are also found in morning glory seeds [40]. It acts at the 5-HT2A receptor as a partial agonist and 5-HT1A as an agonist [41]. LSD causes a number of sympathetic and parasympathetic manifestations including increase in heart rate, blood pressure, perspiration, salivation, core temperature, and blood glucose levels. Pupillary dilation is also seen. LSD can be seen in urine specimens obtained within 96 hours after last use, and medications such as amitriptyline and sumatriptan can result in false positives [8]. On rare occasions, LSD can lead to seizures and apnea [11].

Tryptamines

Tryptamines are a group of hallucinogenic compounds that share a similar basic molecular structure as serotonin and are formed through decarboxylation of tryptophan [37]. Two of the more common substances in this class are psilocybin and ayahuasca. As with other substances in this class, the mechanism is mainly via 5-HT_2A receptors [36]. Psilocybin induces minimal changes in physiological parameters or lab values, although a smaller degree of secondary sympathomimetic signs can be observed [42]. Ayahuasca is a plant brew used in holistic medicine as well as spiritual and cultural rituals in South America [43]. It includes two plant strains which together contain N,N-dimethyltryptamine (DMT) and β-carbolines, which prevent the deamination of DMT [43]. Additionally, the β-carbolines reversibly inhibit the A-type isoenzyme of the monoamine oxidase and inhibit reuptake of serotonin [38]. However, the main mechanism of the psychedelic effect of this class is again due to 5HT2A agonism [38, 43]. Ayahuasca consumption produces an intense state of altered consciousness that can include changes in perception of reality, reliving and resurfacing of repressed emotional memories, and visuals of the “ayahuasca world” which can include spiritual guides, power animals, “ayahuasca beings” that are said to guide self-reflection and support personal growth [38]. This state of being lasts on average about 4 hours [38].

NBOMe Derivatives (NBOMes)

NBOMes (or 25X-NBOMe), short for N-(2-methoxybenzyl) phenethylamines, are the newest class of synthetic psychedelics that are ultrapotent and highly efficacious 5HTA receptor agonists [44]. These substances are a novel alternative to LSD. Like cathinones, this class of substances often is labeled as a “research chemical” or “not for human consumption” to skirt the Controlled Substance Analogue Enforcement Act [19, 45]. In addition to hallucinogenic properties, one potent NBOMe, 25B-NBOMe, has been found to activate reward pathways and the dopaminergic system and therefore has heightened abuse potential [46]. Furthermore, 25I-NBOMe has activity at the 5HT2A receptor, but also is an alpha-adrenergic agonist [47]. NBOMes appeared on the scene for recreational use around 2012 with an explosion of compounds occurring over the last decade. Both the desired psychoactive effects and adverse cardiovascular and neurologic effects are consistent with other drugs in this class of psychedelics. The difference seems to be in the intensity and frequency of severe adverse effects including seizures, rhabdomyolysis, renal failure and even death.

Mescaline

Mescaline is a naturally occurring hallucinogen that is found in several species of cacti [48]. Some of these cacti have long been used by Central and South American cultures for religious ceremonies [48–51]. The mescaline compound was first synthesized in 1919 [48]. As with other psychedelic substances, mescaline is a 5-HT2A agonist, and it also has some affinity for dopaminergic, histaminergic, and alpha-2 adrenergic receptors [48, 52]. It induces a psychedelic state including euphoria, open and closed eye hallucinations, altered cognitive processes, altered sense of time and self, and possibly paranoia and delusions [48]. Clinically, patients with mescaline exposure will show signs of sympathetic system activation such as hypertension, tachycardia, agitation, and mydriasis [53]. The elimination half-life is around 6 hours [48].

The Dissociatives:

The dissociative class of hallucinogens consists of phencyclidine (PCP) and its derivatives such as ketamine. These substances have a mechanism of action and clinical effects that are well known to anesthesiologists, but are included in this review of hallucinogens for completeness and comparison to the lesser-known substances. These drugs all act as NMDA receptor antagonists. The main effect of this class is a feeling of detachment (or dissociation) from the environment and self, along with distortion of sight and sound perception. Other common effects are nausea, diaphoresis, hypertension, tachycardia, agitation, disorientation, slurred speech, confusion, nystagmus, amnesia, hallucination, ataxia, muscle rigidity, rhabdomyolysis, kidney and bladder dysfunction, and catatonic stupor.

PCP (Phencyclidine)

PCP is a hallucinogen with frequently sought effects of euphoria, hallucination, and illusion of superhuman strength and omnipotence. It is also known as “angel dust” and the acronym PCP comes from its organic name 1-(1-phenylcyclohexyl) piperidine. The term “angel dust” refers to a white crystalline powder form of PCP, but PCP can also present in the form of tablets or liquid also known as “whack”. Its main mechanism of action is NMDA receptor antagonism. However, it has numerous other mechanisms such as a dopaminergic agonist, adrenergic partial agonist, and serotonergic antagonist [39]. It also decreases dopamine and norepinephrine reuptake, whilst also increasing production, leading to dopaminergic and sympathomimetic effects [7]. It was originally used as an anesthetic agent but was soon discontinued for that purpose due to patients experiencing agitation, delirium, psychosis, and hallucinations [7]. Recently it has again emerged as a recreational drug and can be found laced in marijuana [7]. PCP intoxication frequently presets as agitation, nystagmus, tachycardia, hypertension, and diaphoresis [7]. Patients may wax and wane between agitation and sedation as PCP’s many mechanisms of action can produce both stimulating and depressing effects in the CNS [7]. It is known to cause a dissociative state that can also include hallucinations and delirium as well as sympathetic nervous system activation and respiratory depression [39]. In rare cases it has also been shown to induce cardiac arrhythmias and hypertonic muscle activity leading to hyperreflexia, myoclonus, torticollis, or even rhabdomyolysis [7]. This substance, as well as many hallucinogens, have effects that can last upwards of twelve hours after last use [27].

Ketamine

Ketamine is a derivative of PCP and therefore has similar clinical manifestations as those listed above for PCP [39]. Its mechanism involves antagonism of the N-methyl-D-aspartate receptor [27]. Newer compounds such as ephenidine exhibit similar mechanisms of action and have seen a recent uptick in popularity [54]. Acute symptoms of ketamine intoxication include agitation, dissociation, hallucinations, nystagmus, and muscle rigidity [22]. Sympathomimetic signs such as tachycardia and hypertension are also present [22].

Ketamine has recently become a more mainstream substance of abuse and it has seen increased illicit production with cheaper prices which has increased access [55]. Chronic ketamine abuse may also lead to bladder dysfunction, liver dysfunction, ulcerative cystitis, and renal damage [55, 56]. Symptoms of ketamine abuse often include severe abdominal cramps, psychosis, and memory impairment [55]. Withdrawal symptoms of ketamine peak two to four days after last use and consist of sweating, anxiety, and palpitations.

Ketamine is often a useful adjuvant multimodal therapy for the patient presenting with a substance use disorder in the perioperative period [39]. Currently there is no evidence regarding ketamine use intra-operatively in patients with ketamine use disorder and the decision is up to the discretion of the anesthesiologist.

Deliriants/Scopolamine-like Substances:

Although antimuscarinic and scopolamine-like drugs are rarely used recreationally for their hallucinogenic properties, it is possible for patients to develop acute toxicity accidently or unknowingly. Substances within this class are generally well understood by anesthesiologists, but are important to consider in the patient presenting with symptoms of hallucinogen exposure. These drugs lead to anticholinergic syndrome, a prodrome that causes tachycardia, hyperthermia, dry mucous membranes, dilated pupils, urinary retention, and CNS symptoms such as psychosis, hallucinations, and seizures. Severe toxicity may lead to coma [57, 58]. Low dose scopolamine may cause CNS depressive effects such as fatigue, drowsiness, and amnesia. High dose scopolamine and antimuscarinic drugs may lead to CNS stimulation including hallucinations. However, case reports have described anticholinergic toxicity even from recommended doses of over-the-counter medications [58]. This highlights the point that antimuscarinic drugs need to be considered on the differential of hallucination eliciting agents. Anticholinergic properties can be found in antihistamines, antidepressants, antispasmodics, antipsychotics, and antiparkinsonian drugs. Antihistamines have the most risk of anticholinergic side effects [59].

Anesthetic Implications of Hallucinogens

Given the common themes in anesthetic management of hallucinogens, the general anesthetic implications are discussed here. If acute intoxication is suspected in the perioperative period, the safest patient management is detoxication before proceeding with surgery unless the surgery is emergent. Clinical management of toxicity for most hallucinogens consists of administration of fluids according to fluid status, correction of electrolyte derangements, assessment and correction of acid-base disturbances when clinically indicated, and supportive treatment in a safe and monitored environment. Patients with acute intoxication should have a constant bedside presence with a low stimulus environment (if possible) in the perioperative period until symptoms subside. Sedation may be provided with benzodiazepines for aggression or seizures. Antipsychotics may also be needed to treat more aggressive patients. Antipyretics and active cooling may be needed in cases of hyperthermia. Antipsychotics such as chlorpromazine should be avoided as it may lower the seizure threshold, along with other alpha-2 antagonist effects.

Additionally, serotonin syndrome should be considered in patients with signs of autonomic instability, neuromuscular changes, and mental status changes [13, 14]. Serotonergic medications should be avoided. Examples of commonly encountered substances that can cause serotonin syndrome include trazodone, methadone, tramadol, fentanyl, dextromethorphan, St. John’s wort, and methylene blue, in addition to the serotonergic antidepressants [60]. The management of serotonin syndrome is beyond the scope of this review, however it has previously been well described in the literature [60]. Neuroleptic malignant syndrome and malignant hyperthermia should also be included on the differential diagnosis of a patient presenting with possible serotonin syndrome [61].

If surgery is emergent and crucial to proceed, it is important to note that anesthesia may precipitate a panic response in a patient under the effect of a hallucinogen and that the provider should be prepared to treat the response appropriately [11, 12]. Additionally, these patient can have exaggerated responses to sympathomimetic drugs, such as ephedrine, due to the increased sympathetic activation from hallucinogen intoxication [11]. The ventilatory depressant effects of opioids may also be prolonged by hallucinogens [11].

There are a few treatments that are specific to the hallucinogen used. In psychedelic or acute ketamine intoxication, agitation can be treated with diazepam or anti-psychotics such as haloperidol [27] [11]. On the other hand, risperidone should be avoided in LSD intoxication as cases have described return of LSD hallucinations after receiving risperidone [62]. In botanical tryptamine intoxication, monoamine oxidase inhibitors should be avoided as they can extend the half-life of botanical tryptamines [43, 63]. LSD and PCP are presumed to inhibit plasma cholinesterases and can theoretically prolong succinylcholine duration [11, 12]. In cases of scopolamine-like drug intoxication, an acetylcholinesterase inhibitor can be used as a reversal agent [59]. This is the only class of hallucinogens that has an available reversal agent.

Discussion

Hallucinogen exposure in patients presents a variety of perioperative clinical challenges for the anesthesiologist and the surgical team. Most often, the history is unable to be provided by the patient and many of these substances are undetectable on toxicology screens. Therefore, the diagnosis needs to be made based on the clinical presentation. Given the increasing prevalence of use and a growing array of novel hallucinogens, these substances are now more likely than ever to be encountered in the perioperative period. However, these substances may be easily overlooked or misdiagnosed in the perioperative period without verbal screening and a thorough understanding of their clinical signs and symptoms. The manifestations of hallucinogen exposure may result in relatively benign alterations in the sensorium to severe perioperative morbidity and mortality as well as the delayed diagnosis of potential life-threatening conditions which would parallel a delay in the corresponding therapeutic management. In some cases, the exposed patient will need supportive management such as caring for them in a low stimulus environment, administration of fluids if appropriate, and administration of benzodiazepines for treatment of anxiety or aggression. Medications that will exacerbate symptoms or increase risk of serotonin syndrome need to be avoided. The anesthetic implications of hallucinogen use are further summarized in Table 2 for ease of reference.

Table 2.

Anesthetic Implications of Hallucinogens

Supportive treatment is most common (fluids, electrolyte, acid-base balance)

Serotonin syndrome risk exists

Benzodiazepines are useful for anxiety or aggression

Antipsychotics may be needed

Antipyretics and active cooling mechanisms may be needed

No specific antidotes exist (other than cholinesterase inhibitors for the scopolamine-like category)

It is important for the anesthesia team to be familiar with hallucinogenic substances, their mechanism of action, clinical presentation and effects, and possible interactions with other drugs. This knowledge is key to manage patients with hallucinogenic exposure intra-operatively if surgery needs to proceed emergently. Unfortunately, except for the scopolamine-like drug class, no antidotes exist for hallucinogenic substances and generally time is needed for metabolization. Additionally, after the patient has been safely taken through the perioperative period it is important to think of the long-term management of hallucinogen misuse. Anesthesiologists should be prepared to engage the patient in discussion regarding their substance use, assess willingness to terminate substance use, and refer to a treatment center if applicable.

Abbreviations:

5HT2A

5-hydroxytryptamine (serotonin) 2A

CNS

Central nervous system

DMT

N,N-dimethyltryptamine

HPPD

Hallucinogen persisting perception disorder

LSD

Lysergic acid diethylamide

NBOMes

N-(2-methoxybenzyl) phenethylamines

NMDA

N-methyl-D-aspartate

MDMA

3,4-methylenedioxy-methamphetamine

PCP

Phencyclidine

PTSD

Post-traumatic stress disorder

THC

Tetrahydrocannabinol

MAO-I

monoamine oxidase inhibitors

Availability of data and materials:

Not applicable