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Abstract

Over the past decade, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a surge in the use of drugs such as synthetic cathinones and cannabinoids, poison centers throughout the United States have seen a dramatic rise in calls related to these new designer drugs of abuse. In the majority of cases, care is largely supportive but significant medical and traumatic complications may occur. Providers must be aware of the ever-changing trends in abuse, so that they may optimally care for poisoned patients.

Keywords

Drug abuse human toxicology poisoning

Introduction

In recent years, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a surge in the use of drugs such as synthetic cathinones and cannabinoids, poison centers throughout the United States have seen a dramatic rise in calls related to these new designer drugs of abuse. The number of calls made to US poison control centers pertaining to synthetic cannabinoid exposures more than doubled from 2906 in 2010 to 6959 in 2011. Even more dramatic was the rise in calls made regarding synthetic cathinones (commonly known as bath salts), increasing from 304 in 2010 to 6138 in 2011 (Figure 1). Evidence of abuse of other synthetic and plant-derived compounds has been appearing across the United States with trends suggesting peak use is yet to come.¹

Figure 1.

US poison center reported cases by agent.

While trends in drug abuse impact the practicing clinician, they also have significant public health and safety implications. The Office of National Drug Control Policy tracks statistics pertaining to drug use among individuals arrested in five representative counties throughout the United States through the Arrestee Drug Abuse Monitoring Program II (ADAM II). In 2012, ADAM found that of arrestees, over 50% tested positive for marijuana, approximately 25% tested positive for cocaine metabolites, and 10–15% tested positive for opioids. Most notable is the trend in methamphetamine use, whereas only 3–31% were testing positive in 2000, 13–40% tested positive in 2012.² It is important to keep in mind that these newer synthetic drugs of abuse are not commonly detected on routine toxicology screens, making it difficult to quantify their contribution to criminal activity. In addition, the utility of these screening tests to determine current versus more remote use is limited. Nonetheless, there is a strong association between the use of illicit substances and criminal activity.

The emergency department (ED) is often the first and only contact an acutely intoxicated individual may have with the medical community. With this in mind, the US Department of Health and Human Services established a public health surveillance system known as the Drug Abuse Warning Network (DAWN). DAWN monitors the number and characteristics of ED visits attributable to compounds of concern, with data available since 2004. For example, in 2010, DAWN detected a significant increase in the number of visits attributable to synthetic cannabinoids.³ In 2010, there were approximately 2,300,000 ED visits that involved drug misuse or abuse, and of those, 11,406 visits were specifically linked to synthetic cannabinoids. While cocaine and heroin remain common drugs of abuse, the current and dramatic escalation in use is unique to these relatively newer agents.³

This review will focus on the pharmacology, clinical presentation, and management of several common emerging drugs of abuse, combining data from basic science research with clinical experience from case reports and series (Table 1).

Table 1.

Psychiatric and medical side effects of selected substances abuse.

Substance	Psychiatric presentation	Medical presentation	ED management
Synthetic cannabinoids	Excitatory effects: agitation, anxiety, hallucinations, paranoid behavior, and psychosis	Vomiting, tachycardia, hypertension, tremor, seizures, altered mental status, rhabdomyolysis, and renal failure	Airway management, control agitation; mainly benzodiazepines, and supportive care
Synthetic cathinones	Euphoria, excitement, increased alertness, increased libido, hallucinations, and paranoia	Chest pain, sweating, headache, palpitations, seizures, catatonia, and confusion mydriasis	Airway management, control agitation; and supportive care. In severe cases may use antipsychotic agents to control symptoms
Ecstasy (MDMA)	Euphoria, sensations of closeness, and empathy	Tachycardia, hypertension, hyperthermia, altered mental status, diaphoresis, mydriasis, myocardial ischemia, seizures, intracranial hemorrhage, rhabdomyolysis, disseminated intravascular coagulation, and hyponatremia	Supportive care and benzodiazepines for agitation and seizures
Kratom	Euphoria, hallucinations, delusions, and confusion	Seizures, profound sedation, nausea, vomiting, nystagmus, and tremors	Very limited data, naloxone can be used cautiously
Salvia divinorum	Hallucinations, agitation, and anxiety	Tachycardia, diuresis, spinal analgesia, and headache	Supportive care
Desomorphine (Krokodil)	Opioid toxidrome, respiratory depression, coma, and miosis	Cellulitis, osteomyelitis, phlebitis, limb gangrene, and amputation	Naloxone should be used cautiously at the risk of precipitating withdrawal
PCP	Euphoria, hallucinations, perceptual distortions, paranoia, and anxiety	Respiratory depression, tachycardia, nystagmus, laryngospasm, and pulmonary edema	Supportive care and benzodiazepine for agitation

ED: emergency department; MDMA: methylenedioxymethamphetamine; PCP: phencyclidine.

Synthetic cannabinoids

Synthetic cannabinoids were initially developed by pharmaceutical companies in an effort to study the cannabinoid system as a therapeutic target. The first and most common compounds found in the synthetic cannabinoid products are JWH-018, JWH-073, CP 47-497, and JWH-200.⁴ While few resemble the structure of the parent compound tetrahydrocannabinol, all are potent agonists at the cannabinoid receptor. Synthetic cannabinoids are known by a variety of names, such as “Spice” or “K2” and sometimes are referred to as “synthetic marijuana” or “fake marijuana.”

In response to rising rates of abuse, some states enacted bans on a handful of substances. In 2011, the US Drug Enforcement Agency (DEA) made five commonly used synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP47-497, and cannabicyclohexanol) Schedule I-controlled substances. Prior to this legislation, synthetic cannabinoid products were marketed as “legal highs” and labeled “not for human consumption” and were frequently sold in convenience shops and online. With the current ban in place, the distribution of these substances has become more restricted; however, new compounds with similar effects are being continuously developed to evade regulation.⁵

Synthetic cannabinoids are typically sprayed onto herbal or other plant materials and the product is then smoked or occasionally consumed. The clinical presentation of synthetic cannabinoid exposure can be variable depending on the dose, route of exposure, and agent involved; however, patients generally have more profound excitatory effects compared with traditional marijuana. The synthetic cannabinoids have been reported to cause agitation, anxiety, nausea, vomiting, tachycardia, elevated blood pressure, tremor, seizures, hallucinations, paranoid behavior, and decreased responsiveness. Associated psychosis may be prolonged, and there is the potential for long-term psychiatric sequela. Patients can develop rhabdomyolysis and subsequent renal failure. Secondary trauma may be present.^4,
6–8 Because these products are relatively new and clinical experience is limited, long-term outcomes and the public health consequences of their misuse and abuse have not been determined.

Synthetic cannabinoids are not currently identified using routine screening tests, and the continuous development of new products makes it difficult to detect specific compounds.⁸ Assays are available for selected compounds; however, results are not available in a timely manner and rarely alter clinical management.⁹ There is no specific antidote for synthetic cannabinoid overdose, and supportive care is the mainstay of therapy. The patient should first be stabilized.¹⁰ The majority of patients can be managed with directed diagnostic testing based on the history and physical exam. Agitation is treated primarily with liberal use of benzodiazepines. Potential coingestions should be addressed. Medical complications, such as rhabdomyolysis, and any secondary traumatic injuries should be treated. The patient should be observed until symptoms have resolved which could take 24 h or longer.¹¹

Amphetamine derivatives

Synthetic cathinones: “bath salts”

Amphetamines have long been appreciated and utilized for their stimulant properties; they act not only by enhancing the effects of neurotransmitters such as norepinephrine, dopamine, and serotonin but also by inhibiting their reuptake.¹² The most common synthetic cathinones that are used illicitly are mephedrone, methylone, and 3,4-methylenedioxypyrovalerone (MDPV); however, there are many other compounds available. The majority of compounds are formed through minor substitutions to the parent molecule, resulting in β-ketophenethylamines, a more hydrophilic version of amphetamine.⁶ Consumers can purchase synthetic cathinone products in smoke shops, online, or in convenience stores. They are sold in packets containing white or light brown powder that can be ingested, snorted, or smoked. Common names include “ivory wave, vanilla sky, and white ice”.¹³

Synthetic cathinones first became popular in Europe in the early 2000s, and worldwide users began to appreciate this legal alternative to ecstasy and methamphetamine. These agents saw a very dramatic increase in use in the United States over the past few years. In 2011, US poison centers received 20 times the number of calls related to synthetic cathinones as they had in 2010.¹⁴

Like synthetic cannabinoids, sale through online sources and convenience stores, with labels reading “plant food” and “not for human consumption” originally allowed evasion of regulation. However, the dramatic rise in abuse was met with expeditious legislation. In July 2011, President Barak Obama signed a bill permanently banning MDPV, mephedrone, and “similar” analogs.¹⁵ Concern remains that individuals will continue to manufacture structurally similar compounds that remain potentially toxic and yet evade regulation.

The symptoms of synthetic cathinone intoxication, most commonly referred to as bath salts, can last anywhere from 1–6 h, but the let down can prove to be as protracted as 2 days.¹³ Some of the more desirable effects include euphoria, excitement, increased alertness, and increased libido. There is also the potential for prominent adverse effects, with at least one reported by more than half of all users. These include chest pain, sweating, headache, palpitations, hallucinations, mydriasis, paranoia, seizures, catatonia, and confusion.¹² Secondary trauma, rhabdomyolysis, and infectious complications from injection can also occur.¹⁶ Warrick et al., for the first time, reported that patients used these stimulants in attempted suicides.¹⁷

Currently, laboratory tests have been developed for selected agents but are not readily available in the clinical setting; therefore, the diagnosis should be based on history, physical examination, and clinical suspicion.^18,19 Amphetamine screens may yield false positive results.²⁰

Supportive care with directed diagnostic testing is the standard treatment for synthetic cathinone intoxication. Stable patients can be discharged home after a period of observation. Conversely, those with more severe agitation, evidence of trauma, or medical complications such as renal failure generally require admission. Treatment consists primarily of fluid and electrolyte repletion and control of agitation with benzodiazepines. In only the most severe of cases, antipsychotic agents may be required to control the patient and prevent self-harm.²¹

Ecstasy (MDMA)

Ecstasy (methylenedioxymethamphetamine, MDMA) emerged as an alternative to traditional amphetamines in the 1980s and still remains a very popular drug of abuse in the United States today. While DAWN suggests its peak use occurred in 2009, 21,836 ED visits in 2010 were attributed to ecstasy, an increase from only 10,227 in 2004, demonstrating the great potential for fluctuation in use (Figure 2).³

Figure 2.

The emergency department visits attributable to ecstasy.

MDMA is an amphetamine analog, but it differs from traditional amphetamines in that it has more pronounced serotonergic effects and less potent sympathomimetic effects.²² MDMA is best known and widely used for its central nervous system effects, including euphoria, sensations of closeness and empathy, as well as the sexual arousal users experience. It is commonly known as a “party drug” and has become very popular in the rave scene worldwide. Ecstasy has been a DEA-controlled substance for many years. It was originally designated Schedule I in 1986, then it became legal again briefly, until it was permanently relabeled a Schedule I substance in 1988.²³

Most MDMA users ingest the drug, which is commonly formulated into multicolored tablets, but others do choose to crush and nasally insufflate tablets. It is very common to see users of MDMA also using other substances simultaneously; some of the most common coingestants include alcohol, marijuana, and lysergic acid diethylamide.²⁴

Similar to other amphetamines, MDMA users can present with sympathomimetic symptoms, including tachycardia, hypertension, hyperthermia, altered mental status, diaphoresis, and mydriasis. More serious complications include myocardial ischemia, seizures, intracranial hemorrhage, rhabdomyolysis, disseminated intravascular coagulation, and secondary trauma. Okunoye et al. reported a case of acute myocardial infarction in a pregnant woman that demonstrates the potential severity of the aforementioned pathophysiology.²⁵ Hyponatremia is a complication that is more common with MDMA compared to other amphetamines; this can be partly attributed to release of antidiuretic hormone. In addition, users of MDMA often take in large amounts of free water and lose large amounts of sodium via perspiration during dance parties or raves.^26,27 There is no specific antidote for MDMA intoxication, and the mainstay of management is aggressive supportive care, including fluid and electrolyte repletion, benzodiazepines for agitation and seizures, and treatment of any additional medical or traumatic complications. The majority of patients without complications may be discharged after a period of observation. Although MDMA is not specifically included in standard drug screens, patients who have taken MDMA may test positive for amphetamines.²⁴

Nontraditional opioids

Kratom

Although frequently used by opioid-dependent individuals, Kratom is an alkaloid plant derivative compound that does not resemble other opioids in its chemical composition, but acts on μ- and δ-opioid receptors.⁵ Indigenous to Southeast Asia, many users may obtain teas, gums, or powders of the leaves over the Internet. It may also be referred to as “Thang, Thom, or Biak”. Kratom has been used both to treat symptoms of opioid withdrawal, as well as a drug of abuse in and of itself.²⁸ The primary active alkaloid in Kratom is mitragynine, which has pharmacologic effects on opioid receptors, as well as the adrenergic and serotonergic systems. As such, Kratom use has been associated with analgesic and stimulatory effects. At low doses, the stimulant effects are more prominent, but at higher doses, the analgesic effects prevail.⁶

Although currently listed as a “drug of concern”, Kratom is not classified under the Controlled Substances Act at this time in the United States.²⁹ Heavy use can lead to adverse effects such as seizures, profound sedation, nausea, vomiting, nystagmus, and tremors. There is a well-described withdrawal phenomenon in individuals who are long-term Kratom users.²¹ Data regarding the management of Kratom intoxication is limited. Naloxone may be administered cautiously for significant respiratory or central nervous system depression.²⁹ Overall, the mainstay of treatment is aggressive supportive care. Kratom does not show up on routine drug screens. Specific assays have been developed to detect Kratom, but they are not widely available.

Salvia divinorum

Salvia divinorum has recently gained popularity because of its hallucinogenic properties, relatively short duration of action, and ease of accessibility. The plant itself is a member of the mint family, and it is sold in small packages available at many head shops and convenience stores. The crushed plant material is most commonly smoked but can also be chewed. Within the past decade, the United States has seen a surge in use; an estimated 1.8 million Americans have used S. divinorum in their lifetime—the vast majority being adolescents and young adults. Other designations include simply “Salvia” but also “mystic sage”, “magic mint”, and “purple sticky.” Current regulation does not prohibit use in the United States, though many European countries have banned its distribution.⁶

S. divinorum is a diterpene in chemical structure and is highly specific to the κ-opioid receptor, with stimulation resulting in hallucinations, diuresis, and spinal analgesia, with minimal respiratory depression. Users experience positive and negative effects within 5 min, which subsequently resolve in approximately 20 min, although hangover effects can persist for several hours. Positive effects include relaxation, improved mood, calmness, dream-like experiences, and increased self-confidence. Common adverse reactions include diaphoresis, drowsiness, dizziness, psychomotor agitation, anxiety, tachycardia, and headache; however, the majority of patients require minimal observation and supportive care. While exposure to S. divinorum alone rarely leads to clinically significant adverse outcomes, concomitant use of marijuana, alcohol, and other hallucinogenic compounds is common and may exacerbate symptoms. Although assays have been developed to test for S. divinorum, they are not in widespread use and the compound is not detected on routine drug screens.^6,30

Desomorphine (Krokodil)

Desomorphine was originally created as a less expensive morphine equivalent but instead gained a reputation as the “poor man’s heroin”. Krokodil use began to escalate in Russia and Eastern Europe in the early 2000s, but more recently gained popularity in the United States. Desomorphine is manufactured from codeine tablets in a process similar to that of methamphetamine production from pseudoephedrine.³¹ Desomorphine itself is a result of a demethylation process applied to dihydrodesoxycodeine. While significant literature on the substance is lacking due to its only recent resurgence, the majority of existing data is extrapolated from knowledge of the parent compound. When used, desomorphine is most commonly heated and liquefied then injected intravenously. This leads to bumps and a scale-like appearance of the skin surrounding the injection sites. It is from this local soft tissue reaction that the drug acquired the name Krokodil.³²

An individual who has been exposed to an overdose of desomorphine will behave similarly to other opioid overdoses; the provider should be aware of respiratory depression and altered mental status. Desomorphine is known to be 10 times more potent than morphine and a prolonged detoxification period of up to 1 month may be required. Naloxone acutely reverses the effects of desomorphine but should be used cautiously at the risk of precipitating withdrawal.³² Those presenting critically intoxicated may require either airway management or observation until the effects dissipate; however, ischemia due to chronic use may require additional intervention and debridement or amputation depending upon the extent.^32,33 Due to the unregulated and highly contaminated production process, this already destructive drug has been linked to severe forms of infectious complications, tissue necrosis, gangrene, and end-organ failure. Desomorphine may cross react with opioid screens but a specific assay is not readily available.

PCP analogs

Methoxetamine

Methoxetamine is a new drug of abuse, first appearing in 2010 in the United States. It is a synthetic analog of phenylcyclidine (PCP) and ketamine and acts similarly through N-methyl-d-aspartate receptor blockade. Chemical manufacturers have made multiple small substitutions to the parent arylcyclohexylamine compound ketamine to produce this new entity.⁶ Methoxetamine can be used via several routes of administration, including intramuscularly, orally, inhalation, rectally, or intravenously. Common street names are “M-ket” or “Special K”, although the latter can also refer to ketamine.³⁴ Currently, methoxetamine is not regulated in the United States, although with rising trends in misuse and abuse, legislation is likely soon to follow.

Users of methoxetamine appreciate the euphoria, hallucinations, and perceptual distortions attributed to the drug.⁶ Providers should be cognizant of the paranoia, anxiety, respiratory depression, tachycardia, nystagmus, laryngospasm, and pulmonary edema that have been reported in users. Management is similar to that of the patient acutely intoxicated with PCP; supportive care, benzodiazepine administration in cases of agitation, identification and treatment of rhabdomyolysis, and respiratory support are needed. Routine testing for this compound is not available.⁶

Summary and conclusions

Since the early 2000s, there has been a rapid rise in the misuse and abuse of several emerging agents. This review is not all-inclusive, it highlights several common themes. These compounds are heterogeneous in nature and can have a spectrum of clinical presentations. The content of specific products can be highly variable and rapidly evolving to avoid regulation. Confirmatory tests are rarely available in a timely manner, and as such, providers must treat based on clinical presentation. In the majority of cases, care is largely supportive, but significant medical and traumatic complications may occur. Providers must be aware of the ever-changing trends in abuse, so that they may optimally care for poisoned patients.

Current trends of misuse and abuse are anticipated to continue despite more stringent governmental regulation and control. Clinicians must be aware of these emerging agents of abuse and the various presentations and complications that may occur in an effort to mitigate adverse and potentially fatal outcomes.

Furthermore, the lifestyle associated with drug use, abuse, illegal manufacturing, and obtaining these compounds from unregulated sources leads not only to a subset of individuals desperate to acquire these substances but also burdens law enforcement, the medical community, and society as a whole. While federal agencies continue to limit particular compounds, it is often many months or years after they have entered the market. A multi-faceted approach will be required to ultimately curb the morbidity and mortality associated with the use and abuse of these agents.

Footnotes

Conflict of interest

The authors declared no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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