Novel Psychoactive Substances of Abuse: Part II

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

• The NBOMe and 2C drugs are derived from mescaline and typically are used as “party drugs” for their euphoric and psychedelic properties.
• Psilocybin is a naturally occurring psychedelic found in multiple species of mushrooms.
• Synthetic benzodiazepines are used recreationally for their euphoric effects and also by predators for drug-facilitated sexual assault.
• Desomorphine is abused in Russia and Eastern Europe, but it rarely is seen in the United States, where no new cases have been documented since 2004.
• Desomorphine is referred to as “krokodil” because of the characteristic skin changes noted in chronic intravenous users.
• Because of the increased potency of fentanyl analogues, increased dosage and frequency of naloxone may be required to reverse toxicity.
• Xylazine, a sedative legally available for veterinary use in the United States, enhances and prolongs the effects of classic and novel psychoactive drugs.

This is the second of a two-part series. Part I reviewed stimulants and started the discussion of hallucinogens and psychedelics. Part II will finish the discussion of hallucinogens and conclude with novel sedative drugs.

NBOMe and 2C Drugs

NBOMes (N-methoxybenzyl) and 2C-B (4-bromo-2,5-dimethoxyphenethylamine) are a group of psychoactive novel substances that produce psychedelic effects mimicking the classic hallucinogen lysergic acid diethylamide (LSD). They are commonly referred to as “N-Bomb,” “smiley paper,” “pandora,” or “wizard.” There are several subgroups, such as 25B-NBOMe and 25C-NBOMe, that differ slightly in structure, resulting in more potent effects.

Although hallucinogens have been exploited for medicinal and religious purposes among ancient civilizations, NBOMe and 2C drugs are newer substances for which the pharmacokinetics and effects of chronic use are poorly understood. They are increasingly prevalent for recreational use among young adults for the euphoric and psychedelic properties as “party drugs.”¹ Several case reports have documented drug overdoses that have resulted in hepatic failure, irreversible neurological damage, and death.² NBOMe and 2C drugs have been classified by the Drug Enforcement Administration (DEA) as Schedule 1 drugs (no currently accepted medical use and a high potential for abuse).

Mechanism of Action

The 2C phenethylamine drugs are mescaline derivatives that are further synthesized into NBOMe analogs through the introduction of an N-2-methoxybenzyl group. Psychedelic effects are propagated through the activation of serotonin 5-HT receptors.^2,3

Formulation and Route

Most commonly found in the form of dissolvable blotting paper, there also are clear liquid, tablet, and white powder formulations that are used intravenously, sublingually, orally, via insufflation, and, in fewer reports, rectally and vaginally.^1,4 Insufflation is noted to be less popular because of the discomfort reported among users.¹

Dosage

Although the onset and severity of drug effects have been found to be dose-dependent, accurate dosage is difficult to ascertain since the liquid form of the drug typically is concentrated on blotting paper in unknown dosages that vary widely in potency.³ Furthermore, the distribution and, therefore, the dose concentration within a single sheet of blotting paper can vary. NBOMe and 2C drugs have been detected as both adulterants and deceitfully mislabeled as LSD, which further complicates dosing. Toxicology reports note that consumed dosages typically range between 50 mcg and 1,200 mcg, with hallucinogenic effects achieved at a dose of 50 mcg to 200 mcg for a duration ranging from four to 10 hours.^1,5

Clinical Presentation

Acute intoxication will present similarly to intoxication with other hallucinogens, including visual or auditory hallucinations, euphoria, confusion, anxiety, agitation, paranoia, nausea, vomiting, decreased appetite, and palpitations. Physical examination findings include diaphoresis, mydriasis, xerostomia, and labile mood swings.^1,3 Vital sign changes also can be noted and may include tachycardia and hyperthermia.

Cases of severe overdoses can present with seizures, rhabdomyolysis, metabolic acidosis, and multisystem organ failure resulting in death.^2,3 Profound alterations in sensorimotor perception and cognition increase risky behaviors, potentially resulting in secondary injury and death.³ Although sparse, the published literature has not documented presentations of dependency or withdrawal, whereas tolerance has been demonstrated among chronic users. See Table 1 for presentations of novel psychoactive substances and Table 2 for management of novel psychoactive substances.

Diagnosis

The diagnosis is largely clinical, obtained from a thorough history and physical examination, since there is not a routine rapid screening test for detection of the substances.

Management

The emergency department management is largely supportive because a reversal agent does not exist. Stabilize vital signs with intravenous (IV) fluids for hypotension, active cooling for significant hyperthermia, and supplemental oxygen in the event of hypoxia. Benzodiazepines, such as lorazepam and midazolam, can be used for severe agitation, anxiety, and seizures. Obtain laboratory tests to assess for end-organ damage and to guide electrolyte and acid-base disturbances. Admission is required for patients with hemodynamic instability, acute respiratory failure requiring supplemental oxygen, significant electrolyte or acid-base disturbance, or persistent altered mental status.

Psilocybin

Psilocybin is a naturally occurring psychedelic that is produced by multiple species of mushroom, with the most potent being Psilocybe azurescens, Psilocybe semilanceata, and Psilocybe cuanescens. Recreationally, psilocybin is commonly referred to as “magic mushroom,” “shrooms,” “liberty caps,” or “golden tops.” Although natural mushrooms containing psilocybin have been used for centuries for chronic pain management and depression, it will be discussed as a novel psychoactive substance due to both its increasing popularity for recreational use and novel formulations, which have led to their designation as a Schedule 1 drug.⁶

Mechanism of Action

Psilocybin, when consumed, is metabolized to psilocin, which is the active ingredient responsible for the hallucinogenic and psychedelic properties via agonism at serotonin (5-HT) receptors.⁷

Formulation and Route

Psilocybin is commonly processed into a dried material or as a white crystalline powder that then is placed in capsules, pressed into tablets, or dissolved in solution and consumed orally. Dried preparations are sometimes smoked in mixed compounds with cannabis or tobacco.¹ The mushroom itself also can be consumed raw or brewed in teas or other herbal tinctures.

Dosage

In a clinical trial assessing psilocybin therapy for major depressive disorder, researchers found a dose of 25 mg orally yielded euphoric effects, with an onset of 10 to 15 minutes, and without significant adverse reactions.⁸ Another study found a dosage between 0.3 mg/kg to 0.4 mg/kg to be sufficient to result in a positive effect.⁷ The lethal dose of psilocybin is determined to be LD₅₀ greater than 250 mg/kg in its IV form.⁷ Illicit psilocybin dosage varies among samples, which were found to have anywhere from four to 10 times the therapeutic dose previously mentioned.^7,8

Clinical Presentation

In acute ingestion or intoxication, patients may present with euphoria, delusions, auditory or visual hallucinations, paranoia, abdominal pain, nausea, vomiting, diarrhea, headaches, generalized myalgias, palpitations, and chills. Vital sign abnormalities may include tachycardia, hypertension, or hyperthermia. Seizures can occur in serious overdose. In individuals with a personal or family history of psychiatric disease, psilocybin is more likely to unmask psychotic disorders.⁷

The physical examination may reveal diaphoresis, facial flushing, or mydriasis. The onset and duration of symptoms are dependent on the formulation used. Raw mushrooms typically produce symptoms within 30 minutes, while brewed formulations have a symptom onset within five to 10 minutes. The effects can last approximately four to six hours.¹ As symptoms wear off, patients may demonstrate depression, fatigue, insomnia, or have a flat affect. Despite documented reports of tolerance, which resolve within days to weeks, there are no reports of withdrawal.^1,6,8

Diagnosis

Neither psilocybin nor psilocin is readily detected with routine rapid screening tests; thus, the diagnosis is largely clinical and historical. Furthermore, peak levels of psilocin are seen at approximately 50 minutes postprandial, with a half-life between two to two and a half hours, which adds to the difficulty in detection.

Management

There have been no reports of fatal outcome in cases of isolated psilocybin overdose, suggesting that co-ingestions are more likely to be the culprits that place patients at risk for death. Given spontaneous improvement without interventions in documented overdose studies, the emergency department management is largely supportive, including ensuring airway patency, supplemental oxygen in hypoxia, stabilization of hemodynamics, and correction of laboratory abnormalities.^7,8 Additionally, in the rare case of seizures, management includes administration of benzodiazepines such as lorazepam, midazolam, or diazepam, with escalation to barbiturates such as phenobarbital in cases refractory to benzodiazepines.

Sedatives

Synthetic Benzodiazepines

Synthetic benzodiazepines, also known as designer benzodiazepines, are a class of chemically modified compounds that act as sedatives. The typical benzodiazepine chemical structure is slightly altered to produce compounds with increased potency. The term “designer benzodiazepines” is a misnomer, since this category can include benzodiazepines manufactured and legally sold in foreign countries and metabolites of benzodiazepines sold legally in the United States in addition to structurally modified analogues. The most common recreationally used synthetic benzodiazepines in the United States include etizolam, diclazepam, flualprazolam, flubromazepam, and clonazolam.

Misuse of these drugs is a safety concern. Between 2019 and April 2020, the United Nations Office of Drugs and Crime received reports of 10 designer benzodiazepines identified in clinical cases, driving under the influence of drug investigations, and post-mortem analysis. Eighty-three percent of the driving under the influence cases and 48% of the post-mortem cases found the presence of a designer benzodiazepine, most often flualprazolam, flubromazolam, and etizolam.⁹

They often are used as alternatives to prescribed traditional benzodiazepines by users seeking to self-medicate to manage symptoms of anxiety, insomnia, muscle spasms, and undesired withdrawal symptoms associated with other substance use.¹⁰ These synthetic substances also are used commonly in recreational spaces for their euphoric effects, similarly to opioids. Unfortunately, these euphoric effects also are employed by predators on unwary victims for drug-facilitated sexual assault, as synthetic benzodiazepines frequently are detected in the forensic analysis of sexual assault cases.¹¹

Although synthetic benzodiazepines behave in a manner similar to traditional benzodiazepines, the paucity of oversight by a medical professional among users creates uncertainty when equivalizing dosages and the half-life of synthetic benzodiazepines to classic benzodiazepines.^10,12 Clonazolam and etizolam, in particular, have presented heightened dangers because they have been detected in high concentrations circulating as counterfeit midazolam and have been involved in severe overdose resulting in death.^10,12

Mechanism of Action

Benzodiazepines activate the gamma-aminobutyric acid type A (GABA-A) receptors to cause increased frequency of opening of GABA-A channels, resulting in the release of the inhibitory neurotransmitter GABA.¹² The mechanism of action of synthetic benzodiazepines is similar to that of classic benzodiazepines; however, molecular studies have demonstrated some increased receptor affinity compared to classic benzodiazepines.

Formulation and Route

Synthetic benzodiazepines typically are found in tablet or powder form for oral ingestion as well as liquid solution for IV and intramuscular (IM) injection.

Dosage

The dosage varies across different formulations, with different synthetic benzodiazepines, and with the inclusion of adulterants. Doses as low as 0.5 mg of clonazolam have been found to be associated with profound toxicity, whereas 240 mg of diclazepam was found to cause only agitation and disorientation.¹²

Clinical Presentation

The clinical presentation of synthetic benzodiazepine intoxication and overdose is similar to that of the classic benzodiazepines. Ingestion can result in somnolence, dizziness, fatigue, ataxia, loss of coordination, amnesia, and headaches. The central nervous system (CNS) and respiratory depression seen with synthetic benzodiazepine overdose typically is more severe than that seen with classic benzodiazepine overdose. In cases of chronic use extending beyond four to six weeks, worse and longer withdrawal symptoms can occur compared to the classic benzodiazepines, particularly with flubromazolam.¹³

Diagnosis

The diagnosis is largely made through history and physical examination, since many synthetic benzodiazepines are either detected with routine screening or, conversely, cross-react with classic benzodiazepine immunoassay.

Management

Management is largely supportive care with consideration for using the reversal agent flumazenil. However, flumazenil is a controversial agent for use in classic benzodiazepine overdose, and only a few case reports exist to suggest its usefulness in synthetic benzodiazepine intoxication.¹⁴ Flumazenil can be administered with an initial dose of 0.2 mg IV and repeated with increased doses up to 0.5 mg every minute to a maximum dose of 3 mg. The benefits of using flumazenil should be weighed against the risk of precipitating life-threatening benzodiazepine withdrawal in chronic users. Therefore, slow titration to effect with frequent clinical reassessments is required.

Synthetic Opioids

Synthetic opioids are a class of novel psychoactive substances (NPS) representing derivatives of naturally occurring opioids and are produced illegally by street manufacturers.

Deaths from the opioid epidemic can be categorized as occurring in three waves. (See Figure 1.) The first wave was due to the increase in legal opioid prescribing to treat chronic pain, encouraged by a regulatory emphasis on pain management. The second wave occurred when a significant number of patients who were prescribed opioids developed tolerance and then addiction, encountered difficulty legally obtaining their prescribed drugs, and turned to using heroin. The third wave was due to the influx of potent synthetic opioids, such as fentanyl, into the illegal market. Since 2016, more deaths have been reported from fentanyl overdoses than prescription opioids.¹⁵ In 2022, a reported 73,650 people died in the United States from fentanyl overdose.¹⁵

Figure 1. Three Waves of Opioid Overdose Deaths
Source: Centers for Disease Control and Prevention. 2023. Understanding the opioid overdose epidemic. https://www.cdc.gov/opioids/basics/epidemic.html

Desomorphine

Desomorphine is a Schedule 1 synthetic opioid derived from morphine. Its mechanism of action is very similar to that of heroin as a mu-opioid receptor agonist. The compound was first synthesized in the United States as an alternative to morphine with increased potency estimated to be 10 times stronger.¹⁶ Desomorphine has been found to have a more rapid onset of effect of one to two minutes with a shorter duration of one to two hours, resulting in an increased potential for addiction and withdrawal compared to morphine.

Desomorphine is unique as an alternative to heroin because it can be synthesized by street manufacturers from codeine at low cost and with minimal equipment via in-home labs using organic solvents and red phosphorus. Desomorphine has been synthesized and used in Russia for more than 15 years, but reported cases are rare in the United States.¹⁷ The serum half-life of desomorphine is shorter than morphine, which makes it more difficult to detect in clinical and autopsy specimens. Between 2005 and 2014, no submissions to the National Forensic Laboratory Information System have identified desomorphine.¹⁸

Desmorphine is commonly referred to recreationally as “zombie drug,” “crocodile,” or “krokodil,” which refers to the characteristic dry, scaly, discolored skin changes noted among chronic IV users because of venous damage due to caustic damage from substances used during synthesis. Skin ulcerations and infections at injection sites can lead to tissue loss requiring amputations.

Fentanyl Analogs

Fentanyl analogs include various synthetic derivatives, such as carfentanil, sufentanil, and alfentanil, that were synthesized initially in the 1960s for medicinal and veterinarian uses.¹ These substances seldomly were found in recreational use or in cases of overdose until the opioid use epidemic continued to tally staggering numbers of fatalities in the early 2000s secondary to intentional and unintentional opioid overdose.

Newer fentanyl analogs, such as acetylfentanyl, butyryl fentanyl, betahydroxythiofentanyl, alpha-methylfentanyl, and a host of additional analogs, were detected in a large proportion of these cases. Such analogs were obtained from illegal market internet sites and illicitly from street manufacturers. Multiple analogs also were detected as adulterants in other novel psychoactive substances.

In several cases of opioid overdose in which patients reported the intended use of heroin or synthetic heroin, also known as “China White,” routine drug screens were negative for heroin or known opioids. After further subsequent analysis, these specimens later were found to contain multiple fentanyl analogs.¹⁹ Combating fentanyl analog abuse, as with all synthetic novel psychoactive substances, has proven difficult because as analogs are discovered and classified as scheduled substances, new undetectable substances continue to rapidly emerge.

U- and AH-Series

U-series (also referred to as “utopioids”) and AH-series refer to a unique group of synthetic opioids, including U-47700 and AH-7921, that bind mu-opioid receptors with an affinity greater than that of morphine.²⁰ Both synthetic derivatives often are found as adulterants or pressed into pill form and disguised as counterfeit prescribed opioids. They have been associated with numerous fatal overdose cases.

There have been several documented case reports in which U-47700 was distributed as a beige-colored pill advertised as Norco (a brand-name combination of acetaminophen and hydrocodone) that also contained varying concentrations of fentanyl.²¹ AH-7921 has been detected in samples of synthetic cannabinoid products. U-47700 has been detected in drug mixtures containing synthetic narcotics, synthetic opioids, cocaine, and amphetamines in what is commonly referred to as “gray death” because of its resemblance to dry concrete mix and rapid fatality.²² The exact number of compounds that exist is likely severely underreported given the continuous synthesis of new compounds by street manufacturers and organized drug cartels.

Mechanism of Action

The mechanism of action of synthetic opioids is very similar to that of classic opioids via binding of the mu-opioid receptors.¹⁹ Molecular studies have found that synthetic fentanyl analogs demonstrate full agonist properties, with affinities 50-100 times that of morphine, while U-series synthetic opioids demonstrate affinities seven to 10 times greater than morphine.^19,20

Formulation and Route

Formulations can vary, ranging from tablets, liquid solutions, and intranasal solutions. Synthetic opioids can be ingested orally as tablets and injected IM or IV in solution. Generally, depending on the route of use and the type of synthetic opioid used, drug effects may occur in one to two minutes with a duration of one to two hours.

Dosage

Accurate dosage is nearly impossible since clandestine manufacture yields inconsistent concentrations of substances. Overall, synthetic opioids are found to have a shorter duration of action resulting in more frequent redosing by users to reach desired effects and subsequently causing increased risk for significant overdose.

Clinical Presentation

Acute overdose or intoxication presents similar to the classic opioid overdose toxidrome with drowsiness, lethargy, miosis, altered mental status, confusion, impaired gait, chest pain, dyspnea, respiratory depression, cyanosis, seizures, syncope, coma, or death from cardiopulmonary arrest. Vital sign instability can be noted, with bradycardia, bradypnea, hypoxia requiring oxygen supplementation, and hypotension. In injection users, acute overdose presentations can be complicated by the presence of associated skin infections, leading to necrosis and gangrene or in sepsis requiring antibiotic therapy as well as surgical debridement in severe cases.

Diagnosis

The diagnosis is mostly clinical through the recognition of the classic opioid toxidrome, since routine screening tests are lacking that detect synthetic opioids in the emergent setting. However, bloodwork can be obtained and sent for further evaluation via liquid or gas chromatography to assist in detection of specific synthetic opioid compounds.

Management

Similar to classic opioid overdose, the initial management includes the administration of naloxone with a recommended dose varying from 0.04 mg to 2 mg IV, depending on patient severity, repeated every three minutes.²³ Doses of 0.1 mg IV have been observed to reverse acute respiratory failure without inducing acute withdrawal symptoms.^19,20 Given the increased potency of synthetic opioids compared to more traditional opioid compounds, increased dosage and frequency of naloxone administration may be required up to a maximum dose of 10 mg IV.²³

Once the maximum dose of naloxone has been met or surpassed, transition to a continuous infusion may prove useful if the patient demonstrated transient improvement to bolus dosing. The “wake up” bolus dose used to attain transient improvement can be given at two-thirds of that dose per hour mixed with 1 liter D5W (i.e., “wake up” dose of 2 mg translates to an infusion rate of 1.3 mg/hour).²³

As with all other intoxications or overdoses, supportive management remains the mainstay in the emergency setting. This includes IV fluid resuscitation in the dehydrated or hypotensive patient, supplemental oxygen in events of hypoxia with escalation to mechanical ventilation if refractory or with airway compromise, and correction of electrolyte derangements.

In the majority of cases, final disposition may result in discharge of the patient with a home naloxone kit and provision of outpatient resources for assistance with substance use disorder if the patient meets safety criteria. These include the ability to ambulate without assistance, ability to maintain oxygen saturation above 92% on room air, absence of hemodynamic instability, remains afebrile, a return to mental baseline, and a respiratory rate greater than 10 breaths per minute after observation of at least four to six hours after the last dose of naloxone.²³

In cases of opioid use disorder, buprenorphine, a prescribed opioid approved by the Food and Drug Administration (FDA) for management of opioid dependency, has demonstrated promise. Buprenorphine is a partial agonist that binds with high affinity to opioid receptors, producing weak opioid effects while also blocking the binding by other opioids. Its partial agonist properties give buprenorphine an innate upper limit of effect despite increasing dosages, making it ideal for both reducing opioid withdrawal while also reducing cravings and avoiding severe CNS depression.

For treating opioid use disorder, buprenorphine, a partial opioid agonist, is combined with naloxone, a full opioid antagonist, in brand name formulations such as Suboxone, Subutex, and Zubsolv. The naloxone component can prevent misuse should the combination tablet be dissolved and injected or inhaled by antagonizing the agonistic action of buprenorphine.

Before prescribing buprenorphine, it is important that the provider is certain that the patient has not recently used any opioid because this can precipitate acute withdrawal. Prior to disposition, consult social services or a substance use navigator for assistance with obtaining referral to establish the patient with rehabilitation services.

Non-Opioid Sedatives

Xylazine, also referred to as “tranq” in recreational use, is a non-opioid sedative that is used commonly in veterinary medicine as a sedative and analgesic. The potent substance was initially discovered as an adulterant in Puerto Rico in the early 2000s.¹ Between 2019 and 2022, the U.S. Centers for Disease Control and Prevention (CDC) reported deaths involving illicitly manufactured fentanyl (IMF) with the prevalence of xylazine detected as an adulterant to have increased by 276% and a predominance of use throughout the East Coast. In 2022, 23% of seized fentanyl powder and 7% of fentanyl pills were found to contain xylazine.²⁴ (See Figures 2 and 3.)

Figure 2. Number and Percentage of Drug Overdose Deaths Involving Illicitly Manufactured Fentanyls by Xylazine Detection or Co-Involvement — State Unintentional Drug Overdose Reporting System, 31 States and District of Columbia, January 2021-June 2022
IMF: illicitly manufactured fentanyl Source: Kariisa M, O’Donnell J, Kumar S, et al. Illicitly manufactured fentanyl-involved overdose deaths with detected xylazine – United States, January 2019-June 2022. MMWR Morbid Mortal Wkly Rep 2023; 72. https://www.cdc.gov/mmwr/volumes/72/wr/pdfs/mm7226a4-H.pdf

Figure 3. Drug Enforcement Administration Forensic Laboratory Identifications of Xylazine by Region
Source: U.S. Drug Enforcement Administration. The growing threat of xylazine and its mixture with illicit drugs. 2022. https://www.dea.gov/sites/default/files/2022-12/The%20Growing%20Threat%20of%20Xylazine%20and%20its%20Mixture%20with%20Illicit%20Drugs.pdf

Although xylazine can be taken alone, it is more often found as an adulterant or used in combination with many other psychoactive substances, including cocaine, heroin, synthetic benzodiazepines, alcohol, and particularly fentanyl.²⁵ Xylazine has been found not only to enhance but to prolong other drugs’ effects, while it also has been found to have prolonged opioid-like effects with solitary use. Despite its growing deadly reputation, xylazine is readily accessible via illicit internet markets, with users being able to obtain as much as 1 kg for $6 to $20.²⁶

The prevalence of xylazine use and its contribution to fatal overdoses is underestimated given that it is not routinely tested for across all U.S. states in postmortem toxicology screens, that it is not categorized as a controlled substance, nor is it included in many CDC national statistic reports. Because of its ease of access at low costs, prolongation of duration of effects by users, and the increased use of xylazine to cut substances to increase profit margins, it can be expected to see an increase in the presence of xylazine in cases of overdose.

Mechanism of Action

Xylazine exhibits its effects via partial activation of alpha-2 adrenergic receptors in a manner similar to clonidine.^27,28 Molecular studies have demonstrated a longer half-life than standard opioids, which contributes to its profound and prolonged duration of CNS depression and respiratory compromise.²⁸

Formulation and Route

Xylazine is authorized in the United States for veterinary medicine and can be purchased legally as a liquid in vials or preloaded in syringes at prepared concentrations. Unfortunately, it also can be purchased illegally at unknown concentrations as a liquid or powder form.²⁴ Routes of use depend on the formulation and whether xylazine is taken as a mixture without substances, but it can vary from IV injection to inhalation via smoking, and oral consumption.

Dosage

The dosage of legally purchased xylazine for veterinarian use is prepared in specific concentrations depending on the species for which the medication is intended. However, illicit sales of xylazine are obtained in unknown concentrations and may be taken in varying dosages depending on whether xylazine is used as an adulterant or in combination with other harmful substances.

Clinical Presentation

The presentation typically is like that of acute opioid intoxication or overdose and may include xerostomia, drowsiness, lethargy, miosis, and CNS depression resulting in profound respiratory depression. Vital sign alterations vary and may include hypertension, tachycardia, bradycardia, or hypothermia. Cardiac dysrhythmias, electrolyte disturbances, CO₂ retention, or acid-base disturbances are possible.

Particular routes of use, including injection, may result in secondary skin infections, including cellulitis and development of abscesses at the injection sites. Skin ulcerations in the setting of xylazine use also have been observed in locations other than the site of injection.²⁸ Withdrawal potential has been observed among chronic users and has been described as similar to traditional opioid withdrawal, although the presentation may be more severe than even that seen with heroin or methadone.

Diagnosis

The diagnosis is largely clinical since routine rapid screening is not yet available. Providers should be suspicious for the presence of xylazine especially in the setting of patients presenting with opioid toxidromes largely refractory to naloxone administration.²⁸

Management

Management for acute xylazine overdose is very similar to that for classic opioid overdose, with the initial step being administration of the reversal agent naloxone. The recommended dose varies between 0.04 mg to 2 mg IV, repeated every three minutes and escalation to a naloxone infusion after reaching a maximum bolus dose of 10 mg with transient effect and in those patients who need further boluses.²³

Considering that xylazine is not an opioid, the effectiveness of naloxone likely is attributed to the reversal of opioid effects of concomitant substances, likely fentanyl. It is important that the emergency provider realize that with the increasing prevalence of xylazine alone, naloxone may be less useful in cases of overdose, and management will shift largely toward supportive care.

Emergency care can include escalation to mechanical ventilation in cases of severe obtundation with profound respiratory depression. The use of alpha-2 receptor antagonists, such as tolazoline and atipamezole, has been proposed to reverse respiratory and CNS depression in acute xylazine intoxication; however, clinical data are lacking.^25,28

The published literature has only described a few cases of opioid-like withdrawal among xylazine users. The management of withdrawal symptoms and promotion of substance cessation with methadone and buprenorphine has been found to be less effective compared to those using non-xylazine opioids.²⁵

Management and Treatment

The general approach to management of acute intoxication or overdose can be daunting given that the majority of NPS ingestions fail to present as classic toxidromes. Primarily in most cases, supportive therapy exists as the mainstay of management.

After completing the primary survey and stabilization of the unstable patient, seek to obtain a detailed history from the patient, the patient’s relatives, any close contacts, or the emergency response team and perform a thorough physical examination, which could reveal clues or evidence of IV drug use by identification of track marks. Ask about time of use, route (ingestion, inhalation, injection), dosage, and potential co-ingestions to guide management. If appropriate, reversal agents, such as naloxone for suspected opioid ingestion, should be administered; in cases of high suspicion of opioid ingestion, naloxone is reasonable to attempt prior to airway management since this may rapidly improve respiratory distress.

Additionally, contact the local Poison Control Center for all cases of ingestion and send urine and blood specimens out for further analysis. The Poison Control Center not only assists in guidance of acute management but also creates a case file that can be used by governing authorities and research institutions to monitor and bring awareness to the prevalence of NPS that could lead to development of more efficient detection methods, aid clinical and forensic interpretations, and allow investigation of possible therapeutic solutions for substance overdose.

Rehabilitation/Case Management

Prior to final disposition, consult for the assistance of other ancillary staff, such as psychiatrists, social workers, substance use disorder navigators, or case managers, who would assist with the provision of outpatient community resources and assist with enrollment to rehabilitation inpatient programs if appropriate. As discussed previously, for many people with substance use disorder, it is helpful to reveal the underlying cause of their abuse to reduce dependency on harmful unregulated substances as well as inappropriate misuse of legal and prescribed substances.

For patients with opioid use disorder, harm-reduction therapy (e.g., dispensing naloxone nasal spray) and medication assisted therapy (e.g., buprenorphine or methadone) may be appropriate when enrollment in a structured outpatient program is available.

Disposition

In cases of acute ingestion or overdose, the final disposition should consider several important factors, such as resolution of symptoms, hemodynamic stability, potential for relapse of prolonged drug effects, and whether the patient has regained capacity with return to mental baseline to ensure safe discharge.

Patients may require continued therapy for secondary ailments, such as skin and soft tissue infections requiring IV antibiotics, hyperthermia requiring aggressive invasive cooling techniques, rhabdomyolysis requiring IV fluid resuscitation, secondary trauma requiring surgical interventions, or persistent suicidal ideation requiring psychiatric evaluation. Occasionally, due to lack of capabilities or specialized services at certain facilities, disposition may involve arranging for transfer to specialized facilities.

Summary

Many novel substances of abuse are initially synthesized as “legal” alternatives to classic controlled substances. They are frequently labeled as “legal highs,” “herbal highs,” or “research chemicals” and are difficult to regulate.²⁹

Deaths secondary to drug overdose in 2021 were more than six times the number in 1999, with an alarming increase of 16% from 2020 to 2021 alone. Of the approximate 107,000 drug overdose-related deaths in 2021, more than 72% involved an opioid.^20,30,31

Governmental agencies are discovering novel substances of abuse at an alarming rate, making it more difficult for authorities to regulate production and distribution despite “blanket bans” to illegalize use; there are more than 800 novel substances of abuse being tracked globally.¹⁰

New substances of abuse and their derivatives are not detected on routine drug screens, present with nonclassic toxidromes, and are refractory to standard reversal antidotes, making NPS overdose a challenging clinical presentation in emergency medicine.³²

Furthermore, novel substances of abuse often are combined with an assortment of illegal chemicals to intentionally alter the potency, characteristic of toxidrome, drug effects, and detection via routine drug screens.³³

Emergency providers should be knowledgeable of antidotes for both classic and novel psychoactive substances, but they also should be prepared to provide supportive care for undifferentiated intoxication.

REFERENCES

1. Alcohol and Drug Foundation. Drug Facts. Last updated Nov. 8, 2023. https://adf.org.au/drug-facts/#list
2. Martins D, Gil-Martins E, Cagide F, et al. Unraveling the in vitro toxicity profile of psychedelic 2C phenethylamines and their N-benzylphenethylamine (NBOMe) analogues. Pharmaceuticals (Basel) 2023;16:1-27.
3. Tirri M, Bilel S, Arfè R, et al. Effect of -NBOMe compounds on sensorimotor, motor, and prepulse inhibition responses in mice in comparison with the 2C analogs and lysergic acid diethylamide: From clinical evidence to forensic implication in driving under the influence of drugs. Front Psychiatry 2022;13:1-22.
4. Bersani FS, Corazza O, Albano G, et al. 25C-NBOMe: Preliminary data on pharmacology, psychoactive effects, and toxicity of a new potent and dangerous hallucinogenic drug. Biomed Res Int 2014;2014:734749.
5. Vohra R, Seefeld A, Cantrell FL, Clark RF. Salvia divinorum: Exposures reported to a statewide poison control system over 10 years. J Emerg Med 2011;40:643-650.
6. Maia LO, Beaussant Y, Garcia ACM. The therapeutic potential of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness: A systemic review. J Pain Symptom Manage 2022;63:e725-e738.
7. Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE. The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology 2018;142:143-166.
8. Raison CL, Sanacora G, Woolley J, et al. Single-dose psilocybin treatment for major depressive disorder: A randomized clinical trial. JAMA 2023;330:843-853.
9. United Nations Office on Drugs and Crime. Current NPS Threats. Volume IV. November 2021. www.unodc.org/documents/scientific/NPS_threats_IV_web.pdf
10. Holborn T, Schifano F, Deluca P. No prescription? No problem: A qualitative study investigating self-medication with novel psychoactive substances (NPS). Int J Drug Policy 2023;118:104109.
11. United Nations Office on Drugs and Crime (UNODC). Global Synthetic Drugs Assessment: Amphetamine-Type Stimulants and New Psychoactive Substances. United Nations Office on Drugs and Crime; 2017. http://www.unodc.org/documents/scientific/Global_Drugs_Assessment_2017.pdf
12. Brunetti P, Giorgetti R, Tagliabracci A, et al. Designer benzodiazepines: A review of toxicology and public health risks. Pharmaceuticals (Basel) 2021;14:1-46.
13. Andersson M, Kjellgren A. The slippery slope of flubromazolam: Experiences of a novel psychoactive benzodiazepine as discussed on a Swedish online forum. Nordisk Alkohol Nark 2017;34:217-229.
14. Galletta G. Intentional overdose on liquid clonazolam reversed with flumazenil: A case report. Clin Pract Emerg Med 2023;7:250-252.
15. Centers for Disease Control and Prevention. Provisional drug overdose death counts. National Vital Statistics System. Last reviewed March 13, 2024. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm#
16. Florez DHÂ, Dos Santos Moreira AM, da Silva PR, et al. Desomorphine (krokodil): An overview of its chemistry, pharmacology, metabolism, toxicology and analysis. Drug Alcohol Depend 2017;173:59-68.
17. Haskin A, Kim N, Aguh C. A new drug with a nasty bite: A case of krokodil-induced skin necrosis in an intravenous drug user. JAAD Case Rep 2016;2:174-176.
18. Drug Enforcement Administration. Diversion Control Division. Drug & Chemical Evaluation Section. Desomorphine. December 2019. http://www.deadiversion.usdoj.gov/drug_chem_info/desomorphine.pdf
19. Armenian P, Vo KT, Barr-Walker J, Lynch KL. Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review. Neuropharmacology 2018;134:121-132.
20. Gladden RM, O’Donnell J, Mattson CL, Seth P. Changes in opioid-involved overdose deaths by opioid type and presence of benzodiazepines, cocaine, and methamphetamine — 25 states, July-December 2017 to January-June 2018. MMWR Morb Mortal Wkly Rep 2019;68:737-744.
21. Armenian P, Olson A, Anaya A, et al. Fentanyl and a novel synthetic opioid U-47700 masquerading as street “Norco” in central California: A case report. Ann Emerg Med 2017;69:87-90.
22. Hasan T, Sami SA, Barmon J, et al. Gray death: A powerful opioid combination leading to rapid fatality — correspondence. Ann Med Surg (Lond) 2023;85:1308-1309.
23. Donaldson R, Swartz J, Young N, et al. Opioid toxicity. WikEM. Last updated July 25, 2021. https://wikem.org/wiki/Opioid_toxicity
24. U.S. Drug Enforcement Administration. The growing threat of xylazine and its mixture with illicit drugs. DEA Joint Intelligence Report. October 2022. https://www.dea.gov/sites/default/files/2022-12/The%20Growing%20Threat%20of%20Xylazine%20and%20its%20Mixture%20with%20Illicit%20Drugs.pdf
25. Zhu DT, Friedman J, Bourgois P, et al. The emerging fentanyl-xylazine syndemic in the USA: Challenges and future directions. Lancet 2023;401:1949-1952.
26. Rech MA, Donahey E, Cappiello Dziedzic JM, et al. New drugs of abuse. Pharmacotherapy 2015;35:189-197.
27. Forrester MB. Xylazine exposures reported to Texas poison centers. J Emerg Med 2016;51:389-393.
28. Alexander RS, Canver BR, Sue KL, Morford KL. Xylazine and overdoses: Trends, concerns, and recommendations. Am J Public Health 2022;112:1212-1216.
29. Specka M, Kuhlmann T, Sawazki J, et al. Prevalence of novel psychoactive substance (NPS) use in patients admitted to drug detoxification treatment. Front Psychiatry 2020;11:569.
30. Kariisa M, O’Donnell J, Kumar S, et al. Illicitly manufactured fentanyl-involved overdose deaths with detected xylazine – United States, January 2019-June 2022. MMWR Morb Mortal Wkly Rep 2023;72:721-727.
31. Centers for Disease Control and Prevention. Drug overdose deaths. Center for Disease Control and Prevention. Last reviewed Aug. 22, 2023. https://www.cdc.gov/drugoverdose/deaths/index.html
32. Moorthy AS, Erisman EP, Kearsley AJ, et al. On the challenge of unambiguous identification of fentanyl analogs: Exploring measurement diversity using standard reference mass spectral libraries. J Forensic Sci 2023;68:1494-1503.
33. Di Trana A, Berardinelli D, Montanari E, et al. Molecular insights and clinical outcomes of drugs of abuse adulteration: New trends and new psychoactive substances. Int J Mol Sci 2022;23:14619.