Novel Psychoactive Substances of Abuse: Part I

AUTHORS

Jared C. Vaughan, MD, Emergency Medicine PGY-3, Wright State University Emergency Medicine Residency, Dayton, OH

Mara O’Sullivan, MD, Attending Physician, Emergency Medicine, Wright State University, Dayton, OH

PEER REVIEWER

Larissa I. Velez, MD, Associate Dean for Graduate Medical Education, Professor and Vice Chair for Education, Michael P. Wainscott Professorship in Emergency Medicine, Department of Emergency Medicine, UT Southwestern Medical Center, Dallas

EXECUTIVE SUMMARY

• Novel substances of abuse, also commonly referred to as novel psychoactive substances, create a new complexity for medical providers because of uncommon clinical presentations and failure of traditional management strategies.
• The majority of novel substances of abuse are synthetic derivatives not commonly identified on routine blood or urine screens and require detailed history, physical exam, and clinical identification.
• Novel substances of abuse often are used as adulterants and are adulterated with other substances of unknown quantity that alter drug profiles via increased potency, enhancement of pharmacological effects, and deviation from classic toxidromes.
• Lack of reversal antidotes renders supportive care as the primary option for management in most cases of overdose.

There seems to be no limit by some for new methods to induce alterations of consciousness matched with the ability to create compounds to make this happen. More novel or designer drugs are entering use each year, and it is hard for the medical and regulatory communities to keep up. While there may be some benefit for therapeutic use with controlled doses in monitored settings, as testified by a billionaire and a football star, no benefit is likely to occur from uncontrolled use with varying doses in potentially unsafe settings. I am old enough to remember Dr. Timothy Leary and his strong advocacy for widespread use of psychedelic drugs; that “experiment” did not end well for many.

This issue is the first of a two-part series on new novel or designer psychoactive drugs. Many of them represent alterations of existing agents that exhibit new effects from the modification. Keep the possibility of intoxication with these agents in mind when evaluating patients with altered levels of consciousness and mentation.

— J. Stephan Stapczynski, MD, Editor

Introduction

Novel psychoactive substances (NPS) refers to a broad category of synthesized substances designed to mimic classic illicit substances that typically have a chemical structure differing from the parent compound. Novel substances can be divided into four classification groups: synthetic stimulants, synthetic cannabinoids, synthetic hallucinogens, and synthetic depressants.¹ The new compounds often are marketed as safe and legal alternatives to illicit substances; however, they lack governmental regulation and, therefore, contain varying amounts of substances and additional adulterants.

Although many NPS initially were synthesized and identified in the early 2000s, NPS are referred to as “novel” or “new” to emphasize recent increased use recreationally and availability of these compounds in illegal markets. These compounds often are misleadingly labeled as “legal highs,” “herbal highs,” “synthetic drugs,” or “party pills” or sold under the guise of herbal teas, incense, plant fertilizer, or tonics with disclaimers of “not for human consumption,” which allows legal distribution and purchase.²

Challenges encountered by health organizations in combating NPS use include many novel substances of abuse are not detected on routine blood or urine analysis, new synthetic mixtures stray from typical toxidromes, they are easily available from online sources, and the complexities in attempting government regulation. This creates an immense challenge for medical providers because many NPS create mixed clinical presentations and have proven to be resistant to common antidotes.

Healthcare providers should familiarize themselves with NPS of abuse because increased use requires higher suspicion for unique presentations necessitating more complex medical management. The purpose of this article is to provide an overview of current literature highlighting the prevalence of use, categories, clinical presentation, and management of novel substances of abuse. Part I will review stimulants and hallucinogens and psychedelics. Part II will cover sedatives such as synthetic opioids and non-opioid sedatives. See Table 1 for information on NPS of abuse presentations and Table 2 for NPS of abuse management.

Epidemiology

Over the last year, nearly 60 million Americans 12 years of age and older have reported illicit substance use or prescription drug misuse within the last year, with the largest demographic consisting of young individuals with psychiatric disorders.^3,4 One study reviewed anonymous online forums to determine motivations for use of the most common novel substances.⁵ Many users of NPS reported self-medicating to manage depression, anxiety, and attention deficit disorder. Alternatively, individuals with distrust for medical institutions and providers sought more “natural” or “organic” treatments that falsely advertised having low to no possibility of addiction.⁵

The literature describes a subset of NPS users seeking “functional novel substances,” or substances that do not hinder daily activities and that do not require oversight from a medical professional, because of the difficulty obtaining prescription medications to treat anxiety, insomnia, and depression.^3,6 NPS often are less expensive and easily available without government regulation, contributing to the prevalence of abuse and addiction.^5,7,8

The Synthetic Drug Abuse Prevention Act of 2012, which amends the Controlled Substances Act, adds synthetic substances of abuse, such as synthetic cannabimimetic agents and hallucinogenic substances, under Schedule I controlled substances.⁹ However, despite attempts at governmental regulation, availability of NPS through illegal market internet sources in conjunction with the continued production of derivatives with added adulterants by street manufacturers has complicated efforts and medical management in cases of overdose.

Stimulants

Synthetic Cathinones

Synthetic cathinones are a class of NPS derived from naturally occurring cathinones from the Khat plant (Catha edulis), which is a shrub traditionally chewed in parts of Yemen and East Africa for its stimulant effects.⁹ Examples of legal synthetic cathinones include bupropion, commonly used for depression and smoking cessation, and diethylpropion, commonly used for appetite suppression and weight management.

Recreationally, synthetic cathinones are commonly referred to as “bath salts,” “M-CAT,” “ivory wave,” “cloud-9,” “white lightning,” or “explosion.” Synthetic cathinones are seldomly found in isolation; they frequently are added as an adulterant in other traditional substances of abuse, such as 3,4-methylenedioxymethamphetamine (MDMA), to increase potency with shorter durations of action. The decreased duration results in users often increasing both dosage and frequency, leading to hospitalizations secondary to severe overdose and toxicity.

Mechanism of Action

Effects are propagated through stimulation of monoamine transporters, leading to increased serotonin, dopamine, and norepinephrine uptake.¹⁰ Forensic analysis has discovered the presence of three main synthetic compounds in recreational synthetic cathinones responsible for drug effects: mephedrone (4-methyl-N-methylcathinone), methylone (4-methylenedioxy-N-methylcathinone), and MDPV (3,4-methylenedioxypyrovalerone). The chemical structures are similar to traditional stimulants, such as amphetamine and methamphetamines, which furthermore accounts for the similarities in clinical presentation.^10,11 Studies have found MDPV to be three to 10 times more potent compared to mephedrone or methylone, suggesting that MDPV is the chief compound responsible for adverse effects seen in acute intoxication and overdose.¹⁰

Formulation and Routes

Synthetic cathinones can be found in multiple formulations, such as white or brown powders, tablets, or capsules, and used by snorting, smoking, injecting, and in some reports, taking rectally. The onset of action with synthetic cathinones is rapid, similar to cocaine, with a duration of stimulant effect of three to four hours.

Given the lack of regulation and diverse illicit manufactures, the amount of active substance found in street synthetic cathinones can vary widely and often is unknown. In addition, its short duration of action causes users to repeatedly dose to achieve the desired effects.

Clinical Presentation

Acute intoxication mimics sympathomimetic toxidromes, presenting with agitation, altered mentation, hallucinations, tremor, mydriasis, xerostomia, and diaphoresis. Vital sign alterations include tachycardia, hypertension, and hyperthermia. In severe cases, patients with acute ingestions may present with seizures and laboratory abnormalities indicative of acute renal injury or failure and rhabdomyolysis. Although non-life-threatening, withdrawal can be observed within four hours for chronic users and presents with irritability, depression, anxiety, and insomnia.

Diagnosis

Synthetic cathinone overdose or acute ingestion is a clinical diagnosis obtained from history and physical examination since detection is not typical with routine drug screening. In animal studies, the metabolism of MDPV produces the metabolite 4-hydroxy-3-methoxypyrovalerone that potentially could be useful in detecting screens given its prolonged half-life, but unfortunately, there is not yet a rapid screening test available.¹⁰

Management

Management of acute ingestion and withdrawal is largely supportive, as with most NPS overdose. Vital signs should be monitored closely with proper efforts at stabilization. Hyperthermia can be seen and should be addressed with cool intravenous (IV) fluid resuscitation and passive external cooling, with progression to more invasive measures in refractory cases. Tachycardia often is secondary to dehydration, for which IV fluids should be administered, or agitation, for which sedation is administered. For agitation, use benzodiazepines (lorazepam 1 mg to 4 mg IV or intramuscular [IM] every hour) or antipsychotics (haloperidol 0.5 mg to 10 mg IV or IM every one to four hours) until the patient clinically improves.

Admission is advised in severe cases, such as with seizures, or toxicity complicated by electrolyte abnormalities, renal failure, or rhabdomyolysis.

Kratom

Kratom is a nonprescription herbal medication often used as a “natural alternative” for homeopathic therapy. Its leaves are derived from the tropical tree Mitragyna speciosa, native to Southeast Asian countries, including Thailand, Malaysia, Indonesia, and Myanmar. The bitter leaves contain the bioactive alkaloids, mitragynine and 7-hydroxymitragynine, which propagate its stimulant and sedative effects.

Kratom initially was used for treatment of chronic musculoskeletal pain as well as to increase energy, stimulate appetite, and increase libido. In the realm of homeopathic therapy, additional uses have included management of hypertension, diarrhea, cough, depression, and even opioid withdrawal in place of methadone.^12,13

Although kratom has no Food and Drug Administration (FDA)-approved medical uses and has been deemed a drug of concern under the Drug Enforcement Administration (DEA), it remains legal for purchase in most states. The scientific literature is relatively scarce regarding kratom use, thus the need for continued research given its rise in popularity, potential for abuse, and unknown long-term effect on health.

Mechanism of Action

Kratom’s effects are propagated through activation of both mu-opioid and monoamine receptors by the primary active compound mitragynine and its metabolite, 7-hydroxymitragynine.¹³ However, molecular studies have found partial activation with less affinity for the compounds at mu-opioid receptors with a greater preference for monoamine receptors except in cases of higher dosages.^13-15

Uniquely in animal models, 7-hydroxymitragynine has been shown to demonstrate greater affinity for the mu-opioid receptor and naloxone-sensitive antinociceptive activity compared to mitragynine; this likely drives the potential for dependence and withdrawal.¹³ Furthermore, the differences in receptor engagement between the mitragynine and hydroxymitragynine explains the mixed opioid and, to a greater extent, stimulant effects that typically are demonstrated and desired by users, as activation of monoamine receptors results in increased concentrations of serotonin and dopamine.

Formulation and Route

Kratom can be found in several formulations, including powder, capsule, or liquid extract. The most common method of intake involves inhalation via smoking dried kratom leaves, but the plant also can be chewed or consumed orally as herbal tinctures or teas.^2,16

Dosage varies greatly given the lack of regulation of kratom and its combination with other substances across its myriad of preparations. Typically, intake of 1 g to 5 g is considered lower ingestion, whereas 5 g to 15 g would be considered a more moderate ingestion.⁹ Onset of effects typically is observed within five to 10 minutes of ingestion, with a duration of effects ranging from two to five hours.⁹

Clinical Presentation

The clinical presentation is largely dependent on dosage, route of use, and co-ingestions. Uniquely, kratom has been observed to produce mixed presentations that studies have deducted likely are secondary to dosage. At lower dosages, a stimulant effect predominates, with demonstration of increased sociability, agitation, diaphoresis, palpitations, anorexia, hallucinations, psychosis, and seizures.¹² Vital sign changes include tachycardia and hypertension. Conversely, at higher dosages, an opioid-like effect is observed, with demonstration of constipation, respiratory depression, altered mental status, lethargy, and bradycardia.

In severe overdoses, case reports have noted the onset of seizures, respiratory depression, and acute organ failure, including acute liver failure and cardiac arrest, presenting in the majority of cases as asystole.¹⁷ In documented occurrences of severe toxicity or death, exacerbation of kratom effects were attributed to co-ingestions of other illicit substances, presence of adulterants, or adverse reactions with prescribed medications.

Chronic kratom users have been noted to develop hypothyroidism, hepatic failure, and withdrawal symptoms similar to that of chronic opioid use, including abdominal pain, nausea, vomiting, diarrhea, diaphoresis, and irritability.

Diagnosis

As with the majority of NPS, there are no routine screening toxicological tests and the diagnosis hinges on the clinical presentation and patient reports of ingestion obtained through history.

Management

Management is largely supportive because an approved reversal agent does not exist. However, case studies demonstrate a variable response with naloxone (0.4 mg IV in adults), likely due to the inhibition of the kratom constituent 7-hydroxymitragynine.^18-20

As noted, kratom can produce dependence and withdrawal effects in chronic users, which presents similarly to opioid withdrawal; however, symptoms typically are milder and more transient.¹²

Hallucinogens and Psychedelics

MDMA

MDMA is a synthetic compound widely known as a “party drug” and frequently is used by young adults that uniquely acts as a dual stimulant and psychedelic. It is known commonly among users as “ecstasy,” “E,” “X,” “beans,” “Molly,” “disco biscuit,” “peace,” or “lover’s speed.”^16,21

MDMA produces feelings of empathy and euphoria, increased libido, enhanced tactile sensory perception, and extroversion. MDMA is listed under the Controlled Substances Act as a Schedule I substance.

Mechanism of Action

The mechanism of action involves increased concentration of neurotransmitters via activation at serotonin, dopamine, and norepinephrine receptors while also inhibiting reuptake.^22-24 MDMA’s effects at serotonin receptors likely explain its euphoric and mood-
elevating effects. Studies have found MDMA metabolites reduce further metabolism of MDMA, resulting in profound elevation of serum concentrations and worsening of toxicity, especially in the setting of co-ingestions, which is a typical practice.

Formulation and Route

MDMA is commonly distributed as tablets, capsules, powder, and liquid. The tablets resemble a variety of colorful candies, and methods of intoxication are ingestion, snorting, smoking, and, rarely, injection. Users typically will practice “stacking” or “piggy-backing,” which refers to taking multiple 50-mg to 150-mg tablets at once or sequentially, respectively.^16,21 As imagined, this common practice complicates quantification of ingestion.

Clinical Presentation

The clinical presentation after an acute ingestion generally is similar across all stimulants and includes confusion, agitation, insomnia, muscle spasms, nausea, vomiting, chills, tremors, diaphoresis, tachycardia, and hypertension. In acute intoxication, MDMA has been uniquely documented to cause malignant hyperthermia, a condition in which central heat regulation mechanisms are disturbed, resulting in profound elevations in body temperature, which can lead to multiorgan failure in severe cases.²⁵

Hyperthermia can subsequently induce other notable complications, including rhabdomyolysis propagating acute kidney injury and electrolyte disturbances, such as hyponatremia through the stimulation of thirst in hyperthermia, resulting in polydipsia and syndrome of inappropriate antidiuretic hormone (SIADH).¹⁷

Additionally, MDMA users may uniquely present with bruxism, a condition in which users grind or clench their teeth, resulting in dental complications. In chronic use, MDMA can produce depression, anxiety, insomnia, and interference with memory.^21-24

Diagnosis

Although the diagnosis likely can be made via a thorough history and physical examination, routine urine drug screens detect classic stimulants such as amphetamines and cocaine, thus, MDMA may be detected due to its cross-reactivity with rapid amphetamine immunoassays.

Management

Management for acute intoxication is largely supportive because no approved reversal agents exist. Emergent presentations require rapid primary survey: airway management, respiration evaluation, and circulation. Agitation and violent behavior are common following stimulant ingestion and can present a safety hazard for both the patient and medical staff and also can delay management. Escalating doses of anxiolytics, such as IV benzodiazepines, can be administered for management of acute agitation, tachycardia, and hypertension. Avoid antipsychotics, such as haloperidol, as such agents can lower the seizure threshold and contribute to dysrhythmias and hyperthermia.^26,27

Beta-blockers are contraindicated, especially in suspected cocaine intoxication, because this can result in unopposed alpha receptor stimulation, thus paradoxically worsening hemodynamic instability.^26,27 There is scant proposed usefulness of alpha blockers, such as phentolamine, in cases of hypertensive emergency.²⁷ In cases of wide complex tachydysrhythmias, sodium bicarbonate can be considered as well as IV lidocaine, although this is controversial.

In the setting of acute coronary syndrome (ACS) or ST-elevation myocardial infarction (STEMI), consult cardiology for emergent cardiac catheterization and for the decision to administer thrombolytics. Pending cardiology consultation, initiate ACS care pathway with administration of aspirin, clopidogrel, and an antithrombotic such as heparin or enoxaparin.

Basic laboratory tests should be obtained and electrolyte disturbances such as hyponatremia are to be corrected. In cases of hyperthermia (temperature greater than 40° Celsius or 104° Fahrenheit), perform passive cooling techniques, such as applications of cooling blankets and ice packs with cool IV fluids. Advance to more invasive techniques such as Foley catheter placement for bladder lavage, extracorporeal blood cooling, or chest tube placement for thoracic lavage.

Benzofurans

Benzofurans, recreationally referred to as “benzofury,” are a class of synthetic phenethylamines that originally were synthesized for research purposes. Its dioxole ring structure interacts with the serotonin receptors.^28,29 This was done with the intention for potential treatment for eating disorders, seizures, and even as anti-inflammatory agents. However, since 2010, benzofurans, such as 5-(2-aminopropyl)-benzofuran (5-APB) and 6-(2-aminopropyl)-benzofuran (6-APB), along with many other analogs, have appeared in increased prevalence within the recreational drug market as an alternative to amphetamines and MDMA.²⁸

Both 5-APB and 6-APB, and their analogs (5-APDB and 6-APDB) can be acquired for recreational use via online markets. Benzofurans have been banned in several countries; however, rapid synthesis of new analogs has complicated regulatory efforts.

Mechanism of Action

Benzofurans cause effects through activation of serotonin receptors in a manner similar to that of MDMA. This is expected, given the similarities in both chemical structures.²⁸ Their action at serotonin receptors results in increased levels of serotonin and decreased reuptake through inhibition of monoamine oxidase A (MAO-A).²⁹ Some molecular studies also have discovered agonistic properties at dopamine receptors; however, this is thought to be dose-dependent.²⁹

Formulation and Route

Benzofurans commonly are found as a powder, which is insufflated. They also can be pressed into a pill or purchased in capsule form for oral ingestion.

Dosage

Due to lack of governmental regulation in addition to synthesis of benzofurans by street manufacturers, the dosage among acquired samples for recreational use vary widely. In an animal study, stimulant effects were seen with doses ranging from 1 mg/kg to 10 mg/kg.²⁹

Clinical Presentation

In acute ingestions, users often report increased feelings of empathy, euphoria, visual stimulation, elevated positivity, improved mood, hypersexuality, and self-appreciation. The clinical presentation also can include nausea, vomiting, bruxism, xerostomia, diarrhea, photophobia, headaches, and drowsiness, as well as triggering of acute psychosis evident by hallucinations, anxiety, insomnia, and paranoia.

The physical examination may reveal a flushed appearance, lethargy, mydriasis, altered mental status, rapid speech, or clonus of the extremities. Vital sign disturbances, including tachycardia, hypertension, and hyperthermia, also have been reported.

The after-effects of benzofuran use, referred to as the “come down,” may include cognitive fatigue, depression, or anxiety. Although few and only within the context of co-ingestants, toxicology reports have identified benzofurans in overdoses resulting in death.

Diagnosis

Case reports have documented users who presented to emergency departments with admitted acute intoxication of benzofurans and had routine urine drug screens positive for amphetamines. However, subsequent gas chromatography-mass spectrometry (GC-MS) confirmatory tests were negative for amphetamine and MDMA but detected 5-APB and 6-APB.²⁸ However, this cross-reactivity of benzofurans with rapid urine immunoassays that detect amphetamines is considered inadequate for identification of acute intoxications. This highlights the importance of a thorough history and physical examination to confirm the diagnosis in acute intoxication or overdose.

Management

Initial management includes primary assessment by evaluating the patency of airway, assessing ventilation and respiratory effort, and addressing circulation and hemodynamics. Beyond the primary survey, management is largely supportive. In cases of severe agitation or anxiety compromising evaluation as well as patient and provider safety, benzodiazepines such as lorazepam (1 mg to 4 mg IV or IM every hour) or midazolam (1 mg to 5 mg IV or IM every hour) can be used in addition to antipsychotics such as haloperidol (0.5 mg to 10 mg IV or IM every one to four hours) or droperidol (5 mg to 10 mg IV or IM every one to four hours).

Electrolyte abnormalities are to be corrected in severe cases, which also may call for admission. In cases of hyperthermia (temperature greater than 40° C or 104° F), perform passive cooling via applications of cooling blankets and ice packs with cool IV fluids. In more severe cases, advance to more invasive techniques, such as bladder lavage, extracorporeal cooling, or thoracic lavage.

Synthetic Cannabinoids

Synthetic cannabinoids (SCs) are designer drugs intended to replicate the effects of tetrahydrocannabinol (THC), the main driver of the psychedelic effects of marijuana. Recreationally, it has been referred to as “spice,” “diamond,” “krypton,” “K-2,” “Aztec Fire,” “Bombay Blue,” “blaze,” “ninja,” “skunk,” “fake weed,” and a myriad of other nicknames.^9,11,16 These products often are labeled as “legal” alternatives and marketed as herbal incense or potpourri, with warning labels typically stating, “not for human consumption.”^16,30,31 However, due to its ease of availability from convenience stores, gas stations, and internet sources, it is easily abused for its known marijuana-like effects.

SCs typically are packaged and labeled in a creative manner to entice younger demographics. Survey studies have found more than 40% of its users are younger than the age of 19 years.^16,30 Hundreds of SCs are classified into five major categories, including classical cannabinoids, non-classical cannabinoids, hybrid cannabinoids, aminoalkylindoles, and eicosanoids.³² Each category contains numerous analogs that are rapidly modified by street manufacturers to avoid detection and federal regulation by the DEA as Schedule 1 substances. There are more than 40 specifically identified SCs classified as Schedule 1 substances by definition as “cannabimimetic agents” under the Controlled Substances Act.¹⁶

There are limited statistics accurately highlighting the use of SCs in the United States, as it is likely underreported due to legal ramifications as well as due to its use among younger age groups. Calls to U.S. poison centers concerning SC use monitored since 2012 showed a peak in 2015 with more than 7,000 calls, followed by a decline to 1,000 in 2021.^31,33,34

Mechanism of Action

Structurally related to THC, synthetic cannabinoids produce similar marijuana-like effects via activation of central and peripheral cannabinoid receptors (CB1 and CB2), stimulating the release of glutamate and gamma-aminobutyric acid (GABA).^9,10 The effects of synthetic cannabinoids typically are more pronounced and potent due to a measured receptor affinity 100-800 times higher when compared to THC.^9,10 Whereas THC typically yields the metabolite 11-hydroxy-THC, synthetic cannabinoid metabolism yields multiple active metabolites, which also retain great affinity for CB1 receptors, resulting in prolonged duration of effects.

Formulation and Route

Typically, SCs are found in a powder bulk that then is dissolved in solvents such as acetone. This solution form is sprayed on dried plant material as an “herbal incense” or loaded into electronic cigarettes and vape pens or water pipes, bongs, or vaporizers. The dosage duration varies six to 12 hours according to the amount used.

Clinical Presentation

Generally, acute intoxications present with a variety of symptoms across multiple organ systems, even when using the same brand or batch of SCs. Vital sign abnormalities are common, including hypertension, hyperthermia, and tachycardia.

Clinical presentation varies depending on several factors, including those unrelated to the synthetic cannabinoid ingested. Two important ones are referred to as “set” and “setting.”^2,30 Simply stated, “set” refers to the individual’s current mindset or emotional space, such as anxious, stressed, or depressed. “Set” also takes into account individuals’ previous use of and familiarity of NPS in general. Use of SCs has been observed occasionally to exacerbate users’ “set” mood, which can result in negative experiences.³⁰ “Setting” refers to the environment in which users use SCs. Whether the environment is calm and quiet or loud and noisy can contribute to the individual’s experience.

Neuropsychological effects may include anxiety, paranoia, hallucinations, psychosis, seizures, paresthesia, numbness, central nervous system (CNS) depression resulting in respiratory distress, and exacerbation of underlying psychotic disorders and suicidal ideation.

Cardiovascular effects are very common in cases of overdose and may include palpitations, tachycardia, myocardial infarction, cardiomyopathies, dysrhythmias, stroke, hypertension, and cardiac arrest.³⁵ Gastrointestinal effects may result in nausea and vomiting after acute ingestion, while in chronic ingestion and withdrawal, users may experience abdominal cramping and appetite suppression.

Several case reports have revealed hematologic disturbances evidenced by profound SC-associated coagulopathy. These cases were found to be secondary to the presence of adulterants, such as brodifacoum, difenacoum, and bromadiolone, which are potent, long-acting anticoagulant rodenticides. Brodifacoum, also characterized as “super warfarin,” appears to be the most prevalent.³⁵ Case reports also have documented SC-induced nephrotoxicity resulting in hematuria with progression to acute kidney injury.

Events of withdrawal in chronic users have been documented to present similarly to chronic marijuana use, albeit with increased occurrence of future psychotic events and cognitive impairment.^30,31

Diagnosis

The synthetic cannabinoids undergo metabolism via hydroxylation by CYP2C9 and CYP1A2, which render specific metabolites that may or may not be detected with routine blood and urine screens due to alteration in chemical structures.¹⁰ Routine drug screens in this case lack most utility, especially considering the rapid adaptation of synthetic cannabinoid chemical composition by street manufacturers.³⁰ This likely contributes to the increased prevalence of SC abuse, as users can achieve the desired effects of THC while remaining undetectable on routine drug screens.³⁰ Therefore, acute intoxication is a clinical diagnosis largely obtained through in-depth history.

Management

Given there is no current reversal agent for acute intoxication or overdose, the management remains largely supportive. Benzodiazepines (lorazepam, midazolam) or antipsychotics (haloperidol, droperidol) can be used to control agitation, manage anxiety, or for combative patients. Administer IV fluid resuscitation with correction of electrolyte abnormalities and antiemetics for hyperemesis, such as ondansetron (4 mg to 8 mg IV or sublingual every four hours) or promethazine (12.5 mg to 25 mg IV or PO every four hours).

Coagulation laboratory tests should be obtained because of the common occurrence of SC-associated coagulopathy demonstrated via elevated prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) values.³⁵ If present, management for the long-acting coagulopathy requires initiation of intravenous vitamin K (50 mg to 100 mg) with transition to chronic oral therapy, which can average five to six months in duration, with routine laboratory draws toward normalization of INR.³⁵

Admit patients in the event of intractable vomiting, severe electrolyte derangement, coagulopathies with bleeding, and vital instability. Otherwise, most acute intoxications with clinical improvement can be discharged. In the emergency department, it is helpful to consult social services or substance use navigators to assist with referral to substance use disorder (SUD) programs if appropriate.

As with all NPS use, significant adverse reactions are to be expected, especially in the setting of co-ingestions. SCs are metabolized through P450 enzymes, similarly to other common medications such as warfarin, phenytoin, losartan, ibuprofen, and various psychiatric medications and antibiotics.¹⁰ There is a lack of research detailing interactions between prescription medications and SCs, especially given the diversity of their chemical makeup. Routinely review the patient’s medication lists to determine potential risk for subsequent inhibition or prolonged duration of prescribed daily medications.

Tolerance and dependence are common with SC use, often resulting in chronic users requiring increased dosages and development of a sense of need for chemicals to perform routine activities of daily living. Withdrawal has been observed with daily users, with a positive correlation between frequency and duration of use and severity of symptoms. Symptoms of withdrawal can be similar to acute intoxication, albeit with increased severity. Withdrawal may present with decreased appetite, irritability, anxiety, insomnia, nausea, vomiting, headaches, seizures, palpitations, and sensation of cravings. Quetiapine, specifically, has been documented to assist with the relief of anxiety, insomnia, and irritability in withdrawal.³⁶ Nabilone, an FDA-approved CB1 receptor agonist, may be useful for alleviation of cannabis withdrawal symptoms and potentially in cases of synthetic cannabinoid detoxification.^36,37

Salvia

Salvia is a hallucinogen derived from the Salvia divinorum mint plant, which is native to Mexico. It has been used for centuries by shamans in the Mazatecan culture for ritualistic healing practices and propagation of spiritual visions.¹⁶ Salvia has been distributed as a legal alternative to marijuana under the common names of “magic mint,” “diviners sage,” “sally D,” “mystic sage,” and “maria pastora.” The largest demographic of current users is found among adolescents older than 12 years of age and in young adults.⁹

Salvia is an FDA Schedule IV drug (sale, possession, and production of salvia are illegal unless authorized for medical, scientific, or industrial purposes), with many states banning it outright.

Mechanism of Action

The mechanism of action is attributed to the active ingredient salvinorin A, which mostly stimulates the kappa-opioid receptor. However, there have been observations, albeit to a lesser extent, of stimulation of mu-opioid receptors as well as cannabinoid (CB1) receptors.³⁸ First-pass metabolism limits effect via chewing or sublingual absorption, which likely explains its users’ preference for use via smoking or vapor inhalation.⁹

Formulation and Route

Salvia typically is found in its natural form as leaves from the Salvia divinorum plant, which can be chewed, crushed to extract a liquid formulation, or used in herbal tinctures or teas.¹⁶

Dosage

The dosage varies largely across formulations given the varying concentrations of the active ingredient. There appears to be both a route and dose-dependence for severity and duration of effects.^38,39 An inhaled dose of 200 mcg to 500 mcg produces onset of “intense” effect within 30-60 seconds with a duration ranging from 15-45 minutes. Alternatively, oral ingestion has an onset within 10-20 minutes with a duration of 30-90 minutes.^2,16,40

Clinical Presentation

Similar to synthetic cannabinoids, the clinical presentation of acute intoxication can vary depending on factors previously described as “set” and “setting,” which describe the mindset and emotional state as well as the environment in which an individual exists while under the influence of the substance.

Acute intoxication is marked by altered mental status, including confusion, disorientation, auditory and visual hallucinations, slurred speech, dizziness, incoordination, gait instability, agitation, anxiety, and paranoia. A subset of users also describe perceptions of bright lights and vivid colors with distortions of shapes. Vital sign abnormalities are rare, although few cases have noted tachycardia and hypertension.⁴⁰ There is suspicion that the induced psychogenic effects observed in acute intoxication and overdose can be explained by both the active ingredient as well as by the substance unmasking an underlying psychiatric disease.

Diagnosis

Diagnosis primarily is clinical because detection is not obtainable with routine drug screening.^2,41 An in-depth substance use history should be obtained by the provider, especially in cases suspicious for acute salvia ingestion.

Management

Since no antidote for reversal of intoxication exists, the ED management is largely centered on supportive care. This includes IV fluid resuscitation, antiemetics such as ondansetron or promethazine for intractable nausea and vomiting, correction of laboratory abnormalities, and benzodiazepines such as lorazepam or midazolam as appropriate for significant agitation or anxiety.

Although the current literature regarding salvia use is scarce, there have not been any reports of life-threatening withdrawal, chronic illness, permanent debilitation, or death directly linked to salvia use or overdose.^2,39 However, given that its use can impair judgment and coordination, individuals acutely intoxicated have demonstrated increased risky behavior that can lead to secondary impairment or harm. For patients who have failed to return to mental baseline and lack capacity for safe discharge, admission is appropriate.

References

1. Shafi A, Berry AJ, Sumnall H, et al. New psychoactive substances: A review and updates. Ther Adv Psychopharmacol 2020;10:1-21.
2. Alcohol and Drug Foundation. Drug Facts. Last updated Nov. 8, 2023. https://adf.org.au/drug-facts/#list
3. Boys A, Marsden J, Fountain J, et al. What influences young people’s use of drugs? A qualitative study of decision-making. Drugs: Education, Prevention, & Policy 1999;6:373-387.
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