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poppy seed tea and kratom

When good times go bad: managing ‘legal high’ complications in the emergency department

Authors Caffrey CR, Lank PM

Received 29 June 2017

Accepted for publication 20 September 2017

Published 20 December 2017 Volume 2018:10 Pages 9—23

Checked for plagiarism Yes

Peer reviewer comments 2

Editor who approved publication: Dr Hans-Christoph Pape

Charles R Caffrey, Patrick M Lank

Department of Emergency Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Abstract: Patients can use numerous drugs that exist outside of existing regulatory statutes in order to get “legal highs.” Legal psychoactive substances represent a challenge to the emergency medicine physician due to the sheer number of available agents, their multiple toxidromes and presentations, their escaping traditional methods of analysis, and the reluctance of patients to divulge their use of these agents. This paper endeavors to cover a wide variety of “legal highs,” or uncontrolled psychoactive substances that may have abuse potential and may result in serious toxicity. These agents include not only some novel psychoactive substances aka “designer drugs,” but also a wide variety of over-the-counter medications, herbal supplements, and even a household culinary spice. The care of patients in the emergency department who have used “legal high” substances is challenging. Patients may misunderstand the substance they have been exposed to, there are rarely any readily available laboratory confirmatory tests for these substances, and the exact substances being abused may change on a near-daily basis. This review will attempt to group legal agents into expected toxidromes and discuss associated common clinical manifestations and management. A focus on aggressive symptom-based supportive care as well as management of end-organ dysfunction is the mainstay of treatment for these patients in the emergency department.

Keywords: legal highs, novel psychoactive substances, toxicology, opioid toxidrome, anticholinergic toxidrome, sympathomimetic toxidrome, hallucinogens, inhalants

Much of the recent discussion on “legal highs” has focused on the so-called novel psychoactive substances (NPS), an ever-expanding group of chemicals known as designer drugs that has flooded the drug market in the past decade. 1 These chemicals are creatively marketed and continuously re-designed to stay one step ahead of current regulatory legislation. 1 However, the misuse of legal substances to produce hallucinogenic, stimulant, euphoric, or depressant effects akin to controlled substances has occurred since the earliest efforts at drug regulation. After the 1925 Geneva Opium Convention attempted to establish international control over morphine, drug manufacturers started flooding the market with uncontrolled morphine chemical derivatives. 2 Furthermore, people seeking psychoactive effects akin to illicit substances have long turned to not only novel designer chemicals but also household products such as propylhexedrine-based inhalers, dextromethorphan (DXM)-based over-the-counter remedies, and nutmeg, to name only a few.

With this expanded definition in mind, this paper endeavors to cover a wide variety of “legal highs,” or uncontrolled psychoactive substances that may have abuse potential and may result in serious toxicity. Throughout this paper, we recognize that the care of patients in the emergency department (ED) who have used “legal high” substances is challenging. Patients may misunderstand what the substance is they have been exposed to, there are rarely any readily available laboratory confirmatory tests for these substances, and the exact substances being abused may change on a near-daily basis. Recognizing these challenges we will attempt to group legal agents into expected toxidromes and discuss associated common clinical manifestations and management.

Anticholinergic legal highs

Producing the toxidrome of tachycardia, mydriasis, urinary retention, dry mucosal membranes, skin flushing, and hypoactive bowel sounds, anticholinergic agents have long been abused for their hallucinogenic, euphoric, and stimulant effects. 3,4 The major legal sources of anticholinergic drugs of abuse include the over-the-counter agent diphenhydramine as well as the ubiquitous belladonna alkaloid plants. Included in this section are other legal highs such as nutmeg as well as the mushroom Amanita muscaria (aka “fly agaric”), which also cause anticholinergic-like toxicity.

Belladonna alkaloid plants

The belladonna alkaloids are atropine, hyoscyamine, and scopolamine, which are found in large concentrations in plants such as deadly nightshade (Atropa belladonna), Jimson weed (Datura stramonium), and moonflower (Datura inoxia). 5 These plants grow widespread throughout North America. 5 Due to their ubiquity and legality, these plants have found abuse potential for their hallucinogenic properties, typically among adolescents and young adults. 6,7 Among the belladonna alkaloids, scopolamine is considered to mediate the plant’s hallucinogenic effects, while atropine causes more peripheral effects. 7 Ingestion of plant matter will result in marked adverse peripheral effects, including tachycardia and dry mouth, which often occur before the onset of their hallucinogenic effects. 7

Belladonna alkaloid overdoses manifest as anticholinergic toxicity. 7 Although fatalities have been reported from circulatory collapse and hypotension from belladonna alkaloids, 5 they are rare in the setting of isolated ingestion. An analysis of 1458 cases reported to American poison centers revealed no attributable fatalities. 8 Another series of 8 years of poison center data only found 5 reported fatalities attributable to Datura. 7 Notably, Datura ingestions may present with prolonged toxic effects lasting hours to days, given the half-lives of 2–3 hours for atropine and up to 9–10 hours for scopolamine combined with decreased gastrointestinal (GI) motility. 7

In addition to supportive care, management of belladonna alkaloid plant toxicity centers around treating agitation as well as reversing severe anticholinergic effects if needed. Decontamination with activated charcoal is controversial, as most patients will present for medical care when clinically intoxicated and agitated. 7 For cases of minor toxicity, benzodiazepines are one mainstay of supportive care. 7 For severe agitation, the cholinesterase inhibitor physostigmine is effective in reversing isolated anticholinergic toxicity. 7 Due to the risk of triggering a cholinergic crisis, including bradycardia, respiratory distress and seizures, physostigmine should be used with caution, and only with a reversal agent such as atropine on hand. 7 The starting dose of physostigmine is 0.5–2 mg in adults infused intravenously no faster than 1 mg/minute, with redosing occasionally necessary because of the drug’s relatively short half-life of 15–40 minutes. 7

Diphenhydramine (Benadryl ® , Johnson & Johnson, New Brunswick, NJ, USA) is a histamine blocker with central effects as well as anticholinergic and sodium channel blocking properties, found in many over-the-counter medications ranging from sleep aids to allergy and cold medications. 3 Although thought to have limited abuse potential due to its overly sedating qualities, diphenhydramine is, in fact, commonly abused for its euphoric and hallucinogenic effects at higher dosages. 3,9,10 Diphenhydramine is commonly co-formulated with acetaminophen, and in cases of toxic overdoses, the delayed GI motility from diphenhydramine can contribute to delayed and persistent toxic levels of acetaminophen. 11

The classic signs of diphenhydramine overdose are an anticholinergic toxidrome combined with profound sedation and at times marked agitation. 12 Diphenhydramine has also been known to produce rhabdomyolysis. 13 Also, in comparison with other anticholinergics, diphenhydramine is much more likely to cause seizures in acute overdose. 14 Diphenhydramine is chemically similar to the tricyclic antidepressants and has sodium channel blockade effects resulting in seizures and wide complex tachyarrhythmias in higher dosages. 15

Management of diphenhydramine toxicity centers around control of agitation and hyperthermia, as well as treating rhabdomyolysis, potential tachyarrhythmias, and seizures. 16 Although physostigmine has a role in reversing anticholinergic effects, it is contraindicated in cardiotoxic diphenhydramine overdoses due to the risk of asystole, and should not be used if the QRS >100 ms in the setting of a diphenhydramine overdose. 17 In case of QRS widening or tachyarrhythmias, sodium bicarbonate has been used successfully. 15 Massive overdoses due to diphenhydramine with refractory tachyarrhythmias have been treated successfully with intralipid therapy. 18

Widely available, nutmeg is known to provoke hallucinogenic effects in high dosages. According to available case reports, nutmeg reached a peak of abuse in the 1960s and 1970s. 19 It is well documented as a drug of abuse among prisoners, with Malcolm X famously detailing in his autobiography during his incarceration that a “a penny matchbox full of nutmeg had the kick of 3 or 4 reefers.” 20 Most likely due to unpleasant, dysphoric side effects as well as need to consume a large unpalatable amount, nutmeg abuse is not common among the general population. 21–23

Nutmeg’s intoxicating effects are thought to be due to myristicin, the largest chemical portion of the volatile oil of nutmeg. 24 Myristicin acts as a monoamine oxidase inhibitor (MAOI), increasing the amount of serotonin in the brain. 25 It has also been found in animal models to be metabolized into 3-methoxy-4,5-methylene dioxyamphetamine, which is a sympathomimetic with hallucinogenic and euphoric effects. 26

Nutmeg produces a biological effect similar to an anticholinergic toxidrome, with altered mental status, skin flushing, dry mucus membranes, tachycardia, and hypertension. 24 A feature to distinguish nutmeg toxicity from an anticholinergic agent is miosis, although a large amount of nutmeg intoxications with mydriatic pupils have been noted in 1 case series. 27 Treatment for nutmeg intoxications is supportive in nature. 24 One case series reported a provoked seizure in the setting of nutmeg intoxication in a person with a seizure disorder. 23 Only 2 fatalities are known in the literature, with both cases being notable for myriad confounding variables. 22 One regional survey found that nutmeg was commonly associated with concurrent drug exposures. 23

A. muscaria aka “fly agaric” is a mushroom that grows near pine trees throughout the northern hemisphere, identifiable by its bright red caps with white spots (Figure 1). 28 Legal to possess and consumed for its hallucinogenic properties, the main psychoactive components of fly agaric are ibotenic acid, an analog of the excitatory neurotransmitter glutamate, as well as muscimol, an analog of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA). 29 These contradictory chemicals are thought to result in a subjective experience similar to alcohol intoxication due to GABA-like effects, but with hallucinations due to its concurrent glutamate-like effects. 30

Figure 1 Amanita muscaria.

The clinical toxidrome of fly agaric has been said to mimic that of an anticholinergic toxidrome, with flushing, fever, and pupillary dilation. 28,31 Vomiting and diarrhea have also been reported, 31 although some sources report this to be an infrequent feature of fly agaric intoxication. 28 Termed “pantherine-muscarine” poisoning, the neurologic effects of fly agaric mimic its concurrent GABA and glutamate analog components, with sometimes rapid alternation between profound sedation and severe agitation. 31

Treatment is supportive, with consideration of GI decontamination with charcoal. 28 Benzodiazepines can be used for adverse excitatory effects such as seizures, but with caution, given potential rapid switching to muscimol-mediated sedation. 28 Effects can last up to 24 hours, and fatalities are rare. 28 Also, concurrent ingestions should be considered, including accidental ingestion of the more hepatotoxic cyclopeptide-containing mushrooms such as Amanita phalloides. 30

Opioid legal highs

As the USA grapples with unprecedented levels of opioid abuse, there has been an increased push among prescribers and regulatory bodies to curb long-term prescribing of these medications. 32 Opioid-dependent patients seeking to reduce prescription opioid use, or those who have had their prescription sources curtailed by medical providers, have increasingly turned to legally available opioid substitutes to provide euphoric effects as well as to mitigate withdrawal symptoms. 33 Legal substances that have emerged as opioid substitutes include loperamide, kratom, poppy seed tea (PST), and a number of synthetic designer opioids.

Loperamide (Imodium ® , Johnson & Johnson, New Brunswick, NJ, USA) is a peripherally acting opioid derivative used as an over-the-counter antidiarrheal since 1988. 34 Long considered a drug with low abuse potential, its central penetration is thought to be limited by overall poor bioavailability as well as the action of P-glycoproteins that actively secrete the drug from the central nervous system. 35 After many years of only scattered reports of toxicity and abuse, loperamide has recently emerged as a drug of abuse in the USA, largely going hand-in-hand with the opioid epidemic. 35 Known as the “desperate junky’s methadone,” it is mainly abused to alleviate withdrawal symptoms, and by some to provoke an opioid-based euphoria. 36 Abusers of loperamide typically take 3–4 times the recommended daily dose in 1 sitting. 35 Some also take advantage of cytochrome inhibitors such as cimetidine and grapefruit juice as well as P-glycoprotein inhibitors such as quinidine and pepper to raise serum levels of the drug. 35

Loperamide’s main toxic effects include not only the respiratory and central nervous system depression typical of opioid overdoses, but also cardiotoxicity in the form of life threatening cardiac arrhythmias. 35 Loperamide in high doses has been found to have sodium and potassium channel blocking effects, resulting in profound cardiotoxic effects. 37 It has been associated with widening of the QRS complex, prolonged QTc interval, as well as ventricular monomorphic and polymorphic tachycardias resulting in multiple fatalities. 37,38 Syncope or ventricular dysrhythmias and electrocardiogram abnormalities in a patient suspected of opioid abuse should trigger consideration of loperamide toxicity. 37 Loperamide will not show up on a standard urine drug screen. 35

Management of loperamide toxicity includes extended consideration of decontamination, treatment of respiratory depression, and monitoring and treatment of potential cardiotoxicity. 37 Charcoal-based GI decontamination has been advised up to 2–4 hours after a large overdose in the absence of contraindications, due to the drug’s GI motility slowing effects. 37 Naloxone has been used for loperamide-provoked respiratory depression, with one pediatric case needing multiple doses over a 24-hour period, presumably due to the drug’s slow elimination times. 35 Widened QRS complexes due to loperamide may be reasonably treated with sodium bicarbonate, while long QT intervals should be treated with correction of electrolyte derangements. 35 It is reasonable to treat loperamide-induced torsades with standard agents, including magnesium, defibrillation, isoproterenol, and electrical pacing. 37

Although opium and the poppy plant itself are controlled in the USA, poppy seeds are completely unregulated and can be bought in bulk. Although they do not contain any psychoactive opiates, poppy seeds have been shown to have trace amounts of opium latex containing morphine and codeine on their surface. 39 This fact has been exploited by those seeking a legal and readily accessible source of opiates by making poppy seed tea (PST). 40 PST synthesis involves steeping a bulk supply of poppy seeds in water, thus diluting a variable amount of codeine and morphine into a liquid that is then ingested. 40 PST abuse emerged among opiate-dependent patients in New Zealand after a government crackdown on heroin supply to the country. 40 The internet provides both a means of purchasing bulk poppy seeds as well as a source of information on PST use and instructions for preparation. 40 The main limitation on PST use among some users was its foul taste. 40 Users have reported an onset of 15 minutes and sometimes prolonged effects lasting up to 24 hours. 40

Although official case reports of fatalities are sparse, scattered fatalities in the popular media have been reported among young people using PST. 41 Cases of physiologic dependence on poppy seed concoctions have also been reported. 42 An issue with the synthesis of PST is the highly variable opiate content found among different seed sources, ranging from 1–2 orders of magnitude for morphine and codeine content based on seed source. 39 This may make it very difficult for those synthesizing and ingesting opiates by this method to reliably ascertain the morphine and codeine content of their PST, theoretically leading to the potential for overdose.

Kratom is the common name for the plant Mitragyna speciosa, a large leafy tree which is indigenous to Southeast Asia, containing psychoactive alkaloids with dose-dependent stimulatory and opioid-like effects. 43 By way of direct chewing of leaves or through the formation of teas and other mixtures, kratom has been traditionally used throughout Southeast Asia as an antidiarrheal, a painkiller, and a cheap opium substitute. 43 Kratom has emerged in the USA as an easily available and legal opioid substitute, available through internet suppliers as well as brick-and-mortar “smoke shops,” with the number of calls to poison centers regarding kratom increasing from 26 in 2010 to 263 in 2015. 44 In late 2016, the Drug Enforcement Administration (DEA) attempted to classify kratom and its main psychoactive alkaloids mitragynine and 7-hydroxymitragynine as Schedule I substances, a move that was met with such fierce public backlash that the agency backed down from their scheduling decision pending further review in October 2016. 45

Kratom’s main psychoactive alkaloids are mitragynine and 7-hydroxymitragynine, substances that have been shown to have activity at supraspinal μ-opioid receptors, as well as possible stimulant activity through alpha-2 receptors and 5-HT2A receptors. 44 Kratom users commonly report a dose-dependent response with stimulant effects in small doses up to opioid analgesic effects in higher doses. 46 Other subjective effects include euphoria, relaxation, increased energy, with some negative effects, including nausea, vomiting, stomach ache, and constipation. 44

The safety profile of kratom has not been fully evaluated. Well-controlled data on the toxic effects of kratom on human subjects are lacking, and case reports of toxicity are relatively rare. There have been scattered case reports of intractable seizures that are refractory to benzodiazepines in patients with acute kratom ingestions, although many cases are associated with co-ingestion of other prescription and illicit drugs. 44 Regarding their tendency to produce opioid toxicity, animal models have generally found less respiratory depression with mitragynine compared with other opioid receptor agonists, 47 and there has not yet been a case report of kratom inducing an opioid-based hypoventilatory state in which naloxone has been used. However, it would be reasonable to give naloxone in the setting of a kratom ingestion with respiratory depression. Kratom has been frequently adulterated with other opioid receptor agonists such as O-desmethyltramadol, resulting in 9 deaths in 1 case series. 48 Long-term use of kratom has been associated with intrahepatic cholestasis and other liver disease, along with hypothyroidism. 44 Patients can also develop physical dependence with withdrawal symptoms that mimic that of opioids, with symptoms such as abdominal pain, sweatiness, nausea, vomiting, and diarrhea. 147 There have been reports of fatalities with high levels of mitragynine, with kratom presumably as the cause of death, but these reports are also notable for many other co-ingestions such as propylhexedrine, benzodiazepines, and selective serotonin reuptake inhibitors (SSRIs). 49,50

In tandem with the opioid epidemic, synthetic designer opioids such as AH-7921, U-47700, MT-45, and numerous fentanyl (Sublimaze ® , Janssen Pharmaceutica, Beerse, Belgium) analogs have emerged onto the drug market in the past few years. In an effort to stem the flood of these agents, the DEA has continuously added synthetic opioids to Schedule I, including U-47700, AH-7921, and many fentanyl analogs. Still unscheduled, an opioid known as MT-45, a piperazine derivative, has found abuse as a legally available opioid. 51 MT-45 overdose produces an opioid toxidrome, and acute ingestions resulting in respiratory depression have been successfully reversed with naloxone. 52 Users of MT-45 find it to have less opioid-euphoric effects at a relatively higher financial cost and with more adverse effects, likely putting a limit to its potential as a major drug of abuse. 52 Adverse effects unique to habitual MT-45 abuse include hair loss, hearing loss, dermatitis, and cataracts. 51

A more substantial public health threat than MT-45 is the re-emergence of fentanyl and a wide range of fentanyl analogs to the illicit drug market. The abuse of fentanyl and novel fentanyl analogs dates to the 1970s, marketed in pure form such as 3-methylfentanyl being sold as “China White,” but also as surreptitious additions to traditional illicit drugs such as heroin and cocaine. 53 Periodic epidemics of fentanyl abuse has resulted in sporadic outbursts of morbidity and mortality over the past few decades. 53 In 2016 alone, the DEA saw the use of 13 different fentanyl analogs on the illicit drug market, some of which are unscheduled. 54 Fentanyl analogs vary widely in potency compared with morphine, ranging from acetylfentanyl, which is 15.7 times as potent, up to 3-methylfentanyl, which may be 569 times as potent. 53 A major consideration for the emergency medicine provider is that overdoses of fentanyl and the more potent fentanyl analogs may require substantially more naloxone than that of heroin for their reversal, up to 12 mg in a case series from Illinois. 55

Sympathomimetic legal highs

There are many “legal highs” that result in a sympathomimetic toxidrome. Many of them are abused by those seeking similar effects as the classic illicit psychostimulants such as cocaine, methamphetamine, and 3,4-methylenedioxy-N-methylamphetamine (MDMA). Others are abused for their serotonin-mediated hallucinogenic effects, but are notable for producing sympathomimetic toxicity. Many of these agents will share similarities in their treatment approach, which entails benzodiazepines, active cooling for hyperthermia, and specific management of end-organ complications related to hypertension and vasoconstrictive effects.

A Schedule I substance, cathinone is a monoamine amphetamine analog with stimulatory properties found in the shrub Catha edulis, commonly known as khat. 56 Khat is endemic to the Horn of Africa as well as the Southeast Arabian peninsula, where it is only chewed fresh for its stimulatory effects due to cathinone’s quick degradation. 56 Since cathinone’s discovery, many chemical derivatives have been synthesized and researched for possible therapeutic effects, the most successful of which is the antidepressant bupropion (Wellbutrin ® , GlaxoSmithKline, Brentford, UK) (m-chloro-Ntert-butyl-cathinone). 56

In the past decade, many synthetic cathinones have been developed and exploited for their strong stimulant effects as “not for human consumption” legal highs, marketed as “bath salts” or “plant food.” 56 When consumed, these substances have variable stimulatory effects comparable with methamphetamine or MDMA. 57 Cathinone and mephedrone do share chemical structural similarities with methamphetamine (Figure 2). Synthetic cathinones reached a peak of 6137 reports in 2012, declining to 382 in 2016, 58 likely due to federal and state efforts at scheduling and regulating these psychoactive substances. 59 Following a pattern of other NPS, new agents continue to be synthesized and marketed outside federal control according to the DEA’s Emerging Threat Report. 54

Figure 2 Chemical similarity of amphetamine, cathinone, and mephedrone; note the addition of the ketone functional group to the latter two compounds.

The toxicologic effects of synthetic cathinones mimic those of the amphetamines as well as MDMA, and treatment is primarily supportive around managing the agitation, fever, hyponatremia, and end-organ complications that can sometimes occur with these agents. 57 Full evaluation of the toxicologic effects of cathinones is complicated by the breadth and emergence of new agents, as well as the common presence of co-ingestions. 57 Notably, the main adverse effects include both cardiovascular (hypertension, tachycardia, angina, myocarditis) and neuropsychiatric (agitation, aggression, dystonia, and hyperreflexia) complications. 57 There have been a number of case reports of hyponatremia in the context of using these agents, sometimes resulting in cerebral edema and death. 57 Hyponatremia in the context of synthetic cathinone use should be managed much like MDMA-related hyponatremia, with fluid restriction for mild cases up to the use of hyperosmotic agents for cerebral edema. 57 Other noted laboratory abnormalities include metabolic acidosis, elevated creatinine kinase, elevated liver enzymes, and acute renal failure. 57

Commonly known as “Benzo Fury,” the benzofurans refer to the phenethylamine MDA (3,4-methylenedioxyamphetamine) derivatives 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-am-inopropyl)benzofuran (6-APB), currently unscheduled chemicals abused for their stimulant as well as entactogenic effects similar to the Schedule I substance MDMA. 60 Benzofurans have been found to inhibit reuptake of serotonin, dopamine, and norepinephrine, and they also have affinity for adrenergic and 5-HT receptors. 60

The subjective effects of benzofurans have been described as much like MDMA, but with more adverse effects in the form of nausea, dry mouth, dry eyes, insomnia, diarrhea, palpitations, headache, and various adverse psychological symptoms, including visual and auditory hallucinations. 60 The benzofurans have also been shown to have extended persistence of clinical effects, lasting for more than 48 hours in over half of reported cases. 60

Like many of the NPS, detailed toxicological information on the benzofurans are lacking, and acute ingestions are often concurrent with other intoxicants. 61 Case reports point to dramatic sympathomimetic symptoms, including tachycardia, hypertension, mydriasis, hyperthermia, agitation, and tremors after ingestion of benzofurans. 60 There have also been reports of myocardial ischemia, indicating perhaps more profound vasoconstrictive effects than MDMA. 62 These substances have been implicated in more than 10 deaths. 60 Management involves supportive care for sympathomimetic toxicity with benzodiazepines, as well as assessment for hypertensive emergency and rhabdomyolysis.

Benzodifurans: Bromo-DragonFLY, 2C-B-FLY, 3C-B-FLY

The benzodifurans, commonly known as the Bromo-dragonFLY compounds, refer to a relatively novel group of hallucinogenic drugs that saw escalating amounts of abuse as legally available research chemicals over the past decade. 63 They exert their potent hallucinogenic effects through 5-HT2A agonism and serotonergic release. 64 Its first member and archetype is Bromo-dragonFLY, an amphetamine derivative in which the phenyl group is buttressed by 2 dihydrofuran rings that give the compound its characteristic “dragonfly” shape as well as purported greater potency and duration of action than many other hallucinogenic phenethylamines (Figure 3). 63 Its subjective effects have been described as akin to lysergic acid diethylamide (LSD), although onset may be delayed up to 6 hours, and effects may last up to 3 days. 1

Figure 3 Chemical structure of Bromo-dragonFLY, demonstrating the dual dihydrofuran rings.

Case reports indicate that Bromo-dragonFLY compounds have potent sympathomimetic and vasoconstrictive toxicity. 1 Clinical presentations of Bromo-dragonFLY ingestions seeking medical care are notable for sympathomimetic toxidromes in the form of tachycardia, hypertension, mydriasis, diaphoresis, agitation, and seizures. 64,65 Seizure onset can be delayed, up to 8 hours after ingestion in one case. 66 There have also been cases of extended and refractory vasoconstriction lasting days after overdoses, resulting in auto-amputation of digits, renal failure, and rhabdomyolysis. 67 Deaths have been attributed to the drug, including fatalities caused by massive overdoses in Oklahoma that occurred after Bromo-dragonFLY was mistaken for the less potent derivative compound 2C-B-FLY. 65,68

Bromo-dragonFLY overdose treatment is supportive. 1 Sympathomimetic effects and seizures have been treated successfully with large and repeated doses of benzodiazepines. 64 The drug’s purported severe vasoconstrictive effects have proven refractory to a wide variety of vasodilatory therapies in available case reports. 64

A longstanding “legal high,” abused due to its relatively low cost and widespread availability, propylhexedrine (Benzedrex ® , B.F. Ascher & Co., Inc., Lenexa, KS, USA) is a cyclohexylamine nasal decongestant that is chemically similar to methamphetamine, lacking the aromatic ring (Figure 4). 69 Delivered via an over-the-counter nasal inhaler, propylhexedrine’s mechanism as a nasal decongestant is through alpha adrenergic stimulation, resulting in localized vasoconstriction of the nasal mucosa. 69 In higher doses, it also causes release of dopamine, norepinephrine, and serotonin from presynaptic vesicles much like the amphetamines. 70 Since its introduction as a safer replacement of previous amphetamine-based inhalers, propylhexedrine has emerged as a legal substitute for methamphetamine. 71 It is commonly abused by dismantling the inhaler and either ingesting the drug-soaked cotton rods whole, or by soaking the rod in lemon water and injecting or consuming the liquid. 71 Its toxic effects reflect the fact that it is, compared with amphetamine, relatively more effective at promoting peripheral adrenergic stimulation rather than dopaminergic and serotonergic release. 70

Figure 4 The single chemical difference between propylhexedrine (top) and methamphetamine (bottom) is the aromatic ring.

Toxicity of propylhexedrine mimics that of the amphetamines, but with seemingly more profound end-organ complications from its relatively higher hypertensive and vasoconstrictive effects, especially with intravenous injection. Clinical toxicity presents with a sympathomimetic-like toxidrome but with profound tachycardia and hypertension. 69 The case literature is littered with examples of significant end-organ damage from propylhexedrine’s peripheral effects, including cardiogenic shock and pulmonary edema in a 22-year-old who suffered a large anterior myocardial infarction, as well as cases of brainstem dysfunction characterized by ophthalmoplegia. 72,73 One case series from Texas details an association between propylhexedrine injection and 15 cases of sudden death. 74 Management of propylhexedrine toxicity centers around management of sympathomimetic toxicity and careful attention to and treatment of possible end-organ damage from its marked hypertensive effects.

Mescaline is a serotonergic phenethylamine hallucinogen most famously found in peyote, a small spineless cactus found in the deserts between the USA and Mexico that has been traditionally consumed by Native American tribes. 75 Although mescaline and peyote itself are Schedule I substances, other mescaline-producing cacti such as San Pedro cactus and Peruvian Torch cactus are not controlled, and can be legally obtained through horticultural suppliers. 30 Mescaline is a relatively rare drug of abuse, accounting for only 63 total exposures reported to USA poison control centers in 2015. 76

Mescaline is chemically related to amphetamines, and cases of toxicity produce a sympathomimetic-like toxidrome. 75 Sympathetic symptoms such as mydriasis, tachycardia, and agitation are commonly seen. 75 Despite its sympathomimetic effects in overdoses, life threatening toxic effects are rare. 75 In 1 case series, GI symptoms were found to predominate, with marked abdominal pains, diarrhea, and vomiting that led medical providers to misdiagnose 1 ingestion as a possibly surgical abdomen. 77 Management of mescaline intoxication is like that for many other hallucinogens: low stimulation environment and benzodiazepines with supportive care as needed. 75

Dissociative legal highs

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine are abused in recreational settings for their dissociative effects. Ketamine was officially scheduled in 1999, 78 and in the decade to follow the recreational drug market saw the synthesis and emergence of legal ketamine analogs such as methoxetamine and others. Furthermore, the over-the-counter cough remedy DXM has long been abused for its dissociative effects.

Methoxetamine, Diphenidine, 2-Methoxydiphenidine

Methoxetamine, an analog of ketamine that has NMDA antagonist activity, has been marketed via the internet as a legal high, and oftentimes as a safer alternative to ketamine abuse. 79 After many European countries moved to ban the drug in the last 5 years in response to reports of fatalities, methoxetamine was then quickly joined by a flood of other “research chemicals” with dissociative properties, such as diphenidine, 2-methoxydiphenidine, as well as PCP analogs such as 3-methoxy-PCP and 4-methoxy-PCP. 80,81 Many of these agents have not been fully described in terms of their exact pharmacologic and toxic properties, but given their subjective dissociative effects, they are presumed to be potent NMDA antagonists. 82 Methoxetamine is ingested orally or absorbed sublingually, but can also be insufflated or even injected intramuscularly and intravenously. 83 Methoxetamine presents clinically with dissociative effects as well as sympathomimetic effects, including tachycardia and hypertension. 83

Much of the morbidity of methoxetamine and other novel dissociative psychoactive substances seem to be centered around their neurocognitive effects as well as sympathomimetic qualities and propensity to be taken with other stimulatory psychoactive substances. 84 Management is supportive, with benzodiazepines and intravenous (IV) fluids. 83 Reports of diphenidine and methoxydiphenidine intoxications in Europe were noted to have a high percentage of co-ingestion with cannabis as well as other substances, resulting in severe intoxications. 84 Patients commonly presented with hypertension, tachycardia, anxiety, and altered mental status requiring supportive care with benzodiazepines and sometimes propofol. 84 A high proportion of the 20 reported deaths due to methoxetamine intoxication were also notable for numerous co-ingestions of illicit as well as other legal NPS. 85

DXM is a selective σ receptor agonist that has been used for many decades in the USA as an over-the-counter cough remedy. 86 Since its introduction in the 1950s, DXM preparations have been abused for hallucinogenic and dissociative effects at high doses, a fact that led to its brief removal from the market in the 1970s and reformulation into worse-tasting compounds thought to have less abuse potential. 87,88 Akin to many other legal highs, teenagers and young adults comprise the highest proportion of DXM abusers, among whom DXM abuse is known as “robotripping.” 89,90 Those abusing DXM-containing over-the-counter formulations can also exhibit signs of toxicity from coformulatory compounds, including hepatotoxic effects from acetaminophen, anticholinergic effects from diphenhydramine, depressant effects from ethanol, and sympathomimetic effects from pseudoephedrine. 89,91 Those who wish to abuse DXM in purer forms can chemically extract it from over-the-counter preparations, as well as buy pure powder legally from online chemical distributors. 92,93

DXM ingestion produces dissociative effects through its metabolism by cytochrome CYP2D6 to dextrorphan, an NMDA antagonist similar to PCP and ketamine. 90 Like other dissociative agents, dextrorphan is also thought to exert adrenergic effects by inhibiting peripheral and central catecholamine re-uptake. 94 Further, as an isomer of the opioid levorphanol, DXM at high doses can affect opioid receptors, resulting in signs of opioid toxicity, including respiratory depression and miosis. 89,95

The subjective effects of DXM abuse have been noted to entail 3 dose-dependent plateaus, with low doses producing mild stimulant and euphoric effects, middle doses producing an effect like concurrent alcohol and marijuana intoxication, and large doses producing a dissociative effect like ketamine or PCP intoxication. 94,96 Clinically, presentations of DXM ingestions largely depend on the dose ingested, producing mainly effects on the central nervous system, including restlessness, lethargy, ataxia, slurred speech, as well as hyperreflexia. 97 Patients can also present with sympathomimetic effects, including diaphoresis and hypertension. 97 Effects on the ophthalmologic exam produce varying results, including everything from rotary nystagmus and mydriasis to the miosis seen in opioid ingestions. 97 Onset of symptoms usually occurs 30 to 60 minutes after ingestion, and will persist for an average of 6 hours, making any asymptomatic presentation 4 hours post-ingestion at very low risk of later developing toxicity. 89

The major toxic effects of DXM are managed with supportive care, and are centered around benzodiazepines for acute agitation, management of toxicity from coformulatory agents, as well as possible serotonin syndrome. 89 Guidelines also promote the use of activated charcoal up to 1 hour after the reported time of ingestion. 89 It is reasonable to give naloxone to comatose or bradypneic patients in whom DXM ingestion is suspected, as opioid effects or opioid co-ingestants may be present. 89 Long-term DXM abuse has produced cases of physical dependence in which abrupt cessation of the drug results in physical withdrawal symptoms of vomiting, myalgias, diarrhea, and night sweats. 89

A major concern with DXM ingestion, even at therapeutic dosages in concert with certain other serotonin-affective drugs, is the risk of serotonin syndrome. There have been cases of serotonin syndrome when DXM was taken at antitussive therapeutic dosages in patients on therapeutic MAOIs such as phenelzine, as well as selective serotonin reuptake inhibitors such as fluoxetine. 89 Such presentations should be managed aggressively with IV fluids, benzodiazepines, and active cooling measures. 89

As DXM is commonly found in bromide salt, there have been theoretical concerns that massive ingestions will result in bromide toxicity as well as false elevations of chloride and even negative anion gaps due to misidentification of bromide for chloride by laboratory autoanalyzers. However, the only available evidence of bromism in the form of elevated chloride and a low (or negative) anion gap in the context of DXM use comes from a single case report. 98 A more recent case report of DXM-related clinical bromism occurred when DXM was used with an older bromide-containing pharmaceutical. 99

Hallucinogenic and other compounds

There are many legal hallucinogenic compounds that lack a discrete toxidrome. Many do increase serotonergic transmission resulting in stimulatory effects, including tachycardia and hypertension. Agitation and neuropsychiatric symptoms predominate with these agents.

Native to Oaxaca, Mexico, Salvia divinorum is a leafy plant of the mint family that has been long recognized for its psychoactive properties when inhaled or sublingually absorbed. 100 Salvia is not currently controlled at a federal level in the USA, although it is banned by several individual states. 100,101 The active component in salvia is the chemical salvinorin A, a strong hallucinogen with potency similar to LSD but a mechanism of action novel among the hallucinogens, acting at κ-opioid receptors. 102 The subjective effects of salvia have been variably described, with some likening it to LSD but others to a very strong cannabis intoxication. 47,103 Salvia intoxication has a quick onset, within 30 seconds, and a total duration of hallucinogenic effects lasting usually 104

There is a lack of reports of salvia intoxication resulting in any serious physiologic toxicity. 47 A 10-year survey of a major poison control system’s experience with salvia intoxications showed that most patients reporting sole salvia ingestions required only simple monitoring. 105 Patients in this survey who presented with clinical instability or persistently altered mental status were usually under the influence of other concurrent intoxicants, in one case a suspected belladonna alkaloid ingestion. 105 If a patient reports salvia intoxication and becomes unstable or dramatically altered over time, one should suspect coingestion of other toxic substances or possible concurrent medical or psychiatric illness.

Lysergic acid hydroxyethylamide (LSA) plants

A 5-HT2A agonist, LSA is a naturally occurring hallucinogen that is chemically related to LSD and about one-tenth as potent. 106 LSA can be found in the seeds of the ornamental plants Ipomoea violacea (morning glory) and Argyreia nervosa (Hawaiian baby woodrose). Although seeds are often treated with an emetic by seed producers in order to discourage abuse, morning glory and woodrose seeds have been long abused as a legally available LSD substitute. 106 After ingestion of crushed seeds, onset of hallucinogenic effects usually occurs within 1 hour and can last up to 10 hours. 106

Major side effects include nausea, vomiting, and abdominal discomfort, which are thought to limit the abuse potential of LSA-containing seeds. 107 Fatalities are rare, and those reported are usually secondary to self-harm due to acute agitation. 108 In addition to producing hallucinogenic effects and agitation, the LSA-containing plants have been known to produce tachycardia, hypertension, pupillary dilation, flushing and polyuria. 108 In the ED, suspected ingestion can be managed through sensory isolation and benzodiazepines as needed. 109

With street names such as K2 and “Spice,” the synthetic cannabinoids (SCs) are a heterogeneous and continually growing group of chemicals designed to produce the effects of the prototypical chemical tetrahydrocannabinol (THC) by acting on cannabinoid receptors. 110 Given they usually share little to no similarity with THC, almost all will escape detection through standard urine toxicology screens. 110 Many have been added to Schedule I. 111 However, illicit drug manufacturers continue to design new analogs to escape existing regulations. 110 The chemicals in liquid form are typically spread onto plant material that is then smoked or ingested, consumed outright, or vaporized and inhaled through electronic cigarettes. 110

SCs are chemically heterogeneous but what they have in common is their affinity for cannabinoid receptors. 112 A major difference between the SCs and the psychoactive compounds found in cannabis is in their relative affinity for cannabinoid receptors. Unlike marijuana, which contains over 50 known psychoactive chemicals, many of which have attenuating effects on THC, which is itself a partial agonist of cannabinoid receptors, many of the SCs are full agonists that demonstrate a much stronger affinity for these target receptors. 112 It has been hypothesized that this is why, while marijuana results in little overt toxicity, many of the SCs have been found to have marked toxic effects, including excited delirium, seizures, psychosis, cardiotoxic effects, kidney injury, coma, and death. 110 According to 1 survey of cannabis and synthetic cannabinoid users, users of SCs were much more likely to seek medical care for their symptoms. 113 The risk of agitation and cardiotoxicity exceeds cannabis by 3.8 and 9.2 times, respectively. 114

Physical examination findings of those using SCs have been found to be similar to those with cannabis intoxication, with delayed pupillary light reactions, slurred speech, and retarded sequence of movements. 115 More severe clinical presentations may present with nausea and vomiting, abdominal pain, and excited delirium. Cases of rhabdomyolysis, acute kidney injury, and even myocardial infarction have been reported. 115 SCs have also been associated with new onset refractory status epilepticus. 116 There have also been emerging cases of arterial thromboemboli in otherwise healthy young people using SCs. 117 Management centers around control of the excited delirium state as well as management of end-organ damage. 115 Effects usually last around 8 hours for most of the chemicals in question. 115

Ayahuasca, also known as hoasca, yage, and natema, is a hallucinogenic tea brewed traditionally among Amazonian tribes for religious purposes from the jungle vine Banisteriopsis caapi together with the leaves of the Psychotria viridis plant. 118 P. viridis contains most of the hallucinogenic activity through the compound N,N-dimethyltryptamine (DMT), a potent 5-HT agonist similar to LSD. 119 By itself, DMT by oral ingestion is inactivated due to first pass metabolism by GI MAO. 119 However, when combined with MAO-inhibiting beta-carboline alkaloids found in B. caapi, enough DMT is absorbed to produce psychedelic effects. 119 The number of ayahuasca exposures has risen in the last 10 years in the USA, with a peak in 2012 at around 100 reported exposures. 120 Although DMT is a Schedule I drug, and people have been prosecuted for possessing ayahuasca preparations, the plants themselves remain uncontrolled and legal to possess. 120

The most common clinical manifestations of ayahuasca intoxication as reported to poison centers were hallucinations, tachycardia, agitation, hypertension, mydriasis, and vomiting. 120 Altered mental status requiring intubation, seizures, and a few fatalities have been reported. 120 Case reports of fatalities are limited by lack of forensic and toxicologic information, but some experts have suggested possible dangerous effects, including serotonin syndrome between ayahuasca and other serotonergic drugs such as prescription MAOIs and SSRIs. 121 Treatment of ayahuasca intoxications consists of symptomatic supportive care and benzodiazepines for agitation or anxiety. 120

Kava refers to a traditional beverage prepared from the tropical shrub plant Piper methysticum, native to the South Pacific. Used for centuries for its euphoric and anxiolytic effects, kava has seen increased use in the USA, where it is considered a health supplement. 122 Kava is prepared typically by mixing crushed root or prepared extracts or powders with water or coconut milk, and it is also taken in pill form. 123 The psychoactive components of kava are thought to be a group of lipophilic substances known as the kavalactones that exert their effects through numerous possible mechanisms ranging from enhanced GABA receptor binding to reversible inhibition of MAO B. 124

Reports of acute kava toxicity resulting in adverse events requiring medical care are rare, accounting for 20 cases reported nationally in 2015. 76,125,126 Reported adverse events include headaches, dyspnea, nausea, as well as dizziness, for which treatment is supportive. 127,128 There have been reports of neurologic toxicity in the form of acute ataxia as well as dystonic reactions responsive to anticholinergics. 129,130 Kava has been shown to have more profound acute mental status depressive effects when combined with benzodiazepines and alcohol. 126,131,132 Excessive use of kava over a long term has been associated with cases of hepatotoxicity resulting in fulminant liver failure. 133 Laboratory findings in chronic kava users have shown elevated liver enzymes, as well as lower blood lymphocyte counts. 134 Physical exam findings in chronic kava users include skin photosensitivity, which usually resolves after cessation of use. 135

Long abused as readily available “legal highs,” inhalants refer to a heterogeneous group of usually lipophilic chemicals that are inhaled for their immediate consciousness-altering effects. 136 Inhalants are most commonly abused among adolescents, and the most common types of abused chemicals include the volatile hydrocarbons found in widely available products such as air fresheners, paint, gasoline, adhesives, and propellants. 137 The major non-hydrocarbon inhalant of abuse is nitrous oxide, which is found in whipped cream recharging canisters. 136 According to available surveys, reports of abuse of volatile hydrocarbons seem to be decreasing, 137 while reports of abuse of nitrous oxide seem to be increasing. 138 In 1 survey, the inhalants with the highest reported mortality included nitrous oxide, butane, propane, and air fresheners. 137

Patients abusing inhalants may present with a wide variety of subjective complaints, including dyspnea, palpitations, lightheadedness, sneezing and coughing, as well as GI complaints, including nausea and vomiting. 136 Odors may persist in the breath for several hours following inhalation. 139 Patients may also present with acute airway compromise due to chemical injury from aerosolized substances. 140 Other clinical presentations are myriad, and may include altered mental status, headaches, and GI disturbances. 136

The inhalational hydrocarbons of abuse have numerous toxic effects on the body, with cardiotoxic, neurotoxic, hepatotoxic, and nephrotoxic effects having been reported. 136 The most profound cardiotoxic effect of hydrocarbon inhalation includes what is known as sudden sniffing death syndrome, which is thought to be due to cardiac arrhythmias caused by a sudden catecholamine surge in the setting of volatile hydrocarbon-sensitized myocardium. 139 Some patients with cardiac arrhythmias due to inhalants survive long enough to present to the ED. 141 In this setting, propranolol and other beta blockers have been used as agents to decrease myocardial catecholamine sensitivity, which is thought to be the mechanism of inhalant cardiotoxicity. 141 Toluene and other hydrocarbon inhalants are also thought to sometimes cause QTc prolongation and torsades de pointes, as well as myocarditis. 142–144 Acute toluene inhalation has also been associated with marked metabolic derangements such as rhabdomyolysis and type 1 renal tubular acidosis, with hyperchloremia, hypokalemia, and a normal anion gap. 143

Besides possible acute fatal asphyxiation and even barotrauma from inhalation, the major toxic effects of nitrous oxide, aka “whippets” as they are known, are neurologic. Nitrous oxide inactivates vitamin B12, decreasing conversion of homocysteine to methionine, ultimately resulting in demyelination within the central and peripheral nervous systems. 145 This classically results in subacute combined degeneration, especially around the dorsal columns of the spinal cord. 145 Clinically, chronic nitrous oxide abuse may present with peripheral neuropathic effects, including tingling and numbness all the way up to loss of dexterity, poor balance, and leg weakness. 146 Although the neurologic changes may be irreversible, some function may be restored through cessation and B12 supplementation. 136

Existing outside of regulatory drug statutes, the drugs that can be used by patients to get “legal highs” truly represents an astounding array of chemicals, some of which are quite easily obtainable. “Legal highs” can represent a challenge to the emergency medicine physician due to the sheer number of available agents, their multiple toxidromes and presentations, their escaping traditional methods of analysis, and the reluctance of patients to divulge their use of these agents. However, a focus on aggressive symptom-based supportive care is the mainstay of treatment for these patients in the ED.

The authors report no conflicts of interest in this work.

Musselman ME, Hampton JP. “Not for human consumption”: a review of emerging designer drugs. Pharmacotherapy. 2014;34(7):745–757.

When good times go bad: managing ‘legal high’ complications in the emergency department Charles R Caffrey, Patrick M Lank Department of Emergency Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Abstract: Patients can use numerous drugs that exist outside of existing regulatory statutes in order to get “legal highs.” Legal psychoactive substances represent a challenge to the emergency medicine physician due to the sheer number of available agents, their multiple toxidromes and presentations, their escaping traditional methods of analysis, and the reluctance of patients to divulge their use of these agents. This paper endeavors to cover a wide variety of “legal highs,” or uncontrolled psychoactive substances that may have abuse potential and may result in serious toxicity. These agents include not only some novel psychoactive substances aka “designer drugs,” but also a wide variety of over-the-counter medications, herbal supplements, and even a household culinary spice. The care of patients in the emergency department who have used “legal high” substances is challenging. Patients may misunderstand the substance they have been exposed to, there are rarely any readily available laboratory confirmatory tests for these substances, and the exact substances being abused may change on a near-daily basis. This review will attempt to group legal agents into expected toxidromes and discuss associated common clinical manifestations and management. A focus on aggressive symptom-based supportive care as well as management of end-organ dysfunction is the mainstay of treatment for these patients in the emergency department. Keywords: legal highs, novel psychoactive substances, toxicology, opioid toxidrome, anticholinergic toxidrome, sympathomimetic toxidrome, hallucinogens, inhalants

Current perspectives on the impact of Kratom use

Charles Veltri

1 Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, AZ, 85308, USA

Oliver Grundmann

1 Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, AZ, 85308, USA

2 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA

Abstract

The leaves from the tree Mitragyna speciosa, commonly known as Kratom, in the coffee plant family (Rubiaceae) are commonly used in their native habitat of Southeast Asia as a stimulant to sustain energy during hard day labor and as an opioid-like analgesic and sedative. Traditional and modern uses overlap based on the effects of the leaf extract which has also gained popularity in the United States and Europe in the last two decades. Kratom has and is being used for the mitigation of opioid withdrawal symptoms and as a harm reduction agent with a minority of users subsequently developing a dependence on the extract. The respective demographic use patterns of Kratom differ between Southeast Asia and the Western world. While pure Kratom is primarily used by day laborers and misused in conjunction with cough medicine by youth in Southeast Asia, a majority of users in the United States is middle-aged, has at least middle income, private health insurance, and completed some college. Deaths attributed to the use of Kratom have been reported in Europe and the United States but not in Southeast Asia. Although Kratom was detected as the alkaloid mitragynine in the blood of the decedents, causality could not be established in almost all cases because of poly-drug exposures. It is notable that Kratom can cause herb–drug interactions, especially with other central nervous system -active substances. Given the mostly unregulated market for Kratom products in Western countries, consumers may be exposed to adulterated or contaminated products, especially if purchased through websites or the darknet. A number of countries have scheduled Kratom because of its stimulant- and opioid-like effects and the established interaction of the alkaloid mitragynine with opioid receptors.

Introduction

Kratom (Mitragyna speciosa Korth.) is an evergreen tree in the coffee family (Rubiaceae) that is native to Southeast Asia and cultivated especially in Indonesia, Malaysia, and Thailand for its historical medical and recreational uses.1 Kratom is also referred to as biak-biak, ketum, or Maeng Da in different regions and describes both the tree and the varying extracts and preparations derived from it.2 The leaves of the tree, that are used for their pharmacological activity, can have different colored veins (white, green, or red) which are not distinguished in its native habitat but have been attributed to varying effects when sold as powdered leaf extracts in Western countries.3 The main active compounds of current interest are indole alkaloids, primarily mitragynine and 7-hydroxymitragynine that act as partial agonists on opioid receptors.4 Kratom products contain approximately 2% mitragynine and either none or between 0.01% and 0.02% 7-hydroxymitragynine.5 Among other mitragyna indole alkaloids, mitragynine presents with a unique mechanism of action and pharmacology distinct from classical opioids like morphine, heroin, or fentanyl. Binding to the μ-opioid receptor causes recruitment and activation of the G-protein-coupled signaling cascade but does not lead to recruitment of β-arrestin 2 which has been associated with many of the undesired effects of opioid receptor activation such as constipation, respiratory depression, and dependence.4,6 In animal models, mitragynine did not cause dependence or increased self-administration and even reduced prior administration of morphine whereas 7-hydroxymitragynine did present with a dependence liability.7

The use of Kratom in Southeast Asia has been documented back for at least 150 years and described both a stimulant effect for use in hard day labor when fresh leaves are chewed and an analgesic and relaxing effect if brewed into a tea.3 It also serves as a substitute and mitigation strategy for opium that was widely used in Malaysia and Thailand from the 1830s to the 1920s.3 In addition, Kratom remains in use for its antispasmodic, muscle-relaxant, and antidiarrheal effects while both its brief stimulant and analgesic effects remain a popular home remedy in Southeast Asia.8,9 The use of Kratom is prohibited in Malaysia under Poisons Act 1952, but its use remains widely spread because the tree grows natively and tea decoctions are readily available in local communities.1 Thailand lifted the ban on the use, production, and possession of Kratom in 2018 for medicinal purposes.10

The increase of Kratom sales across Europe and North America caused rising concerns about its safety with several European countries banning the plant and its active alkaloids.11 The status of Kratom as a dietary supplement remains vague in the United States as of this writing because the Food and Drug Administration (FDA) does not consider Kratom a recognized supplement that has been present on the US market prior to the enactment of the Dietary Supplement Health and Education Act (DSHEA) of 1994 that would have allowed for such a provision.12 Instead, the FDA has designed mitragynine and 7-hydroxymitragynine as opioids and recommended placement of these compounds into the Controlled Substances Act Schedule I by the US Drug Enforcement Administration (DEA).13 As of this writing, this scheduling action has not taken place despite an earlier attempt by the agency to do so which was withdrawn based on public comments and the action by several members of the US congress. Several US states have either banned Kratom and its active alkaloid compounds or enacted laws that prohibit the sales of adulterated products that are not appropriately labeled according to Good Manufacturing Practices.12,14

Kratom users in the West are using the leaf extract and its varied formulations for a range of health reasons that primarily relate to chronic pain, mood disorders, or mitigating the withdrawal symptoms of a prescription or illicit drug dependency.15 Although the number of Kratom users in the United States remains vague, the estimate ranges from 3 to 5 million based on survey data and membership information provided by the American Kratom Association.16

This review provides a current perspective on the use pattern and impact of Kratom use on the individual and society. The implications of Kratom use are discussed both from the use as a traditional herb and supplement as well as a potential future medicine, either as a pure drug or complex natural extract.

Methods

PubMed and Google Scholar databases were searched on April 9, 2019, for all research and review articles covering Kratom use patterns. The initial search terms were: “Kratom” AND “use pattern” or “Kratom use pattern” or “Kratom” AND “misuse” or “Kratom” AND “abuse”. The search returned a total of 2,596 sources. Of these, 91 resulted from PubMed and 2,505 from Google Scholar searches. Both authors evaluated articles for inclusion in the review independently. Initially, duplicates were eliminated, reducing the total number of references to 2,364. Further exclusion of non-English literature resulted in further reduction of the number of references to 1,823. Following evaluation of references, a total of 467 references were initially deemed relevant to the topic of the review. Exclusion of several book chapters that referred back to primary literature and references that referred to original research articles narrowed the references to a total of 44 that were included in this narrative review.

Kratom use pattern in Southeast Asia

The first reported use of Kratom in the scientific literature dates back to 1836 when it was noted that the leaves of the tree were used by Malays as a substitute for opium.17 In addition, other observations documented the traditional use of Kratom leaves and its preparations as a wound poultice, for fever, and for mitigating the withdrawal symptoms from opium and later heroin.17 Its traditional use has not been dated and has likely been part of the social fabric for hundreds of years given that the tree grows indigenously throughout Malaysia, Thailand, and Indonesia.8 Its use in Malaysia and Thailand has been primarily for two broad applications: as a stimulant to increase work efficiency, endurance, and tolerance to hot and humid climate conditions for manual laborers and as a medical remedy for a range of symptoms. The latter practice as a traditional medicine and home remedy primarily uses fresh or dried leaf material to prepare a decoction by brewing the leaves and ingesting it as a beverage either hot or cold. In this form, the effects have been primarily described as analgesic, relaxing, anti-diarrheal, antipyretic, and anti-diabetic.18 Far less common is smoking of the dried leaf although it is occasionally reported in Malaysia and associated with a relaxing effect.18

The most recent study investigating the prevalence of Kratom use was conducted in 2007 in Thailand among 26,633 respondents between the ages of 12 and 65 years.11 The lifetime prevalence for Kratom use among all users was 2.3% which was higher than for marijuana use while 13- to 16-year-old students reported a 9.4% lifetime prevalence in a 2004 survey. Kratom is the most commonly used illicit drug in Thailand, and similar percentages are likely for Malaysia based on conducted seizures of Kratom. The high prevalence can be explained by the long history of use as both medicine and recreational drug, readily accessible plant material that grows natively in the area, and perceived safety of Kratom preparations.

Despite its traditional medical uses, Kratom dependence has been known and observed for a long time and is well documented.17 Unlike opium, opioid, or heroin addiction, Kratom addiction is not associated with a significant stigma in rural communities if a husband is taking it to support his family. However, female Kratom use is much less tolerated and there are far fewer female users in local communities.8

Scientific research on Kratom and its effects on users in Thailand and Malaysia has increased in the past 10 years given the rising interest in Kratom extracts in other countries. With a long use history and a socially acceptable tradition of use among the general population, human studies in general appear to be easier to conduct compared to Western countries although Kratom is illegal in Malaysia.

Given the long-term use of Kratom especially by day laborers to boost endurance and withstand physical labor and harsh work conditions, both the stimulant and opioid-like analgesic effects can contribute to dependence development and addiction.19,20 Two surveys conducted in Malaysia and Thailand reported that the average age of long-term Kratom users was in their mid-30s and a majority were married with lower education levels.19,20 While Kratom is both used for its stimulant and opioid-like effects, a majority of users had a history of drug abuse and primarily used Kratom to mitigate opioid and stimulant withdrawal symptoms. It was not uncommon among survey respondents to develop a dependence on Kratom. Those with lower education attainment were more likely to successfully stop using Kratom compared to those with a higher level of education.20 One potential explanation for this inverse correlation is the use of Kratom among higher educated individuals who had previously used a prescription opioid and are now either self-treating a pain condition or mitigating withdrawal symptoms from the former prescription drug. Maintaining the use of Kratom products can be relatively expensive which can correlate higher educational attainment with higher income to allow this habit. Another explanation could be the use of Kratom as a perceived “natural” alternative to prescription or “synthetic” drugs for the self-treatment of a health condition. The belief that “natural” equals safe is prevalent among more educated individuals despite a lack of support for such a statement especially in Western countries.

A cross-sectional survey investigated the correlation between amount and frequency of Kratom consumption and risk of dependence and addiction development in long-term users in three northern peninsular states of Malaysia.21 There was a correlation between increased consumption of Kratom and risk of dependency development, severity of withdrawal symptoms, and cravings for the extract. Physical withdrawal symptoms manifested as muscle spasms, diarrhea, lack of appetite, fever, pain, and runny eyes and nose. Psychological withdrawal was characterized by mood swings such as anger, nervousness, restlessness, disturbed sleep, tension, and sadness.21 Despite these findings that are similar to opioid withdrawal and craving symptoms, a majority of participants in surveys and case studies as well as their providers and caretakers do not characterize Kratom withdrawal and cravings as severe as those experienced during opioid withdrawal and those symptoms were of shorter duration.18,21,22 Although Kratom dependence is widespread, treatment admissions for withdrawal have increased in recent years from 1,000 in 2007 to almost 3,000 in 2011 in Thailand where Kratom accounts for approximately 2% of all drug treatment admissions.11 It is not yet clear if this change is based on a stricter enforcement of drug policies and how it will change with the legalization of Kratom for medical purposes in 2018.

Even if Kratom dependence and withdrawal are not perceived to be as severe as for opioids, the question of impairment with the chronic use of Kratom remains. A study involving 70 regular Kratom users and 25 control participants evaluated cognitive functioning using the Cambridge Neuropsychological Test Automated Battery (CANTAB) found deficits with higher chronic Kratom consumption (more than 3 glasses of kratom decoction consumed per day) in new learning and visual episodic memory.23 However, the authors conclude that overall Kratom users independent of the amount they consumed were comparable in their cognitive and executive functions to control participants and does not impair motor, memory, or attention function.

Kratom use and even dependence does not impair social functioning according to several studies conducted in Malaysia.9,24 A majority of chronic Kratom users are employed, married, and live with their family and rarely present with health problems. This stands in contrast to alcohol, opioids, or amphetamine abuse that are not accepted in society.25

Aside from the traditional uses of pure Kratom for its medicinal properties and as an endurance enhancer for hard labor, newer preparations of the plant have emerged that are seen as problematic. Because of its bitter taste, Kratom tea preparations are often sweetened or mixed with beverages to make it more palatable.9 However, teenagers and young adults in urban areas do mix Kratom leaves and teas with caffeinated beverages such as Coca-Cola and cough syrup containing codeine or diphenhydramine. The mixture is boiled to create a syrup referred to as 4×100.9 In many cases, the syrup provides for a more intense euphoria and is often consumed together with other drugs such as an antidepressant, anxiolytic, alcohol, or analgesic. Poly-drug use with Kratom increases the risk of fatal additive or synergistic toxic effects whereas there have been no reports in Southeast Asia of fatalities caused by the ingestion of pure Kratom preparations.

Another folkloristic use of Kratom is as a potential aphrodisiac that has been reported in several surveys of chronic Kratom users.19,20 This activity contrasts with the opioid-like effects since classical opioids are commonly associated with sexual dysfunction and decreased libido. Direct measurement of testosterone, follicle-stimulating and luteinizing hormone did not indicate any differences between Kratom users and non-users although there were some non-pathological differences in blood profiles between the low-dose and high-dose Kratom users.26 Furthermore, other studies and epidemiological data indicate that despite its use as an aphrodisiac and the potential for impairment, Kratom is not associated with an increased risk for sexually transmitted diseases or needle sharing.11

Use pattern in the United States and Europe

Unlike Kratom use in Asia, emergence into the Western markets is a relatively new occurrence. Anecdotal reports suggest that immigrants from Southeast Asia first imported Kratom into the United States in the 1980s and 1990s with an expansion of use in the United States within the past decade.5,12 In the West, Kratom is sold through the Internet and at herbal stores, tobacco/smoke shops, and “head” shops where it is primarily marketed as an herbal medicine/supplement to treat a variety of ailments (pain, mental health, opioid withdrawal symptoms) as well as a “legal” or “natural” high and alternative to traditional opioids and even promoted as an “herbal speedball.”1,11,15,27–29

Consumption of Kratom in the United States is predominantly by liquids, but the use of powders added to food or beverages and consumption of Kratom capsules is growing in popularity.12 Users brew Kratom in a similar fashion as making tea or coffee where the leaf material (whole leaf or powder) is steeped in boiling water or cold extracted. Acids have been used to enhance the extraction. The resulting tea is bitter, so sugar, honey, or various sweeteners are often added.12

Because of the route of administration as an oral supplement, there is considerable discussion about the classification of Kratom. To date, there have been few reports of injections or other routes of administration that would indicate a higher degree of abuse and dependence. Furthermore, isolation of mitragynine or 7-hydroxymitragynine has not been attempted for misuse or abuse purposes in a fashion similar to morphine from opium. However, the legality of Kratom as a supplement with limited regulatory oversight has been challenged or restricted in several countries because of its opioid-like effects and the presence of compounds that interact with opioid receptors.

The legal status of Kratom varies in the West from region to region. While the European Union has open borders between members and a shared currency, the legal status of Kratom varies. Kratom is an illegal drug/substance in Denmark, Finland, Ireland, Latvia, Lithuania, Poland, Romania, and Sweden.30 The legal status of Kratom in the United Kingdom is complex. While Kratom or M. speciosa is not listed as a commonly encountered Schedule 1 controlled substance, it most likely falls under the term of “psychoactive substance” of the Psychoactive Substances Act 2016 in the United Kingdom.31,32

Kratom is not scheduled under the US Controlled Substances Act; however, the DEA does not recognize any legitimate medical use for Kratom.29 The DEA based its stance on the FDA warning that Kratom “should not be used to treat medical conditions, nor should it be used as alternative to prescription opioids,” and that the FDA finds no indication that Kratom is safe.33 As of this writing, Kratom is legal in all US States except Arkansas, Alabama, Indiana, Rhode Island, Wisconsin, and Vermont and the District of Colombia. There are also city bans in Alton, IL; Columbus, MS; Denver, CO; Jerseyville, IL; San Diego, CA; and Sarasota, FL, as well as a county ban in Union County, MS.34 Further legislation regulating, restricting, banning the use of Kratom or reversing such bans is pending in other jurisdictions.

There are relatively few studies describing Kratom use in the West compared to studies focused on use in Asia. An online anonymous survey in the United States was utilized to answer three questions: 1) Who is consuming Kratom and for what purpose? 2) What perceived beneficial and detrimental effects are reported by Kratom users if dose and frequency of consumption are considered? 3) Does Kratom present with an abuse potential and withdrawal symptoms?15 Analysis of the demographics of this survey found that US Kratom users are white non-Hispanic males between 31 and 50 years of age, married or partnered, employed with an annual household income of US$35,000 or higher, have private health insurance, had at least some college education, and had used Kratom for more than one year but less than five years. Respondents predominantly identified Kratom use to relieve acute or chronic pain followed by use for an emotional or mental condition. Respondents identified increased energy, decreased pain, increased focus, less depressed mood, lower levels of anxiety, reduced or stopped the use of opioid painkillers, reduction of PTSD symptoms, and elevated mood as beneficial effects of their Kratom consumption. Self-reported detrimental effects appeared to be dose-dependent and included nausea, constipation, and dizziness or drowsiness as the most frequently identified negative effects. Doses of up to 5 g of Kratom presented with lower odds ratios for detrimental effects than doses of 8 g or more. Less than half of the respondents reported withdrawal effects within 12–48 hrs after discontinuation of Kratom and the withdrawal symptoms were mainly rated at a 2 or 3 on a 5-point Likert scale (from 1-severe to 5-not severe at all). This study shows that the US Kratom user population is diverse in demographics and motives for Kratom consumption and that doses of up to 5 g consumed 3 times per day were able to provide beneficial effects while having lower rates of negative effects.

Cinosi and colleagues evaluated literature from 1967 to 2015 to better understand Kratom pharmacology, Kratom use cross-culturally, experience of the user, and to identify risks and side effects related to Kratom consumption.11 Their analysis identified a growing popularity of Kratom use in areas outside of Southeast Asia, specifically the European Union and United States. The increase in Kratom consumption in the European Union and United States corresponds to an increasing availability of Kratom for sale through the Internet. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) conducted an Internet survey of 27 European online shops in 2008 that identified Kratom as one of the most widely offered “legal highs” along with Salvia divinorum, Hawaiian Baby Woodrose seeds, Spice, and stimulant-containing capsules.35 A more extensive study by the EMCDDA in 2011 showed Kratom as the most widely offered product with 20% of the online retailers shipping it to the European Union.35 More studies are necessary to help understand the impact of Kratom as its use increases in the West, especially if Kratom follows the pattern of novel psychoactive drugs.11,36

The increasing trend in Kratom consumption in the West has corresponded with an increase in reports of Kratom-related exposures to Poison Control Centers in the United States, care received at a health care facility due to Kratom consumption, and association with overdose fatalities.12,37–39 A retrospective analysis of poison center charts collected from January 1, 2002, to November 30, 2016, in the electronic database Toxicall™ using the keywords Kratom and M. speciosa was performed to summarize the clinical effects of Kratom.39 The study evaluated 12 cases of Kratom exposure (dose and frequency were largely unknown) reported from health care facilities and described the clinical effects to include altered mental status, agitation, central nervous system depression, seizures, and tachycardia.39 Admission to psychiatry and benzodiazepines were the most frequent treatment methods and no deaths were reported.39 A larger analysis of data reported to Poison Control Centers using the National Poison Data System database from 2011 to 2017 identified 1,174 Kratom-only exposures where 1,020 cases resulted in one or more clinical effects.38 The most common clinical effects reported were agitation/irritability, tachycardia, nausea, drowsiness/lethargy, vomiting, confusion, and hypertension.38 Serious clinical effects included seizures, respiratory depression, coma, increased bilirubin, bradycardia, rhabdomyolysis, renal failure, respiratory arrest, cardiac arrest/asystole, and cyanosis.38 More than half (51.9%) of these cases received one or more therapies which included IV fluids, benzodiazepines, oxygen, naloxone, and tracheal intubation.38

The national poison center reporting database documented 1,807 calls related to Kratom exposure from 2011 to 2017.37 The Centers for Disease Control and Prevention analyzed data on unintentional and undetermined opioid overdose deaths from the State Unintentional Drug Overdose Reporting System.37 Kratom was detected on postmortem toxicology testing in 152 cases of 27,338 overdose deaths from data collected from 11 states during July 2016-June 2017 and 27 states during July–December 2017.37 Kratom was identified as the cause of death by a medical examiner in 91 of the 152 Kratom-positive deaths, but was the only identified substance in just seven of these cases.37 Presence of additional substances in these seven Kratom-only cases cannot be ruled out.37,40 The co-occurring substances in the 91 cases where Kratom was identified as the cause of death include fentanyl (including analogs), heroin, benzodiazepines, prescription opioids, cocaine, and alcohol.37 Multi-substance exposures involving Kratom, predominantly in combination with opioids, are associated with a greater odds ratio of admittance to a health care facility and occurrence of a serious medical outcome when compared to Kratom-only exposure.38 These data highlight that Kratom use is associated with a complex population of poly-drug users and especially with opioid use disorder. These data further suggest that a deeper investigation into the toxicity of Kratom is needed, especially focusing on drug–herb interactions.

Kratom–drug interactions are further indicated in several case reports resulting in hepatotoxicity or death.41–45 A 70-year-old man with a history of hypertension and osteoarthritis, treated with amlodipine and oxycodone, presented with jaundice.42 The patient admitted to consuming Kratom twice daily for 4 days approximately 2–3 weeks before his initial presentation at a medical center for jaundice.42 He presented with elevated creatinine (2.3 mg/dL) and total bilirubin levels (33.7 mg/dL) and clinically improved with supportive care, but required a readmission at which time he received 3 units of packed red cell transfusion to treat anemia.42 His abnormal liver tests normalized after three months, except his creatinine level remained slightly elevated (1.8 mg/dL).42 The liver damage in this case is most likely due to an amlodipine–kratom interaction involving the enzyme cytochrome P450 3A4 (CYP3A4).46,47

The elderly are not the only individuals at risk of adverse events due to drug–kratom interactions. A 32-year-old male with a history of hypertension, anxiety, and lower back pain presented to an Emergency Department with jaundice, nausea, fatigue, joint pain, and night sweats after completing a dose of 60 Kratom tablets over 1 week (as per recommended dose on the bottle) and had mitragynine (47.8 ng/mL) and 7-hydroxymitragynine present in his urine.45 The patient’s history includes alcohol use and acetaminophen use for his back pain, but he has no history of smoking or illicit drug use. The patient received a loading dose of N-acetylcysteine (150 mg/kg/hr) but developed an anaphylactic response and further doses withheld. While the patient’s liver enzymes were trending down, he was discharged prior to them normalizing. The authors attributed the acute liver injury solely to the patient’s use of Kratom;45 however, the repeated use of acetaminophen could have attributed to the liver injury and the consumption of Kratom could have been overwhelming to an already damaged liver.

Hepatotoxicity associated with Kratom use is rare and appear to be associated with chronic or high consumption of the product.48 In animal experiments, high concentrations of mitragynine (100 mg/kg) or a methanolic Kratom extract (1000 mg/kg) in rats showed organ damage primarily to the kidneys and liver with elevated liver enzymes and hepatic cellular damage. Although these doses exceed both acute and chronic human doses, further research on the impact of chronic kratom consumption on liver and kidney function is warranted.

Kratom use could have serious adverse events due to drug–herb interactions, specifically with the antipsychotic quetiapine. A 27-year-old male with a history of Asperger Syndrome, bipolar disorder, and substance abuse was found deceased.43 The postmortem analysis of subclavian blood revealed valproic acid (8.8 µg/mL), quetiapine (12,000 ng/mL), and mitragynine (qualitatively positive).43 The death was ruled an accident and due to acute toxic effects of quetiapine.43 The high levels of quetiapine were ruled to be due to a drug–herb interaction with Kratom since there was no evidence of significant discrepancies in quetiapine pill quantities in his residence.43 This case further highlights the need for more investigation into Kratom–drug interactions, specifically involving CYP2D6 and CYP3A4.

A better understanding of Kratom–drug interactions is needed specifically when dealing with consumption of Kratom to aid with withdrawal symptoms from, or as a substitute for, traditional opioids. Individuals suffering from opioid addiction are using Kratom out of curiosity and ease of purchasing.49,50 These individuals are highly variable and have an extensive substance use history.49 The variability in both user and drug use/preference will further complicate developing a treatment plan and dealing with patients consuming Kratom. It is necessary for scientists to further elucidate Kratom drug–herb interactions to aid physicians who can then better educate their patients about the potential benefits and harms associated with Kratom through a more open dialog.

Discussion and conclusion

The traditional and current diverse uses of Kratom in both Southeast Asia and the Western world indicate that the impact of the leaf and its extracts are of multidimensional complexity including sociocultural, economic, medico-legal, and often individual issues. Throughout its history of use, Kratom has been known to exert stimulant- and opioid-like effects that is raising concerns with regulatory agencies and resulted in scheduling actions in various countries. Although knowledge from clinical studies is limited, epidemiological data obtained from Southeast Asia, Europe, and the United States indicate that Kratom has a distinct user profile and presents with discrete effects from other stimulants or opioids. A substance-dependent opioid user does not prefer Kratom over another opioid but instead would utilize Kratom as a harm reduction or mitigation agent. This has been the conclusion from studies in Malaysia and the United States although the current information is preliminary in scope based on the small sample sizes and regional limitation of the surveys. The findings do align with preclinical observations in rodents that report a reduction in morphine self-administration with the use of mitragynine. This current knowledge points to a potential for further development of mitragynine or use of Kratom as a harm reduction agent similar to methadone or buprenorphine. This will have to be further studied under controlled clinical conditions.

The toxicity of Kratom remains a topic of discussion. From the CDC report and published cases, it is clear that Kratom has the potential to cause herb–drug interactions and even be involved in fatalities. While a majority of regular Kratom users in Southeast Asia and the West alike do not experience acute or chronic adverse effects, the incidence of unwanted side effects remains unknown and can include both stimulant and opioid-like sedative effects. Although some regulatory agencies, including the US FDA, have determined that Kratom and the alkaloids mitragynine and 7-hydroxymitragynine are opioids and thus should not be available without regulation, a direct causative link between the fatalities in which Kratom was detected cannot be drawn because nearly all of them involved poly-drug exposures.51 The toxicity of Kratom in various animal species is variable and has not been determined for most of them following acute and chronic exposure. The only clinical pharmacokinetic study in humans that provides blood concentrations of mitragynine does not correlate with post-mortem blood mitragynine concentrations thus not allowing for the determination of a toxic or lethal cut-off level. In addition, at this point, only the concentration of mitragynine is reported as indication of the presence of Kratom while it is not clear that mitragynine is in fact the toxic compound.

Reports and studies of the dependence potential to Kratom are of serious concern given the current opioid crisis in the United States and rising abuse of opioids in other countries. It appears that a majority of Kratom-dependent users had a prior substance use disorder or were seeking relief from a chronic pain condition but wanted to avoid opioid use. The severity of Kratom dependence symptoms appears to be milder compared to opioid use disorder and can be treated in a similar manner with buprenorphine or methadone and subsequent tapering. The incidence of Kratom dependency is not known and to date no US nationwide reporting system such as the National Survey on Drug Use and Health (NSDUH) or Monitoring the Future have indicated the use of Kratom in their reports.

Given the diversity in patterns of use for Kratom, additional research is paramount to support and expand on current findings. The labeling of Kratom products available to consumers needs to follow appropriate regulatory standards as well as quality good manufacturing practices to ensure that consumers who seek out Kratom are not exposed to adulterated or contaminated products.51 Health care providers should be trained on the science of Kratom and its clinical implications to assist consumers in making the right choice and avoid herb–drug interactions.

Disclosure

The authors report no conflicts of interest in this work.

Current perspectives on the impact of Kratom use Charles Veltri 1 Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, AZ, 85308, USA Oliver