Newly Emerging Drugs of Abuse and Their Detection Methods

An ACLPS Critical Review

Li Liu, MD, PhD; Sarah E. Wheeler, PhD; Raman Venkataramanan, PhD; Jacqueline A. Rymer, MT(ASCP); Anthony F. Pizon, MD; Michael J. Lynch, MD; Kenichi Tamama, MD, PhD


Am J Clin Pathol. 2018;149(2):105-116. 

In This Article

Overview of Emerging Drugs of Abuse

Synthetic Cathinones ("Bath Salts")

Amphetamine is a potent and prototypical central nervous system stimulant. It is medically used for attention deficit hyperactivity disorder and narcolepsy, but its analogs, such as methamphetamine and MDMA, are abused worldwide. Cathinone, with an extra β-keto group to the amphetamine structure, is an active compound in Catha edulis (khat), a flowering plant indigenous to the Horn of Africa and the Arabian peninsula.[6]

Synthetic cathinones, known as "bath salts" or "legal high," are the new designer stimulant drugs of the 21st century. They emerged around 2007 in the US, and their popularity quickly gained and peaked in 2011. Since then, their use showed a slow decline, with 522 poison control center calls for exposure in 2015, representing a 10% decrease from the 582 calls in 2014.[2,3] These drugs have been "rebranded" or falsely represented as "MDMA" or "Molly"; therefore recreational users may consume synthetic cathinones unknowingly, and the data about the usage of synthetic cathinone may be underrepresented.[2]

More than 100 different synthetic cathinone compounds have appeared on the underground market and sold as "bath salts" or "plant food" and labeled "not for human consumption" in order to circumvent abuse drug regulations. The commonly abused synthetic cathinones include, but are not limited to, ethylone, 3-fluromethcathinone (3-FMC), 4-FMC, methedrone, methylenedioxypyrovalerone (MDPV), methylone, pentylone, and pyrovalerone Figure 1 . These drugs cause amphetamine-like sympathomimetic effects, including tachycardia and hypertension, as well as psychoactive effects such as euphoria, increased alertness, and violent behavior. Cardiac arrest, rhabdomyolysis, acute kidney failure, and death have been reported following use.[6]

Figure 1.

Chemical names and structures of synthetic cathinones.

In 2015, there was a dramatic increase in the overdose cases related to a new synthetic cathinone alpha-pyrrolidinopentiophenone [also known as alpha-pyrrolidinovalerophenone (α-PVP) or "Flakka"]; in Florida.[2] "Flakka"-associated psychosis (eg, hyperstimulation, paranoia, hallucinations, and violent aggression) and cardiotoxicity have been reported.[7–11]

Synthetic Cannabinoids ("Spice")

Various synthetic cannabinoid receptor agonists were originally developed through pharmacological studies of the receptors, but these compounds have subsequently been produced by illegal laboratories and sold as herbal incense products such as "Spice" or "K2".[12–14] These products started to emerge in the US in 2008 and quickly gained popularity among adolescents and young adults as legal alternatives to marijuana because of their psychoactive effects and elusiveness in routine drug screening.[15] Their availability and usage have also been increasing recently. In 2015 there were 7,779 calls to poison centers across the country regarding synthetic cannabinoid exposure, which is a 111% increase from the 3,682 calls in 2014, and is the highest number of calls ever recorded since these drugs first appeared on the recreational drug market[2,3]

Synthetic cannabinoids are two to 100 times more potent than tetrahydrocannabinol (THC) because both the parental compounds and their metabolites are potent agonists of the THC receptors, as opposed to having partial agonist effect like traditional marijuana.[16] As cannabinoid receptor agonists, they can cause similar psychoactive effects such as elevated mood or relaxation; however, severe acute toxicity including agitation, delirium, psychosis, and death have been reported due to increasingly potent pharmacological effects.[2,15]

Synthetic cannabinoids are not structurally related to the THC or the "classic" cannabinoids. The first generation of "Spice" (eg, JWH-018 and 073, JWH 250, and CP 47,497) was quickly replaced with the next generation (eg, AM-2201, XLR-11, AB-CHMINACA, and AKB48 [APINACA]) Figure 2,[17] which has caused outbreaks of severe intoxication or death.[18]

Figure 2.

Chemical names and structures of natural and synthetic cannabinoids. Both JWH-018 and JWH-073 are metabolized through hydroxylation at ④, [JWH-018 N-(4-hydroxypentyl) metabolite, ⑤, [JWH-018 N-(5-hydroxypentyl) metabolite], or ③, [JWH-073 N-(3-hydroxypentyl) metabolite].


Fentanyl-Tainted Drugs and Fentanyl Analogs. Fentanyl abuse is currently exploding across the US. As a prescription synthetic opioid and a Schedule II controlled substance, fentanyl was originally developed in the 1960s as an analgesic for pain management in cancer patients. Its potency is approximately 80 to 100 times higher than morphine and 25 to 40 times higher than heroin at the μ opioid receptor. This powerful opioid activity has made it an attractive drug of abuse. Fentanyl users experience an intense but temporary feeling of euphoria. Adverse effects include a dangerous reduction in respiration and hypoxemia, which may result in hypotension, fainting, anoxic brain injury, seizures, and death.[19,20] Recent reports have shown a dramatic increase in fentanyl-related deaths since 2010.[21–23]

Fentanyl and its analogs such as acetylfentanyl, butyrylfentanyl, and 3-methylfentanyl Figure 3 have been used as adulterants in not only heroin but also in cocaine.[3] Unlike fentanyl, its analogs have no licensed medical use but have similar or greater potency at the opioid receptor, leading to life-threatening respiratory depression. Fentanyl and its analogs, sold as heroin or instead of heroin, are widely available and greatly increase the risk of overdose death. According to the 2016 DEA Emerging Threat Report, of the 15 synthetic opioids identified in seized drug specimens, nine were reported for the first time in 2016. Submitted samples included fentanyl and its analogs being sold alone or in combination with heroin.[5] The DEA reported that fentanyl and its analogs were responsible for more than 700 deaths across the US between late 2013 and late 2014.[2] Data from the CDC indicate that the number of deaths attributable to fentanyl and its analogs has increased significantly since that time and is continuing to rise.[1]

Figure 3.

Chemical names and structures of fentanyl and fentanyl analogs.

AH-7921 and U-47700. Both AH-7921 and its structural isomer U-47700 (Figure 3) were developed as structurally unique synthetic opioid analgesics in the mid-1970s but were never subjected to clinical trials.[24–26] AH-7921 is as potent as morphine,[24] but U-47700 is 7.5 times more potent than morphine in animal models.[27] The recreational use of these compounds was first reported in 2012.[28] Since then, several fatalities secondary to overdose of these compounds have been reported.[29–31]

Mitragynine. Mitragynine Figure 4 is the major psychoactive alkaloid of the plant kratom, which is indigenous to Southeast Asia. While illegal in some countries, mitragynine started to emerge in the US as a legal psychoactive product available online. Pharmacological studies have shown that mitragynine produces stimulant effects at a low dose, while sedative narcotic effects at a high dose by acting as a selective and full agonist of the μ-subtype opioid receptor. Traditionally, mitragynine has been used in Eastern medicine to treat a variety of ailments.[32] In the US, mitragynine has been used recreationally as well as a means to treat symptoms of opioid withdrawal outside of established medical programs.[33] Toxicity from use can include agitation, as well as sedation. 7-Hydroxymitragynine is a minor constituent of kratom, but it demonstrates potency 46 times higher than mitragynine.[34]

Figure 4.

Chemical names and structures of AH-7921, U-47700, and mitragynine.

Regulatory Aspects and Laboratory Detection of Emerging Drugs of Abuse

All of the aforementioned compounds except fentanyl have been listed as Schedule I controlled substances (no currently accepted medical use) under the United States Controlled Substances Act. However, as emerging drugs are identified and scheduled, new analogs or derivatives of existing drugs are developed to circumvent regulation more rapidly than law enforcement and regulatory agencies are able to respond. Similarly, laboratory detection capability always lags behind the pace of emergence of new drugs due to the analytical chemistry work required to develop a reliable method of accurate identification. In the next section, we will discuss the laboratory detection of these newly emerging drugs.