Perioperative Considerations for Patients Exposed to Psychostimulants

Abstract

Concerns regarding the perioperative management of acute psychostimulant intoxication have been recognized for decades, but novel and diverse substances in this class continue to be developed. Despite the similarities in mechanisms of action among psychostimulants, each subclass within this broad category has unique receptor specificity and different mechanisms that play a role in the patient’s’ clinical presentation. These issues present challenges to anesthesia providers when caring for patients with either acute or chronic exposure to psychostimulants during the perioperative period. Challenges result from both physiological and psychological effects that influence the action of the primary anesthetic agent, adjuvant anesthetics, and analgesics used for perioperative management of pain. The epidemiology, pharmacology, and perioperative implications of psychostimulant use are presented for amphetamines and similar acting non-amphetamines, cocaine, and finally the mixed-action drugs known as entactogens that share stimulant and psychedelic properties. This information is then used as the foundation for safe and effective perioperative management of patients exposed to psychostimulants.

Introduction

The use of psychostimulants is widespread with an estimated lifetime prevalence of 7% ^1,2, and psychostimulant-related mortality continues to rise ³ (Figure 1). The well-known stimulants methamphetamine and cocaine remain readily accessible as new substances are synthesized. Escalating legal use of prescription psychostimulants, particularly treatment of attention deficit hyperactivity disorder (ADHD) and even narcolepsy, has contributed to increased non-medical use ⁴. Psychostimulants may play a role in the management of chronic non-cancer pain as well, especially pain of neuropathic origin⁵.

Figure 1.

Increase in Psychostimulant Use. Overdose deaths with cocaine and psychostimulants in the United States from 1999-2020. Over the time period, deaths have increased, with a rapid escalation over the last 5 years. From 2019 to 2020, the rate of drug overdose deaths involving cocaine increased 22%, while overdose deaths involving psychostimulants with abuse potential increased 50%. Cocaine is the blue line and psychostimulants with abuse potential are the orange line. Psychostimulants with abuse potential include such drugs as methamphetamine, amphetamine, and methylphenidate. Deaths may involve more than one drug. The percentage of drug overdose deaths that identified the specific drugs involved varied by year, ranging from 75% early to 94% in 2020. Adapted from Hedegaard et al., Drug Overdose Deaths in the United States, 1999–2020. NCHS Data Brief³

Many psychostimulants used recreationally act by increasing catecholamine levels, generally by increasing release or blocking reuptake, while others are more varied in their neurotransmitter activity. Some compounds display both psychostimulant and hallucinogenic activity through a combination of pharmacological activities.

Considering the ubiquity of psychostimulants, anesthesia providers should be familiar with the clinical features of acute intoxication and chronic use. Patients exposed to these substances present for both elective and emergent surgeries. Appreciation of the perioperative implications is essential to effectively manage patients in the safest manner. Herein, we review the pharmacology of these drugs and the considerations of exposure in patients presenting for anesthetic care, particularly focusing on substances with known perioperative implications.

Common Themes with Psychostimulants

Many psychostimulants have been available for a long time, and novel mental health use has sparked renewed interest. Some are botanicals and others are novel or derived synthetic molecules. In some cases, slight structural modifications result in hallucinogenic effects and make classification difficult, often resulting in properties of both stimulants and hallucinogens. This has resulted in a separate classification of drugs with dual effects called entactogens ^6,7. In addition, illicit compounds classified as “novel psychoactive substances (NPS)” are being synthesized at a rapid rate ^8–10.

While unique molecular structures are often responsible for both desired and adverse effects, minor structural or chemical modifications can produce significant clinical changes. An example of this is methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), which have differing effects on serotonin and dopamine release and will be described in detail in this manuscript¹¹.

A variety of desirable psychological and physiological effects of psychostimulants promote misuse. These include heightened energy, improved focus, enhanced performance, and euphoria (Table 1). Improved physical capacity, cognitive ability, and wakefulness are other generalized effects. With entactogens, the added perceptions of social connectivity and sociability also drive demand. The use of psychostimulants for pain relief and to treat pain-related comorbidities (depression, fatigue, daytime somnolence) may contribute to increased use⁵. There is also a growing concern and alarming trends for overdose due to polysubstance use of both psychostimulants and opioids.¹²

Table 1.

Classification of Psychostimulants and Entactogens with Summary of Action and Side Effects

Categories	Example	Principle Mechanism of Action	Other Actions	Desired Effects	Specific Adverse Effects	Shared Common Adverse Effects	Abuse	Physical Dependence
Amphetamines and similar acting non-amphetamine stimulants	Amphetamine and methylphenidate	Increased norepinephrine and dopamine; release of dopamine and norepinephrine and inhibition of transporters	Release of epinephrine, serotonin, and histamine; also inhibits MAO	Increased energy, wakefulness, excitement/euphoria, improved cognition, enhanced physical performance, decreased appetite		Tachycardia, tachypnea, hypertension, diaphoresis, agitation, confusion, delirium, psychosis, hyperthermia, hypovolemia	Yes	Yes
	Amphetamine derivatives: Methamphetamine	Release of dopamine and serotonin; reverse transport of dopamine	Release of norepinephrine, epinephrine; and inactivates reuptake		Dopaminergic toxicity and resulting Parkinsonism; Short and long term paranoia and psychosis		Yes	Yes
Local anesthetic based stimulant	Cocaine	Increase dopamine and norepinephrine by inhibiting reuptake; also blocks sodium channels	Also increase serotonin and epinephrine	Increased energy, sense of well-being, euphoria/invincibility, confidence, elevated mood, increased libido	Peripheral vasoconstrictive effects on heart and vasculature; chest pain, arrhythmias, myocardial ischemia		Yes	Yes
Entactogens: Stimulants with psychedelic properties including social and sensory effects	Synthetic amphetamine derivatives: MDMA/Ecstasy	Release of serotonin	Release of dopamine	Increased energy feeling of personal relatedness/connectedness, euphoria, perception of sociability and enhanced communication, ability to empathize, sexual arousal	Serotonin syndrome		Yes	Yes
	Non-amphetamine Synthetics Khat derivatives: Cathinones*	Release dopamine, norepinephrine and serotonin; reverse transport	May interact directly with monoamine receptors; may block reuptake		Excited/agitated delirium; Serotonin syndrome		Yes	Yes

Psychostimulants can be categorized based on actions and effects (Table 1). The neurotransmitter effects that result in altered activity are generalizable (Figure 2A). Serotonin, epinephrine, dopamine and histamine can be affected, and monoamine oxidase (MAO) can be inhibited. Central and peripheral neurotransmitter effects result in common side effects and toxicities. This manuscript will focus on substances that provide a representation of implications for anesthetic management for both acute and chronic use (Table 1).

Figure 2.

Sites of Activity for Psychostimulants and Changes from Chronic Exposure. A. Possible sites of action at the neuronal synapse for psychostimulants are shown. In general, these drugs act to either increase the level of neurotransmitter in the synapse or activate post-synaptic receptors to mimic the cognate ligand. Altered transport occurs commonly as well. B. Potential neuronal homeostatic mechanisms to accommodate for chronic exposure to psychostimulants are shown. The figure highlights postsynaptic receptor-mediated effects. Presynaptic changes can occur as well at the transporter or the presynaptic receptors. The result is reduced effects of these substances, however altered effects of clinical anesthetics or adjuvant drugs can also occur as a result of these neuronal adaptations.

Amphetamines and Similar Acting Non-Amphetamines

Amphetamines and similar acting substances (some legally prescribed) work by releasing additional serotonin, norepinephrine, and dopamine into synaptic clefts ¹³. Acute or chronic amphetamine use has different ramifications for patient care. This is in part related to differences in neurotransmitter effects at the cellular level (Figure 2B). The presentation of acute ingestion can range from mild desired effects of euphoria and increased energy to toxic adverse effects of hypertension, tachycardia, rhabdomyolysis, panic attacks, and paranoid as well as delusional psychosis (Table 1 and Table 2).

Table 2.

Therapy for Management of Acute Psychostimulant Intoxication

Indication	Medication Class	Medications/therapies	Effects	Adverse Effects
CNS excitement and agitation, tachycardia, hypertension	Benzodiazepines	Midazolam, Lorazepam	Sedation, blunt hyperadrenergic effect, reduce motor agitation, reduce violence; reduce centrally mediated tachycardia and hypertension	Respiratory depression
CNS excitement and agitation, tachycardia, hypertension	Alpha-2 agonists	Dexmedetomidine	Sedation, reduce blood pressure and heart rate	Transient increase in blood pressure
Psychotic features and benzodiazepine failure	Neuroleptics	Haloperidol	Sedation	Long QT, Reduce heat dissipation, neuroleptic malignant syndrome, may lower seizure threshold
Hypertension, Stroke, myocardial ischemia, hemorrhage	Direct acting vasodilators	Nitroprusside, nitroglycerin, hydralazine	Reduce blood pressure; compensatory increase in heart rate	Toxicity of nitroprusside
Reduce blood pressure and/or heart rate control	Calcium channel blockers	Nicardipine, diltiazem, clevidipine	Reduce blood pressure, decrease tachycardia	Cardiac conduction disturbances
Hypertension and tachycardia	Mixed alpha- and beta-antagonists	Labetalol	Reduce blood pressure, decrease tachycardia	Much more beta than alpha antagonist
Hypotensive vasoplegia	Monoamine oxidase inhibitors	Methylene blue	Inhibits vasorelaxation	Serotonin Syndrome
Serotonin syndrome	Benzodiazepines, serotonin antagonists	Midazolam, Lorazepam, Cyproheptadine, fluid management, supportive treatment	Sedation, reduce motor agitation, maintain normothermia, minimize hemodynamic and autonomic instability, minimize agitation, reverse serotonin effects	Respiratory depression: benzodiazepines; antihistamine effects of cyproheptadine: urinary retention, dry mouth, blurred vision
Rhabdomyolysis	Crystalloid	Normal saline fluid management, supportive treatment, monitor for compartment syndrome, monitor serum electrolytes	Maintain appropriate urine output, avoid hypovolemia, manage potassium	Fluid overload, acid-base or electrolyte disturbance

Prescribed amphetamine and amphetamine-related drugs include the enantiomeric mixture of amphetamine (Adderall®) and the non-amphetamine stimulant methylphenidate (Ritalin® and Concerta®) (Supplemental Table 1). These are commonly prescribed to treat ADHD, but also to improve wakefulness and enhance weight loss ¹⁴. Another common drug is lisdexamfetamine (Vyvanse®), which requires metabolic conversion to l-lysine and d-amphetamine for activity after oral ingestion ¹⁵. This prodrug displays slower onset than d-amphetamine while providing longer duration of action, with reduced abuse liability as injecting or nasally inhaling does not produce immediate effects ¹⁵.

Misuse is common, and examples of misuse include individuals that knowingly take the wrong quantity or consume the substance without a prescription. The most commonly cited reasons for misuse include cognitive performance enhancement, or a desire to create an amphetamine high, with high schoolers and college students being at highest risk^14,16. In a survey, prescription stimulant use had a prevalence of 6.6% in the United States, with only one third of these individuals admitting to misuse, primarily for cognitive enhancement¹⁷. Other reasons for misuse are enhanced physical performance in athletes, improved focus and cognition, as well as reduced sleep requirements amongst professionals that experience a high degree of sleep deprivation ¹⁸. Medical students are known to misuse amphetamines, with prevalence rates ranging from 20-50% ^19,20. In this case, drug acquisition likely occurs illegally, either through illicit channels, or from another person who has obtained drugs legally. As with other controlled substances, prescribing amphetamine derivatives has inherent risks. Although the risk is typically low, deviation from a prescribed pattern and misuse can lead to drug seeking behaviors and development of a SUD.

Methamphetamine and MDMA are the two most commonly encountered amphetamine derivatives, but MDMA is considered separately as an entactogen due to social and perceptual effects not classically seen with amphetamines ^21,22. These two represent the uniqueness of amphetamine derivatives, and novel derivatives will continue to be developed considering the abuse liability of these drugs, likely related to enhanced dopamine and serotonin effects.

Methamphetamine has been used for treatment of ADHD, but has high abuse potential and its use readily leads to substance use disorder ²³. It can be synthesized from ephedrine and pseudoephedrine which are found in regulated over-the-counter cold medicines ²⁴. It is slightly different from amphetamine in that it is highly efficient at releasing dopamine and also releases serotonin, epinephrine and norepinephrine. The release of dopamine is known to cause excitotoxicity in the brain and can lead to early Parkinsonism in chronic users ²⁵.

Cocaine: A Local Anesthetic-Based Stimulant

Cocaine has a long history of recreational use and as a local anesthetic ²⁶. Outside of cultural, ancestral, and traditional uses, cocaine has a legitimate medical use in otolaryngological surgeries as a combined vasoconstrictor and local anesthetic and does not specifically elevate the risk of cardiac complications during these procedures^27,28. Outside of this limited scope and other traditional uses, it is seen as a substance of abuse ¹⁴.

Cocaine has a dual mechanism - as a local anesthetic due to sodium channel blockade, while its stimulant properties result primarily due to its effects as a presynaptic reuptake inhibitor of monoamines including epinephrine, norepinephrine, serotonin, and dopamine ²⁹. The local anesthetic mechanism of cocaine creates cardiac conduction abnormalities in the form of a widened QRS, decreased inotropy, and decreased chronotropy. The bioavailability of cocaine varies depending on the route of administration, from 30% with oral ingestion to 90% when inhaled or used intranasally ²⁹. The effects of cocaine may only last 60 minutes after last use ³⁰. Other forms of administration include dissolution in water and injecting intravenously, sometimes in conjunction with an opioid ¹⁴. Cocaine metabolites can be routinely detected in urine screens up to 72 hours after administration ²⁹.

Entactogens

Entactogens include the amphetamine derivative MDMA, other novel amphetamine-based synthetic molecules, and cathinones⁶. Enhanced euphoric and even psychedelic effects make them act in many ways like both hallucinogens and stimulants. The psychedelic-like effects of creating social connectivity and perceptual changes places them in a separate group called entactogens (Table 1)^6,7. The word entactogen was proposed to emphasize the specific effects of touching within or inner connection, but specific enhancement of feelings of empathy, love and closeness to others are described⁷. The separate classification as entactogens emphasizes the duality of stimulant and special perceptual effects. Consistent with their psychostimulant nature, acute entactogen intoxication should be entertained in the face of common shared sympathomimetic features that include hypertension, tachycardia, dilated pupils, diaphoresis and CNS excitation: agitation, delirium, and psychosis ³¹ (Table 1 and Table 2). While there is overlap with other psychostimulants, differences likely result from greater effects on serotonin release, although misuse potential is not just due to changes in serotonin at the synaptic cleft¹¹. Nevertheless, serotonin effects contribute to a greater concern for serotonin syndrome with acute entactogen intoxication.

One of the most commonly abused entactogens is MDMA²⁹. MDMA use provides feelings of sociability and sexual arousal as well as feelings of altered sensory perceptions, usually heightened, which is common to many psychedelics. MDMA, otherwise known as ecstasy, is a club drug that has very rapid sublingual absorption with significant safety implications ³². MDMA differs from classic amphetamines mechanistically as it primarily releases serotonin into the synaptic clefts, with much less dopamine release ¹¹. The serotonin effects give MDMA characteristics that are shared with psychedelics like mescaline that result in altered or distorted sensory perceptions and are part of the allure of the “experience” from the drug ³³. MDMA can cause a number of severe clinical effects, ranging from tachycardia and profuse sweating to rhabdomyolysis, hyperthermia, disseminated intravascular coagulation, strokes, and seizures; these are effects shared with other psychostimulants (Table 1) ²⁹. MDMA and amphetamines can routinely be detected in urine screens for approximately 48 hours after ingestion ²⁹, but these are qualitative tests for amphetamines in most cases and are not very reliable, subject to false positives and false negatives and do not detect other synthetics that may be mixed with MDMA.

The dominant serotonin increases relative to other amphetamine derivatives makes MDMA much more likely to induce serotonin syndrome^34,35. This can occur from MDMA alone, but taking other serotonin altering prescription medications can contribute. These include SSRIs and SNRIs. Patients, particularly adolescents, are not aware of the potential interactions between these prescribed medications and MDMA or ecstasy-like party substances. The effects of taking SSRIs and SNRIs with MDMA are varied. SSRIs may reduce some of the desired physiologic effects of MDMA, increase the potential for serotonin excess and alter the effectiveness of MDMA to treat other mental health disorders like post-traumatic stress disorder (PTSD)^36,37. Additionally, other substances that can precipitate or exacerbate serotonin syndrome include lithium, MAO inhibitors (methylene blue), and opioids (meperidine, fentanyl) among others³⁴.

Finally, among the entactogens are substances called cathinones. Cathinones are considered non-amphetamines, but are closely related structurally to the base amphetamine molecule producing profound CNS and cardiovascular effects. They are synthetic derivatives of molecules derived from the plant Catha edulis known as khat ³⁸. These substances contain a carbonyl group at the β position of the phenethylamine skeleton ³⁹. Cathinones, along with synthetic cannabinoids, are the most common NPS especially in young adult and adult age groups ⁸.

The naturally occurring compounds largely release dopamine, serotonin and norepinephrine ^40,41. Cathinones also reverse transport monoamines; these substances also affect the serotonergic system and its downstream effects on mood and behavior ^42,43. Some of the synthetic derivatives can increase release of dopamine and norepinephrine and have less overall effect on serotonin when compared to amphetamines, but they can also have other variable effects ^44,45,40.

Cathinone itself can be naturally ingested by chewing the leaves of the khat shrub which is endemic to Africa and parts of the Middle East ⁴⁴. While ingestion of khat leaves produces effects similar to amphetamine with sympathomimetic effects that can be problematic, the synthetic derivatives modify this effect to create other properties. Many are familiar with the pharmacologically efficacious cathinone derivative bupropion. This drug is synthesized from methcathinone⁴⁶. Bupropion acts as a norepinephrine–dopamine reuptake inhibitor and a nicotinic receptor antagonist and is used as an antidepressant and to aid smoking cessation⁴⁷.

Substances of specific concern are the synthetic cathinones. Synthetic cathinones are examples of NPS that in many cases are manufactured to avoid regulations around similar substances already banned ⁸. These substances are non-amphetamine synthetic molecules that have amphetamine like-properties. Many cathinones have been moved into the Schedule I category under the Controlled Substances Act ⁴⁸. One example of a cathinone is “cat,” or methcathinone, which caused numerous deaths internationally and led to its listing as a Schedule I drug in 1992 ⁴⁹. Methylenedioxypyrovalerone (MDPV), mephedrone, and methylone are three of the most common synthetic cathinones, which are also referred to as “bath salts,” although other names exist ⁴². These substances are often listed as “not for human consumption” to avoid regulatory concerns ^42,50.

Perioperative Management of Acute Intoxication of Psychostimulants

Patient history may be unreliable, and many psychostimulants are not detected in qualitative urine tests. Additionally, mild intoxication may go undetected. However, acute psychostimulant intoxication should be entertained in the face of common sympathomimetic features that include hypertension, tachycardia, dilated pupils, diaphoresis and central nervous system (CNS) excitation: agitation, delirium and psychosis ³¹ (Table 1 and Table 2). While acute intoxication may be suspected, the possibility of other diagnoses should be a part of the differential (malignant hyperthermia, thyroid toxicosis, opioid withdrawal, neuroleptic malignant syndrome, etc.). Additionally, with illegal or synthetic substances, contaminants or adulterants can complicate the picture ⁵¹. There are concerns for management of the patient with acute intoxication of psychostimulants that increase risk in the perioperative period. Therefore, surgery that is not urgent or emergent should be postponed. During this time, patient referral to a SUD expert should be entertained to facilitate patient care and safely determine optimal timing of surgical intervention (Figure 3A).

Figure 3.

Flow charts for Acute and Chronic Psychostimulant Use in Surgical Patients. A. For the patient suspected of acute psychostimulant intoxication, it is important to consider alternate problems as part of the differential diagnosis. With acute psychostimulant intoxication, the time sensitivity of the surgical procedure (elective versus urgent/emergent) dictates whether to postpone or proceed with the surgery and anesthesia. If the surgery is not time sensitive, the case should be postponed, SUD expert referral sought and surgery scheduled electively. If the case is time sensitive, surgery should proceed with appropriate cautions for perioperative care that include intraoperative and postoperative modifications based on altered pharmacology and physiology to optimally manage the patient under the circumstances. B. Patients with chronic psychostimulant use present for surgery in two separate circumstances; the patient taking prescription psychostimulants under physician supervision and the patient with SUD. With prescription use, continuation of the medication in the perioperative period is preferred as this maintains the patient’s routine physiology and mental health treatment to better meet the psychological needs and thus maintain homeostasis. This also prevents perioperative withdrawal. While a taper could be used, and may be valuable if the psychostimulant is no longer needed or when a longer and more difficult postoperative course is anticipated, this is not the preferred path (denoted by the red dotted line, instead of the blue arrow). In the face of SUD, if acute intoxication is present, elective surgery should be postponed and SUD expert referral should be sought. If acute intoxication is not present, there are two pathways for management: 1. postpone surgery and consider referral for SUD management and/or taper; 2. Proceed with surgery as scheduled with appropriate cautions and also refer patient to SUD expert for care perioperatively and follow-up management. Chronic psychostimulant use changes patient care based on long term effects on neurotransmitters. Chronic exposure to psychostimulants can lead to peripheral catecholamine depletion; chronic psychostimulant use without acute intoxication still requires direct acting adrenergic agonists. These patients may also have reduced MAC requirements. MH: Malignant Hyperthermia, NMS: Neuroleptic Malignant Syndrome, SUD: Substance Use Disorder, MAC: Minimum Alveolar Concentration, ICU: Intensive Care Unit, CNS: Central Nervous System, CV: Cardiovascular

Regional anesthesia is not contraindicated with acute psychostimulant use as local anesthetic function does not seem to be affected⁵². It may even be beneficial, allowing better monitoring of neurologic status. This must be balanced with the possibility of acute agitation or poor cooperation making it difficult to place a block and may expose additional risk to the patient or provider⁵³. General anesthesia may help control central nervous system (CNS) stimulation-related problems, reduce metabolic demands and manage cardiovascular issues. It may also facilitate core temperature reduction in patients with stimulant-induced hyperthermia. The combination of benzodiazepines, alpha-2 agonists, and propofol may function quite well. Mental status issues may not be seen until attempting to emerge from anesthesia and can be confused with other etiologies of delayed emergence, delirium, or agitation.

Greater cardiovascular perturbations may be challenging and delayed emergence, emergence delirium, or agitation may be problematic. Other clinical manifestations include tachycardia, hypertension, arrhythmia, myocardial infarction, and vasospasm²². Ketamine is not the best choice for induction of general anesthesia as there can either be catecholamine depletion or exaggerated increase in heart rate and blood pressure^54,55. A sympathetically-overdriven patient may be catecholamine deplete and more likely to suffer from the cardiac depressant effects of ketamine. Furthermore, amphetamine toxicity may lead to a risk of noncardiogenic pulmonary edema²².

A summary of the anesthetic implications of the patient presenting with acute intoxication are presented in Table 2, 3, and Figure 3A. Beta-blockers are generally contraindicated due to unopposed alpha-adrenergic agonism; labetalol, with its dual mechanism of alpha and beta antagonism, is still less than ideal⁴⁴. Nitroglycerin and nitroprusside, or calcium channel blockers such as clevidipine, are alternatives that avoid concern of unopposed alpha-adrenergic agonism. Other issues in patients acutely intoxicated with amphetamines include metabolic acidosis, hyponatremia, hypertension, arrhythmias, and disseminated intravascular coagulation ¹⁴. Benzodiazepines and antidepressants can be used to treat withdrawal symptoms of amphetamines, which generally develop several days after last use and include anxiety, insomnia, paranoia, and depression ¹⁴.

Table 3.

Anesthetic Implications of Psychostimulants

Common Issues with Psychostimulants	Tachycardia, hypertension, arrhythmia, myocardial infarction, vasospasm, delayed emergence, emergence delirium, agitation
Regional Anesthesia	May be beneficial to monitor neurological status; general anesthesia may be of benefit to control CNS stimulation-related problems, reduce metabolic demands, manage cardiovascular issues, and to facilitate cooling
Adrenergic Blockade	Beta-blockers are generally contraindicated, as with other stimulants such as cocaine, due to the unopposed alpha-adrenergic agonism; labetalol, with its dual mechanism of alpha and beta antagonism, is also still less than ideal
Commonly Used Medications	Benzodiazepines, alpha-2 agonists, and propofol are often useful. Benzodiazepines and antidepressant medications can be used to treat withdrawal symptoms of amphetamines
Serotonin Syndrome	Serotonin syndrome risk exists (especially MDMA)
Treatment of Hypotension	Direct-acting vasopressors, phenylephrine, epinephrine, or norepinephrine should be used to treat hypotension; ephedrine should be avoided
Change in Anesthetic Requirements	Initial sympathomimetic state from amphetamines may initially raise the minimum alveolar concentration (MAC); chronic use of amphetamines seems to lower MAC or have little effect
Pulmonary Complications	Pulmonary complications are common from inhalational injury, noncardiogenic pulmonary edema, pulmonary hypertension, pneumonia, or aspiration pneumonia
Medications to Avoid	Succinylcholine should be avoided (or dose reduced) due to possible rhabdomyolysis and hyperkalemia
Supportive Care	Supportive treatment is critical (fluids, electrolyte, acid-base balance)
Thermoregulation	Antipyretics and active cooling mechanisms may be needed

Methamphetamine:

Acute intoxication with methamphetamine can present with the common adverse effects from stimulation of the alpha- and beta-adrenergic receptors. Furthermore, tachypnea, agitation, irritability and hostility as well as paranoia, hallucinations, psychosis and picking and scratching the skin can also occur ⁵⁶.

Respiratory changes may be present from acute intoxication with increased minute ventilation, respiratory rate and tidal volume. Since methamphetamine vapor may be inhaled, pulmonary injury may be present; concern for pulmonary edema, pulmonary hypertension, or thermal injury should be considered in patients suspected of acute inhalation, similar to smoking “crack” cocaine ^57,58. These patients can present for trauma related injury requiring emergent surgery, but can also present for vascular compromise including ischemic bowel or acute bleeding from hypertension ⁵⁹.

Concerns in managing patients for surgery with acute intoxication include CNS stimulation and agitation which leads to elevated temperature, hypovolemia and underlying muscle injury or rhabdomyolysis ⁵⁶. Acute intoxication leads to increased general anesthetic requirements. Succinylcholine should be avoided to reduce the likelihood of precipitating hyperkalemic arrest from muscle injury related rhabdomyolysis. Even with no clinical evidence of rhabdomyolysis, the effects of stimulants such as cocaine and amphetamines on depolarizing muscle relaxants are variable and unpredictable ^60,61. Metabolic acidosis may be severe and should be aggressively managed. Also, in the face of hyperthermia, active cooling measures may be beneficial; cooling blankets and evaporative and conductive heat loss as well as fluid resuscitation both for cooling and to address hypovolemia^62,63. General anesthesia and paralysis may be beneficial to reduce metabolic demands and provide vasodilation thereby improving cooling. However, hypotension is a concern, as response to vasoconstrictors to treat hypotension may be unpredictable. When hypotension needs to be treated, direct acting vasoconstrictors would be the best choice⁶⁴.

Finally, postoperative monitoring for organ dysfunction is essential. This may be in the acute care setting or even the intensive care unit depending on presentation. Monitoring for myocardial ischemia, dysrhythmias and metabolic derangements to facilitate rapid intervention to correct problems and optimize patient care is valuable. Additionally, psychostimulant withdrawal symptoms such as lethargy, confusion, increased appetite, agitation, and depression may require active management in the postoperative setting as well.

Cocaine.

Acute cocaine intoxication manifests as agitation, hypertension, hyperthermia, tachycardia and tachyarrhythmias, and myocardial ischemia ¹⁴. The fever may originate from combined vasoconstriction and central temperature dysregulation ⁴⁴. Anesthesia providers should feel comfortable managing sequelae of acute cocaine intoxication by utilizing calcium channel blockers, dexmedetomidine, sodium nitroprusside, and nitrates (Table 2) ¹⁴.

As previously mentioned, beta blockers should be avoided due to unopposed alpha adrenergic activity ³⁰. For treatment of hypotension, as with other stimulants, direct acting vasoconstrictors should be used. Pulmonary complications from chronic cocaine use include noncardiogenic pulmonary edema, pulmonary hypertension, pneumonia, and aspiration pneumonia ¹⁴. Smoking “crack” cocaine raises concerns as it can be associated with inhalational injury and pulmonary dysfunction which may include “crack lung” with hemorrhagic alveolitis, shortness of breath and cough and may include pulmonary infarction which can make perioperative management more difficult ^57,58,65

If succinylcholine is used for neuromuscular blockade, a reduced dose should be considered, as cocaine is also metabolized by plasma cholinesterase ¹⁴. Cocaine can reduce seizure threshold and other drugs that reduce seizure threshold should be avoided ⁴⁴.

Benzodiazepines may help reduce agitation and centrally-mediated excitation causing hypertension and tachycardia in conjunction with the peripheral acting drugs. As with other stimulants, alpha-2 agonists may be beneficial although intravenous use may produce an initial exaggerated hypertensive response before the central effects ensue and caution should be used to prevent exaggerated hypertension ⁶⁶. Impurities or adulterants may exist in cocaine used by the patient, and these can also be problematic. One of the more common additives is fentanyl, and this should be suspected with concomitant positive opioids on the urine drug screen or with signs of opioid exposure (lethargy, respiratory depression and pinpoint pupils) not normally seen with stimulants. Although awareness of this problem exists, due to the cheap and plentiful supply of fentanyl, this practice continues to take its toll ⁵¹. Combined effects of drugs may lead to a need to change the approach to the patient.

MDMA.

The ramifications of the derivatives are similar to other amphetamines. A risk of hyperkalemia with MDMA exists ⁶⁷. Hyperkalemia is likely due to a combination of factors including a hypermetabolic state, metabolic acidosis, and a decreased glomerular filtration rate. Interestingly enough, one study has shown that a urine drug screen positive for cocaine or amphetamines in trauma admissions was not associated with worse outcomes for myocardial infarction, stroke, or mortality. However, cocaine and amphetamine has been associated with worsening postoperative complications such as ventilator associated pneumonia or postoperative infection ⁶⁸.

Cathinones.

Clinical signs and symptoms that need to be monitored during the perioperative period include agitation, hypertension, tachycardia, hyperreflexia, seizures, hyponatremia, rhabdomyolysis, and decreased renal function ⁴². Like other sympathomimetics, cardiac side effects including coronary vasospasm, myocardial ischemia, and hypertension can be present ⁶⁹. The approach to these patients would be similar to that with other stimulants and should center on reducing the CNS excitation with benzodiazepines and alpha 2 agonists, assuring homeostasis and reducing or managing electrolyte, volume, and other systemic consequences of ingestion. Again, many drugs in this class will not show up in urine drug screens or toxicology screens ^70,71. Benzodiazepines are often used to manage agitation seen with cathinones, and antipsychotics should be avoided as cathinones may lower the seizure threshold ⁷⁰.

Serotonin Excess and Serotonin Syndrome

Many manifestations of psychostimulant toxicity result from excess monoamines in the CNS. Symptoms may be related specifically to excess serotonin; characterized by the triad of altered mental status, neuromuscular effects, and autonomic hyperactivity and referred to as serotonin syndrome ⁷². Serotonin syndrome is most common with exposure to substances that simultaneously cause release of serotonin and reduce its uptake, but may occur with drugs that act as serotoninergic agonists when combined with drugs that release or reduce uptake of serotonin.

Opioid administration can paradoxically increase the risk of precipitating serotonin syndrome due to re-uptake inhibition⁷³. The most efficacious opioids for inhibition of serotonin reuptake are methadone, meperidine, and tramadol, but fentanyl can inhibit the transporter. Tramadol also has direct serotonin releasing capability and is higher risk than alternative medications for patients using psychostimulants.

Serotonin syndrome should also be considered in patients taking prescribed medications that alter serotonin metabolism as part of their routine care and present with symptoms of stimulant misuse; combinations of drugs that alter serotonin availability have the greatest likelihood for adverse events ⁷⁴. These include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and MAO inhibitors. Concerns include hyperthermia, tachycardia, mydriasis under anesthesia and signs of rigidity. Manifestations of serotonin syndrome include hyperthermia, tachycardia, and rigidity - all of which should be addressed while simultaneously considering alternative diagnoses (i.e. malignant hyperthermia and thyroid storm, etc.).

Perioperative Management of Chronic Psychostimulant Use

Unlike acute intoxication, chronic amphetamine use can produce paradoxical effects of fatigue and lethargy ⁷⁵. With chronic prescription use, few adverse issues arise from continuing administration (Figure 3B). Tapering can be done and can reduce withdrawal, but continuation will also reduce withdrawal risk while having the added benefit of maintaining better mental and physiologic homeostasis through the perioperative period ^76,77. This likely occurs for not only chronic use of prescribed amphetamine and similar acting non-amphetamines, but also for other psychostimulants. However, it may be naïve to assume that the same stability will exist with patients suffering from SUD given the myriad of potential administration methods and variable doses, number of exposures, or history of use. Therefore, patients with chronic misuse of psychostimulants who present for elective surgery should not be counseled to continue to use these substances through the surgery, but rather should be referred to appropriate SUD experts for treatment and guidance as to timing and management of perioperative care. Additionally, withdrawal may occur and render the patient more sensitive to routine anesthetic agents and lethargy. Similarly, while acute intoxication of psychostimulants may increase MAC, chronic use of amphetamine derivatives seems to lower MAC or have little effect ^44,75,78. This likely results from homeostatic changes that occur at the level of the neurons (Figure 2B)^79–82. While use of alpha 2 agonists for sedation in the face of acute intoxication seems to be beneficial, with chronic amphetamine exposure the sedative effects of dexmedetomidine may be less robust or exaggerated. Overall, general and/or regional anesthesia may be considered for these patients.

Due to methamphetamine producing excessive dopamine centrally, dopamine antagonists such as metoclopramide are likely not contraindicated and may have some benefit. However, with depletion of dopamine following prolonged use of methamphetamine, the use of dopamine antagonists in the perioperative period are better avoided to reduce precipitation of acute dystonic or Parkinsonian-like symptoms ⁸³.

It is generally accepted that chronic exposure to psychostimulants can lead to peripheral catecholamine depletion. As a result, direct-acting vasopressors, phenylephrine, epinephrine, or norepinephrine should be used to treat hypotension; ephedrine may not yield the desired hemodynamic response ^75,84. Vasopressin may be used for hypotension refractory to adrenergic vasoconstrictors and one report exists where methylene blue was used for refractory vasoplegia in a chronic polysubstance use disorder patient known to take amphetamines⁸⁵. Although methylene blue may treat refractory vasoplegia, it can be deleterious with stimulants that have predominant serotonergic effects because it increase serotonin through MAO inhibition ⁸⁶. The alpha 2 agonist dexmedetomidine may be beneficial for reducing acute CNS excitation and improves sedation in conjunction with benzodiazepines, but potential adverse effects including bradycardia and hypotension should be considered and monitored ⁸⁷.

The chronic use of cocaine may result in structural airway concerns. For example, airway manipulation or insertion of a nasogastric tube must be attempted with extreme caution due to the potential for septal tissue and soft palate destruction ^30,88.

Postoperatively, all patients with a history of chronic psychostimulant use should be monitored for signs of withdrawal. Symptoms can include anxiety, agitation, and psychosis but can also commonly include lethargy, somnolence, fatigue, and depression. A SUD expert should be engaged, if possible, to facilitate postoperative care and follow up after discharge.

Special Considerations for Psychostimulants in the Parturient

There are highly specific preoperative and peripartum considerations for the parturient with acute and/or chronic psychostimulant use. Chronic prescription psychostimulant use has mental health benefits but does increase the likelihood of pre-eclampsia and preterm delivery⁸⁹. However, SUD significantly accentuates risks. Many of the psychostimulants can cause vasoconstriction with resulting hypertension and impairment in fetal blood flow. The sympathomimetic effects of psychostimulants may appear similar to gestational hypertension or pre-eclampsia with signs of hypertension, and/or seizures and hyperreflexia⁹⁰. Cocaine and methamphetamine both increase myocardial oxygen demand beyond that which already occurs during pregnancy and results in increased rates of emergency caesarean section from abruption and fetal distress ⁹¹. This also predisposes the parturient to myocardial ischemia, infarction and arrhythmias. Serotonin syndrome may also be misdiagnosed as pre-eclampsia as it can present with hypertension, and/or seizures, hyperreflexia, thrombocytopenia, proteinuria and edema⁹² . Prenatal methamphetamine exposure has been shown to lead to prolonged postnatal infant drowsiness, impaired infant growth patterns that may persist for the first few years of life, and also the possibility of teratogenicity in animal models⁹³.

Neuraxial techniques are considered the ideal method to deliver analgesia and anesthesia in obstetric patients who present with SUD ^94,95. This method needs to be balanced in the face of acute agitation or poor cooperation that may make it difficult to place a block and may expose additional risk to the patient or provider⁵³. Other concerns with neuraxial procedures include severe hypotension with sympathectomy and the fact that neuraxial approach may be contraindicated in patients with cocaine-induced thrombocytopenia ⁹⁵. General anesthesia may be needed either as an initial approach or in the face of failed neuraxial technique. The combined use of knowledge of perioperative management of psychostimulants outlined and the routine care of the obstetric patient can effectively guide the conduction of general anesthesia and perioperative care in the parturient. Certainly, close attention to cardiovascular responses is essential and invasive pressure monitoring may be helpful for both neuraxial or general anesthesia; direct acting agents are optimal with phenylephrine the preferred vasopressor of choice for both, as resistance to ephedrine can occur.

Discussion

Psychostimulants present a variety of perioperative clinical challenges. Often, the substances are undetected in toxicology screens, and diagnosis may need to be made on signs and symptoms alone. In many cases, the perioperative management involves supportive care and management of acute symptoms (Table 2) as well as avoidance of medications and conditions that exacerbate the patient’s clinical state. The anesthetic implications of the psychostimulants are further summarized in Table 3 for reference. Perioperative management has been complicated by new substances and designer drugs over the last decade and the increased use of these substances will likely continue. Although the long-term management of patients misusing psychostimulants is not the focus of the manuscript, it is worth noting evidence-based treatment options. Contingency management therapy (i.e. receiving a reward such as gift card for a desired behavior such as a negative urine drug screen) has been shown to be beneficial for stimulant use disorder, while other therapies such as n-acetylcysteine, disulfiram, and antidepressant medications have not proven beneficial.⁹⁶ Anesthesiologists should feel comfortable not only with the management of psychostimulants in the perioperative period, but should be adept at taking part in appropriately-timed patient discussions regarding referral to a SUD treatment center for management. Lastly, stereotypes and bias should not influence safe and appropriate perioperative treatment of pain in patients with a SUD history. While many physicians and healthcare providers have little experience or knowledge of these substances, familiarity with the pharmacology including mechanisms of action, clinical effects, and interactions with other drugs will be valuable to optimize effective management strategies in the perioperative period for patients with acute exposure or psychostimulant related SUD.

Glossary of Terms

ADHD

Attention Deficit Hyperactivity Disorder

MDMA

3,4-methylenedioxymethamphetamine

MAO

Monoamine Oxidase

CNS

Central Nervous System

MAC

Minimum Alveolar Concentration

SSRIs

Selective Serotonin Reuptake Inhibitors

SNRIs

Serotonin-Norepinephrine Reuptake Inhibitors

SUD

Substance Use Disorder

PTSD

Post-Traumatic Stress Disorder

NPS

Novel Psychoactive Substances

MDPV

Methylenedioxypyrovalerone