H: Substances of Abuse

HISTORY AND EPIDEMIOLOGY

Amphetamine is the acronym for racemic β-phenylisopropylamine or α-methylphenylethylamine. Amphetamine is representative of a broader group of compounds with a shared structure known as phenylethylamines, which is a more precise term. Numerous substitutions are possible on the phenylethylamine structure, resulting in a variety of compounds, some with unique properties. For the purposes of this chapter, all phenylethylamines that are not actually amphetamine will be called amphetamines, and the name amphetamine specifically refers to β-phenylisopropylamine.

Amphetamine was first synthesized in 1887, but was essentially lost until the 1920s, when there were concerns about the supply of ephedrine for asthma therapy.⁷¹ The attempt to synthesize ephedrine lead to the rediscovery of dextroamphetamine in the United States and methamphetamine (d-phenylisopropylmethylamine hydrochloride) in Japan.⁷¹ Amphetamine was first marketed by Smith, Kline, and French in 1932 as the nasal decongestant Benzedrine.¹⁵ Amphetamine tablets were later available in 1935 for the treatment of narcolepsy and were advocated as anorectants in 1938.⁷⁶

Both amphetamine and methamphetamine were supplied as stimulants for soldiers and prisoners of war in World War II. The stimulant and euphoric effects of amphetamine were recognized, with abuse reported as early as 1936.¹³⁷ As a result, Benzedrine inhalers were banned by the US Food and Drug Administration (FDA) in 1959. From 1950 to the 1970s, there were sporadic periods of widespread amphetamine use and abuse in the United States. In the 1960s, various amphetamines such as methylenedioxyamphetamine (MDA), para-methoxyamphetamine (PMA), and para-methoxymethamphetamine (PMMA) were popularized as hallucinogens.³⁴ The Controlled Substance Act of 1970 placed amphetamines in Schedule II to prevent the diversion of pharmaceutical amphetamines for nonmedicinal uses.⁵ Amphetamine abuse subsequently declined.⁹³

In the 1980s, use of methylenedioxy derivatives of amphetamine and methamphetamine surfaced and were able to circumvent existing regulations. The best known of these derivatives were 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethamphetamine (MDEA).⁴⁶ Since the late 1980s, a dramatic resurgence of methamphetamine abuse has spread throughout much of the United States. A high purity preparation of methamphetamine hydrochloride was marketed in a large crystalline form termed “ice” by abusers.^7,49 From 1991 to 1994, the number of methamphetamine-related deaths in the United States reported by medical examiners tripled from 151 to 433, with a disproportional distribution from the Los Angeles, San Diego, San Francisco, and Phoenix metropolitan areas. Methamphetamine use is particularly prevalent among men who have sex with men in New York City.⁷⁴ Because of the ease and low cost of methamphetamine synthesis and the local production, methamphetamine is the most common illicit drug produced by clandestine laboratories in the United States.^28,31 Since the mid-1990s, MDMA has become widely used by college students and teenagers in large gatherings, known as “rave” or “techno” parties in England, Australia, and the United States.^135,136 Methcathinone (a khat-derived substance) use in the midwestern United States and 4-bromo-2,5-methoxyphenylethylamine (2CB) use in dance clubs were popular in the 1990s, but the use was not widespread.^63,67,180 Recently, synthetic cathinones have resulted in serious toxicity and death³⁰; these drugs have been sold as “bath salts” or “legal highs” to circumvent existing laws. There are also older amphetamines such as PMA and PMMA that have made a resurgence, with recent reports of toxicity and deaths.

PHARMACOLOGY

The pharmacologic effects of amphetamines are complex, but their primary mechanism of action is the release of catecholamines, particularly dopamine, norepinephrine, and serotonin from the presynaptic terminals, leading to a hyperadrenergic state. Although there are conflicting mechanistic models of amphetamine induction of catecholamine release, these variable results may be directly correlated with the different concentrations of amphetamine used in experimental models. The mechanism of action of amphetamines are based on dopaminergic neurons; similar mechanisms occur with norepinephrine and serotonin. Two storage pools exist for dopamine in the presynaptic terminals: the vesicular pool and the cytoplasmic pool. The vesicular storage of dopamine and other biogenic amines is maintained by the acidic environment within the vesicles and the persistence of a stabilizing electrical gradient within the cytoplasm. This environment is maintained by an adenosine triphosphate (ATP)-dependent active proton transport system.^117,147

Amphetamines will enter the nerve cell either by passive diffusion or by exchange diffusion through a reuptake transporter that is partially dose dependent. At low concentrations, amphetamines release dopamine from the cytoplasmic pool by exchange diffusion at the dopamine reuptake transporter site in the membrane. At moderate concentrations, amphetamines diffuse through the presynaptic terminal membrane and interact with the neurotransmitter transporter on the vesicular membrane to cause exchange release of dopamine into the cytoplasm. Dopamine is subsequently released into the synapse by reverse transport at the dopamine reuptake site.^147,161 At high concentrations, an additional mechanism is invoked as amphetamines diffuse through the cellular and vesicular membranes. Because amphetamine are bases, they alkalinize the vesicles, permitting dopamine release from the vesicles and delivery into the synapse by reverse transport (Fig. 76–1).^161,162 Amphetamines may also block the reuptake of catecholamines by competitive inhibition.^72,177 However, the effects of this mechanism are considered minor. Amphetamines are structurally similar to amphetamine derived monoamine oxidase inhibitors such as tranylcypromine, so amphetamines are weak monoamine oxidase inhibitors, the clinical significance of which is unclear.¹³¹

Binding selectivity to the neurotransmitter transporters largely determines the range of pharmacologic effects for the particular amphetamine. The affinity of MDMA for serotonin transporters is 10 times greater than that for dopamine and norepinephrine transporters; hence, it produces primarily serotonergic effects.⁶⁸ There are also other amphetamines that are predominantly serotonergic such as paramethoxyamphetamine and BromodragonFLY (Table 76–1).

The most identifiable effects of amphetamines are those caused by excessive catecholamine release and the resultant stimulation of many receptors that include α-adrenergic receptors, β-adrenergic receptors, dopamine, and serotonin. The majority of the serotonergic neurons in the central nervous system (CNS) are located in the raphe nuclei. Serotonin within the CNS regulate a wide variety of functions, including, but not limited to, mood, memory, temperature regulation, sleep, and pain.⁷¹ Serotonin is primarily responsible for the hallucinogenic and illusionic properties of amphetamines. Serotonin is also involved with the release of antidiuretic hormone, which may lead to hyponatremia, particularly with amphetamines with potent serotonergic effects such as MDMA.⁷⁵ Serotonin is also concerned with regulating fluid secretion and peristalsis. In addition, serotonin is involved in the regulation of many vascular beds, although the role of amphetamines in the regulation of the peripheral effects of serotonin is not clear.

Norepinephrine is another important neurotransmitter involved with amphetamines. Norepinephrine is found in the CNS and is also released from the postganglionic sympathetic fibers. The main noradrenergic nucleus in the CNS is the locus ceruleus. The release of excessive norepinephrine within the CNS from amphetamines results in decreased fatigue and increased attentiveness. Excessive norepinephrine in the peripheral nervous systems leads to many of the findings that occur with other sympathomimetic drugs such as cocaine. Norepinephrine will act on the adrenergic receptors (α and β), which mediate vasoconstriction and increased cardiac activity resulting in hypertension and tachycardia.

Dopamine also plays an important role in the setting of amphetamine use. The increase in CNS dopamine, particularly in the neostriatum, mediates stereotypical behavior and other locomotor activities.^39,65,89,90 The activity of dopamine in the neostriatum appears to be linked to glutamate release and inhibition of γ-aminobutyric acid (GABA) ergic efferent neurons.^65,90 Stimulation of the glutamatergic system contributes significantly to the stereotypical behavior, locomotor activity, and neurotoxicity of amphetamines.^90,153,154 The effects of serotonin and dopamine on the mesolimbic system alter perception, cause psychotic behavior and anorexia.^78,160

Structure Modification

A phenylethylamine is any structure with an ethyl group backbone that has an aromatic group and a terminal amine. Specific substitutions made to the phenylethylamine backbone have led to the wide variety of novel drugs, described below. Substitutions at different positions of the phenylethylamine molecule alter the general pharmacology and clinical effects of amphetamines, as demonstrated by both animal and human observations. Large-group substitution at the α carbon reduces the stimulant and cardiovascular effects but retains the anorectic properties (such as phentermine). Substitution at the para position of the phenyl ring enhances the hallucinogenic or serotonergic effects of amphetamines (such as in para-chloroamphetamine and MDMA).⁴⁹ Although some of these generalizations enable an understanding of the effects of amphetamines, there are many exceptions, and such generalizations may not apply when large doses of a particular molecule are ingested. In terms of the spectrum of activities, methamphetamine results in the most potent cardiovascular effects, and 2,5-dimethoxy-4-bromoamphetamine (DOB) results in the most consequential hallucinogenic and serotonergic effects.¹⁰⁵ Table 76–2 further describes the pharmacology of specific substitutions.

Other certain substitutions are worth noting, such as the addition of an extra methyl group to the terminal amine in amphetamine to produce methamphetamine that greatly increases CNS activity. This extra methyl group also makes methamphetamine more lipid soluble, allowing faster penetration across the blood–brain barrier and more resistance to degradation by monoamine oxidase. In addition, amphetamines with this methyl group also possess strong stimulant, cardiovascular, and anorectic properties.¹⁰⁵ Addition of a methoxy group to either the 2 or 5 position of the aromatic ring on the amphetamine or methamphetamine compound increases serotonergic activity. Another important substitution to the phenylethylamine backbone is the addition of a halogen group (such as iodine or bromide), which increases the potency of the compound and leads to it being considered more neurotoxic when compared to nonhalogenated compounds. This is thought to be due to significant serotonin depletion leading to irreversible neuron damage.

Because amphetamines directly interact with neurotransmitter transporters, minor modifications of the molecule may significantly alter its pharmacologic profile.⁸² The addition of an α-methyl group in amphetamines confers resistance to metabolism by monoamine oxidase. These characteristics permit better oral bioavailability and longer duration of effect. The α-methyl group in the amphetamine structure also introduces chirality to the molecule. Except for MDMA and several other amphetamines, the d-enantiomers are typically 4 to 10 times more potent than the l forms of amphetamine.

Chronic administration of certain amphetamines to animals alters dopamine and serotonin transporter functions, depletes dopamine and serotonin in the neuronal synapses, and produces irreversible destruction of those neurons.^{14,60,141,142,147,176} The etiology of neuronal toxicity may be related to the generation of oxygen free radicals, resulting in the generation of toxic dopamine and serotonin metabolites as well as neuronal destruction. Based on animal models, dose, frequency and duration of exposure, and ambient temperature. Intact dopamine or serotonin transporters are necessary to produce neurologic injury. Xenobiotics that inhibit transporter function may prevent neurologic injuries in animals.⁶⁸ Significant differences are also noted across species; mice are typically resistant to MDMA-induced neurologic injury. Although not as well studied as MDMA, studies of former methamphetamine users demonstrated impaired memory and psychomotor functions, as well as corresponding dopamine transporter dysfunction and abnormal glucose metabolism on positron emission tomography scans. However, it is still not clear as to the difference in species susceptibility to neurologic injuries, the duration of effects in primates and humans, and functional consequences of neurotoxicity in humans. The potential for permanent neurologic effects associated with chronic amphetamine use in humans requires further study.

PHARMACOKINETICS AND TOXICOKINETICS

Absorption

Amphetamines can be administrated intravenously, orally, intranasally, and by inhalational route, with good absorption. All amphetamines are rapidly absorbed, with bioavailability that ranges between 60% and 90% depending on the route of administration. Peak serum concentrations are achieved in approximately 3 to 6 hours postadministration.

Distribution

Following absorption, amphetamines are distributed to most compartments of the body. Most amphetamines are also relatively lipophilic and readily cross the blood–brain barrier. Amphetamines have large volumes of distribution, varying from 3 to 5 L/kg for amphetamine, 3 to 4 L/kg for methamphetamine and phentermine, and to 11 to 33 L/kg for methylphenidate. Some amphetamines such as pemoline have a small volume of distribution (0.2–0.6 L/kg).

Metabolism

Amphetamines are eliminated via multiple pathways, including diverse routes of hepatic transformations, and by renal elimination. For MDMA and its analogs, N-dealkylation, hydroxylation, and demethylation are the dominant hepatic pathways. Depending on the particular amphetamines, active metabolites of amphetamines and ephedrine derivatives may be formed. N-demethylation of methamphetamine and MDMA result in the formation of amphetamine and MDA, respectively.^33,111 Dealkylation and demethylation are mainly performed by CYP1A2, CYP2D6, and CYP3A4, but they are also performed by flavin monooxygenase. Polymorphism of CYP2D6 in humans was recognized due to the diversity of rates of p-hydroxylation of amphetamines. Since its discovery, CYP2D6 polymorphism has been implicated in drug toxicity, substance use and abuse, and lack of drug efficacy in selected individuals.¹⁴⁸ Increased amphetamine toxicity is a potential concern in patients with decreased CYP2D6 activity. Although animals with CYP2D6 deficiency are more susceptible to MDMA toxicity, limited studies in humans do not demonstrate an association between mortality and CYP2D6 polymorphism.^59,122 In general, because multiple enzymes and pathways (including renal) are involved in amphetamine metabolism, it is less likely that CYP2D6 polymorphism or drug interactions with CYP3A4 alone will significantly increase toxicity. However, it is unclear if toxicity is enhanced when multiple mechanisms for altering drug metabolism and kidney dysfunction are present simultaneously.

Elimination

Renal elimination of the parent compound is substantial for amphetamine (30%), methamphetamine (40%–50%), MDMA (65%), and phentermine (80%). Amphetamines are bases with a typical pK_a range of 9 to 10, and renal elimination varies depending on the urine pH, with elimination increasing as pH decreases. The half-life of amphetamines varies significantly: amphetamine, 8 to 30 hours; methamphetamine, 12 to 34 hours; MDMA, 5 to 10 hours; methylphenidate, 2.5 to 4 hours; and phentermine, 19 to 24 hours. Repetitive administration, which occurs typically during binge use, may lead to drug accumulation and prolongation of the apparent half-life and duration of effect.⁷⁷

CLINICAL MANIFESTATIONS

Acute Toxicity

Most of the complications associated with amphetamines are a result of an uncontrolled hyperadrenergic state similar to what occurs with other sympathomimetics such as cocaine, except the duration of effect may be longer (Table 76–3). Most patients with acute amphetamine toxicity manifest effects in the CNS and cardiovascular system. The majority of the specific effects are from excessive catecholamine release as opposed to direct effects from the amphetamines themselves. Refer to the section Individual Amphetamines for specific effects.

Central nervous system effects from acute amphetamine use include anxiety, agitation, hallucinations, mydriasis, diaphoresis, and hyperthermia.^19,50,51,145 Psychosis appears to be a more prominent feature than following cocaine use.⁶⁵ Intracerebral hemorrhage and cerebral infarction are also reported with amphetamine use.^{53,86,113,129} Seizures may be the direct result of amphetamine use or may occur secondarily from hyponatremia as reported with MDMA and certain synthetic cathinones.¹⁸

Cardiovascular toxicity from acute amphetamine use involves hypertension, tachycardia, and dysrhythmias; this varies from premature ventricular complexes to ventricular tachycardia and ventricular fibrillation.⁸⁰ Other vascular complications reported with acute use include myocardial ischemia or infarction,^115,169 aortic dissection,^52,172 acute respiratory distress syndrome,^165,171 obstetrical complications, fetal death,¹⁰⁴ and ischemic colitis.^79,84 Other complications are metabolic acidosis, rhabdomyolysis,⁵⁴ acute kidney injury (acute tubular necrosis), and coagulopathy, often from uncontrolled agitation and hyperthermia^43,73,167 (Fig. 5–29). Unless these systemic signs and symptoms are rapidly reversed, multiorgan failure and death may ensue.

Chronic Toxicity

Amphetamine users seeking intense “highs” may go on “speed runs” for days to weeks. Because of the development of tolerance, they use increasing amounts of amphetamine during these periods, usually without much nutritional sustenance or sleep, while attempting to achieve their desired euphoria.¹⁵¹ Acute psychosis resembling paranoid schizophrenia may occur during these binges and has contributed to both amphetamine-related suicides and homicides.⁵⁵ Return to a normal sensorium occurs within a few days after discontinuation of the drug. Once an amphetamine user experiences psychosis, it is likely to recur with subsequent use, even after prolonged abstinence, which may be related to a kindling phenomenon.¹¹⁴ Typically, after such binges, patients may sleep for prolonged periods of time, feel hungry and depressed when awake, and often have amphetamine cravings.^95,99

Compulsive repetitive behavior patterns from the use of amphetamines are reported in humans and animals. Individuals may constantly pick at their skin; grind their teeth (bruxism); or perform repetitive tasks, such as constantly cleaning the house or car. MDMA users often carry pacifiers to relieve bruxism. Choreoathetoid movements, although uncommon, are reported with acute and chronic amphetamine usage.^94,106,110 The etiology of the choreoathetoid movements may be related to increased dopaminergic stimulation in the striatal area.

Necrotizing vasculitis is associated with amphetamine abuse. Angiography typically demonstrates beading and narrowing of the small- and medium-sized arteries (Fig. 5–29). Progressive necrotizing arteritis can involve multiple organ systems, including the brain, heart, gut, and kidney.^{17,35,98,110,164} Complications include cerebral infarction and hemorrhage, coronary artery disease, pancreatitis, and acute kidney injury. The etiology of the arteritis remains unclear. Although various contaminants associated with injection drug use are postulated as potential etiologies, in animal models oral and intravenous amphetamine administration is also associated with vasculitis, suggesting that this is a direct amphetamine effect. Cardiomyopathy is also reported with acute and chronic amphetamine abuse.^157,178 Excessive catecholamine exposure may be responsible for their associated cardiomyopathies similar to patients with pheochromocytomas and chronic cocaine use.^88,173 Other reported effects include valvular disease and pulmonary hypertension with certain amphetamines used as dieting agents such as fenfluramine, dexfenfluramine, and phentermine.^146,163

Finally, complications can result from intravenous drug use and from the associated contaminants. Contamination with microbials may lead to human immunodeficiency virus infection, hepatitis, and malaria. Bacterial and foreign body contamination may result in endocarditis, tetanus, wound botulism, osteomyelitis, and pulmonary and soft tissue abscesses.³⁴

DIAGNOSTIC TESTING

The choice and extent of diagnostic tests should be guided by the history and physical examination. In all patients with altered mental status, blood specimens should be sent for glucose, blood urea nitrogen, and electrolyte assays. An electrocardiogram should be obtained in all cases, and continuous cardiac monitoring should be initiated. A complete blood count, urinalysis, coagulation profile, creatine phosphokinase, chest radiograph, computed tomography scan of the head, and lumbar puncture may be necessary, depending on the clinical presentation.

Qualitative urine immunoassays are available for amphetamines, but several considerations limit their utility in the management of acutely poisoned patients. While point of care urine tests are available, the turnaround time for many urine immunoassays is at least several hours so they rarely contribute to management in the acute setting. Another important limitation to consider is the rate of false-positive and false-negative results that are common with the amphetamine immunoassay. For example, many cold preparations contain pseudoephedrine, which is structurally similar and may cross-react with the immunoassay.^36,41,57,132 Likewise, selegiline, a selective monoamine oxidase type B inhibitor used for the treatment of parkinsonism, is metabolized to amphetamine and methamphetamine. Other common drugs that produce false-positive outcomes include bupropion, trazodone, and amantadine.^120,124 Even a true-positive result only means the patient has used certain amphetamines within the past several days and does not distinguish remote from acute use. False-negative results may occur with certain amphetamines such as MDMA and cathinones, which are not recognized on standard urinary drug testing.^36,156 Although newer, rapid, serum qualitative drug screens are available, false-positive and false-negative results remain common and may be misleading and do not directly contribute to the acute management of patients. The gold standard for drug testing, gas chromatography–mass spectrometry analysis, can misidentify isomeric substances such as l-methamphetamine, which is present in nasal inhalers, with d-methamphetamine, if performed by inexperienced personnel.⁹⁶ In summary, the use of urine immunoassays should not guide clinical management of patients who present with suspected toxicity from amphetamines.

MANAGEMENT

The initial medical assessment of the agitated patient must include vital signs, a rapid glucose and a complete physical examination. Determination of core body temperature is essential to diagnose the presence and degree of hyperthermia, which is a frequent and rapidly fatal manifestation in patients with drug-induced delirium. Significant hyperthermia necessitates immediate interventions to achieve rapid cooling.^16,23,62 Some patients require temporary physical restraint to gain pharmacologic control and prevent personal harm to themselves or others. Physical restraints should be discontinued as soon as possible; prolonged restraints may result in rhabdomyolysis and continued heat generation. Intravenous access should be obtained so that intravenous sedation can be initiated. In the event that intravenous access cannot be obtained, it is necessary to attempt to administer intramuscular benzodiazepines such as midazolam until definitive access is made.

The most appropriate choice of chemical sedation is a benzodiazepine because of the characteristic high therapeutic index, good anticonvulsant activity, and predictable pharmacokinetic properties. The benzodiazepines are effective not only for the treatment of delirium induced by acute overdose of cocaine, amphetamines, and other xenobiotics but also the delirium associated with ethanol and sedative-hypnotic withdrawal (Antidotes in Depth: A23).^47,48,66,123 Sedation should be titrated rapidly until the patient is calm. In our clinical experience, cumulative benzodiazepine dosages required in the initial 30 minutes to achieve adequate sedation frequently exceed 100 mg of diazepam or its equivalent. Intravenous glucose (D₅₀W, 0.5–1 g/kg) and thiamine 100 mg should be given as indicated (Table 76–4).

Antipsychotics, particularly potent dopamine antagonists such as haloperidol and droperidol, are frequently recommended by others for amphetamine-induced delirium. Antipsychotics may antagonize some of the effects of amphetamines via dopamine blockade, but they have not been shown to be as effective as benzodiazepines in experimental models.^44,66,123 Additionally, antipsychotics may lower the seizure threshold, alter temperature regulation, cause acute dystonia, and precipitate cardiac dysrhythmias, and they do not interact with the benzodiazepine-GABA-chloride channel receptor complex. All of these effects may aggravate the clinical outcomes related to occult or concomitant cocaine toxicity and ethanol withdrawal.^66,69,123 Based on these concerns, benzodiazepines should be utilized as first-line treatments in the management of acute toxicity from amphetamines.

Rhabdomyolysis from amphetamines usually results from psychomotor agitation and hyperthermia.¹⁴³ Sedation prevents further muscle contraction and heat production. External cooling should be instituted for hyperthermia. Adequate intravenous hydration and cardiovascular support should maintain urine output of at least 1 to 2 mL/kg/h. Although urinary acidification can significantly increase amphetamine elimination and decrease the half-lives of amphetamine and methamphetamine,^11,12 pH manipulation does not decrease toxicity, and, in fact, it may increase the risk of acute kidney injury from rhabdomyolysis by precipitating ferrihemate in the renal tubules.⁴⁰ Patients with acute kidney injury, acidemia, and hyperkalemia may require urgent hemodialysis.

Amphetamine body packers, although uncommon, should be treated similarly to those who transport cocaine (Special Considerations: SC5). Any sympathomimetic symptom suggesting leakage of the packets requires surgical intervention.¹⁶⁸ Intravenous fluids, benzodiazepines, intubation, and external cooling may be necessary to stabilize these patients.

INDIVIDUAL AMPHETAMINES

Methamphetamine

Methamphetamine is known by many names, including, but not limited to, “yaba,” “speed,” “go,” “crack,” “uppers,” and “dexies.” The terms “crystal,” “shard,” and “ice” refer to the crystalline form of methamphetamine. Methamphetamine was first synthesized from ephedrine in Japan in 1893, soon after the synthesis of amphetamine in 1887. Crystallized methamphetamine was synthesized in 1919 through the reduction of ephedrine using red phosphorus. From the 1950s to the 1970s, there were multiple epidemics of methamphetamine abuse in the United States.⁶⁴ Methamphetamine is approved by the FDA for the short-term treatment of attention-deficit/hyperactivity disorder and obesity, and it is sold under the trade name Desoxyn as a Schedule II drug. It is also prescribed for off-label use for refractory depression and narcolepsy.

The production of methamphetamine is relatively simple, requiring minimal equipment and chemicals. There are many methods of methamphetamine production which initially utilize pseudoephedrine, ephedrine, or phenyl-2-propone (P2P). The primary ingredient of methamphetamine synthesis is ephedrine, which can be hydrogenated into methamphetamine. The ephedrine method, using pharmaceutical grade l-ephedrine, produces a product with few contaminants that is stereochemically pure.^49,133 P2P, as an alternative ingredient, can be methylated into ephedrine and then transformed into methamphetamine.²² Because of the strict control of ephedrine and P2P, illicit chemists use phenylacetic acid to synthesize P2P.^22,42 Lead acetate, which is used as a substrate for the reaction, has resulted in an epidemic of lead poisoning associated with methamphetamine abuse in Oregon.^2,121 Mercury contamination was also documented, although clinical mercury toxicity has not been reported.²⁰ Methamphetamine laboratories use many xenobiotics, including phosphine gas, methylamine gas, chloroform, and hydrochloric acid^3,81; therefore, these laboratories pose a significant health risk to law enforcement officers and the general public, causing respiratory and ophthalmic irritation, headaches, and burns.^28,155 Currently, the sale of other potential amphetamine synthetic ingredients, such as hydrochloric acid, hydrogen chloride gas, anhydrous ammonia, red phosphorus, and iodine, are also monitored and restricted in the United States.^22,29

Methamphetamine exists as a chiral molecule with two isomers that include levomethamphetamine and dextromethamphetamine. Although the levorotatory form is devoid of CNS stimulatory properties, it retains its vasoactive effects and is used in nonprescription nasal decongestant inhalers. In the racemic mixture, the dextrorotatory form is responsible for the entire stimulant effects observed with methamphetamines. Methamphetamine undergoes metabolism in the liver mainly to amphetamine and 4-hydroxymethamphetamine and has prolonged half-life of 19 to 34 hours, although the duration of its acute effects can be greater than 24 hours.⁴⁹

3,4-Methylenedioxymethamphetamine (MDMA)

3,4-Methylenedioxymethamphetamine, also known as MDMA, was first synthesized in 1912, and was rediscovered in 1965 by Shulgin. MDMA is known as “ecstasy,” “E,” “Adam,” “XTC,” “molly,” and “MDM,” and it is commonly abused by college students and teenagers.^128,170,174 Other amphetamines that are similar to MDMA, include MDEA (“Eve”) and MDA (“love drug”), which have similar clinical effects, are also used or distributed as MDMA in areas of MDMA use. Amphetamines sold as MDMA include 2CB, 2,4-dimethoxy-4-(n)-propylthiophenylethylamine (2C-T7), and N-methyl-1-(3, 4-methylenedioxyphenyl)-2-butanamine (MBDB).^27,63,92 The term “ecstasy” may be used for all these xenobiotics. Typically, MDMA is available in 50 to 200 mg colorful and branded tablets.

MDMA and similar analogs are so-called entactogens (meaning touching within), capable of producing euphoria, inner peace, and a desire to socialize.¹⁵² In addition, some psychologists used MDMA to enhance psychotherapy until the Controlled Substances Act of 1986 placed MDMA in Schedule I, thereby eliminating its medical use.¹¹⁹ People who use MDMA report that it enhances pleasure, heightens sexuality, and expands consciousness without the loss of control.⁷⁰ Negative effects reported with acute use included ataxia, restlessness, confusion, poor concentration, and impaired memory.¹⁵² MDMA has about one-tenth the CNS stimulant effect of amphetamine. Unlike amphetamine and methamphetamine, MDMA is a potent stimulus for the release of serotonin.^24,45,72 The concentration of MDMA required to stimulate the release of serotonin is 10 times less than that required for the release of dopamine or norepinephrine. In animal models, the stereotypic and discriminatory effects of MDMA and its congeners can be distinguished from those of other amphetamines.²⁴

The sympathetic effects of MDMA are mild in low doses. However, when a large amount of MDMA is taken, the clinical presentation is similar to that of other amphetamines, and deaths can result from abuse.^61,91,138 Those patients at greatest risk develop dysrhythmias, hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation.¹³⁸ Significant hyponatremia is reported with MDMA use.^1,21,75 MDMA and its metabolites increase the release of vasopressin (antidiuretic hormone), and this may be related to the serotonergic effects.⁵⁶ Furthermore, substantial free water intake combined with sodium loss from physical exertion in dance clubs may exacerbate the development of hyponatremia.

Most recently, reports of poisoning from a form of MDMA known as Molly have emerged. Molly is initially thought to be a purified or crystallized form of MDMA that is typically taken orally. Molly use has increased due to what was perceived as a more rapid onset of symptoms and a subtler offset or “come down” period. Molly is also commonly viewed as a safer form of MDMA, since it is believed to contain no adulterants. The use of Molly is associated with adverse effects such as intracranial hemorrhage.⁸⁵ While Molly is often sold on the street as MDMA, Molly may not be pure MDMA but actually may contain 2C compounds, amphetamines that have two methoxy groups and a halogen such as iodine (2C-I) or bromide (2C-B). The compound 2C-I is known as “smiles.”

A major concern with MDMA use is its long-term effects on the brain. In numerous animal models, acute administration of MDMA leads to the decrease in serotonin reuptake transporter (SERT) function and number. Recovery of SERT function may take several weeks. Repetitive administration of MDMA ultimately results in permanent damage to serotonergic neurons, typically causing injury to the axons and the terminals while sparing the cell bodies.^112,140,141 Some regeneration of synaptic terminals can occur even with neuronal damage, but functional recovery is incomplete. Intact SERT function is necessary for MDMA-induced neurotoxicity. Xenobiotics that inhibit the reuptake of serotonin prevent MDMA-induced neurotoxicity in animals. Animal data suggest that MDMA induces hydroxyl free-radical generation and decreases antioxidants in serotonergic neurons.¹⁴⁹ MDMA itself is not the ultimate neurotoxin, rather its metabolites 3-methyldopamine and N-methyl-α-methyldopamine appear to be responsible in animals.¹¹⁶ When antioxidants are depleted, neuronal damage may occur.

Paramethoxyamphetamine (PMA) and Paramethoxymethamphetamine (PMMA)-Monomethoxy Derivatives

Para-methoxyamphetamine (PMA) is the 4-methoxylated analog of amphet-amine, and para-methoxy-N-methylamphetamine (PMMA; methyl-MA) is the 4-methoxy analog of methamphetamine. PMA was first produced in 1973 and sold as a hallucinogen for a short period of time, and it reemerged in the 1990s. PMMA soon appeared after PMA, with multiple reports of death also emerging during that time.^10,83,97,102 PMA and PMMA are commonly found as tablets or capsules sold as MDMA or “ecstasy.” While the effects of PMA and PMMA mimic some aspect of MDMA and methamphetamine, there are unique properties of PMA and PMMA, that make them considerably more lethal and earning the street name “death.” In recent years, there have been more than 100 fatalities and severe poisonings attributed to PMMA and PMA in the United States, Canada, and Europe.^{87,100,103,107,109}

Methoxy ring substitution of amphetamine or methamphetamine at the 3 or 4 positions (para substitution is the most common) yields PMA and PMMA derivatives that have significantly less sympathomimetic activity than amphetamine but very potent serotonergic activity.^38,158 Both PMA and PMMA inhibit reuptake of serotonin and inhibit monoamine oxidase A found centrally and peripherally. The methoxy ring substitution is also responsible for poor penetration of the blood brain barrier.^6,58

PMA and PMMA poisoning lead to autonomic hyperactivity similar to what is observed in other amphetamines such as hypertension, tachycardia, and agitation. The use of PMA and PMMA results in a weak euphoric effect and delayed onset of CNS effects due to poor blood–brain barrier penetration. These properties will often lead users to repeatedly dose themselves that result in serious toxicity and are responsible for the seemingly high mortality rate.

Cathinones (Methcathinone, MDPV, and Mephedrone)—”Bath Salts”

Cathinone ({S}-2-amino-1-phenyl-1-propanone) is a naturally occurring substance found in the leaves of the Catha edulis (khat) plant. Also known as guat and gat, the fresh leaves and stems are commonly used as a stimulant in Africa and certain Middle Eastern countries such as Yemen. While there are numerous other amphetamines in minute quantities, the primary active ingredient is cathinone. As the leaves age, cathinone is degraded to cathine, which has about one-tenth the stimulant effect of d-amphetamine. Imported fresh khat must be consumed within a week, before it loses much of its potency. The primary effects of khat are increased alertness, insomnia, euphoria, anxiety, and hyperactivity. Khat chewing is linked to cardiac and gastrointestinal disease.^125,126

The syntheses of cathinone derivatives were reported in the early 1920s, with the production of methcathinone in 1928 and mephedrone in 1929. Methcathinone, the methyl derivative of cathinone, was used in Russia as an antidepressant in the 1930s and 1940s. Also known as “Cat” and “Jeff,” cathinone has been used recreationally, most often in countries formerly part of the Soviet Union, but it also gained popularity in the United States, particularly in Michigan, in the 1990s. Synthetic cathinones have become popular drugs of abuse due to a combination of media attention and widespread Internet availability.^134,150 Many other synthetic cathinones have been produced including methylone, mephedrone, butylone, methylenedioxypyrovalerone (MDPV), dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, and MDPV.

The synthetic cathinones differ from other amphetamines because they contain a ketone at the β position. For this reason, they are often known as bk-amphetamines. The β-ketone group is responsible for increased polarity, which decreases penetration of the blood–brain barrier. They possess amphetaminelike properties and have sympathomimetic effects, although as a group, they are considered less potent. Some of the synthetics cathinones are reported to cause hyponatremia. Although the mechanism is not clear and may not be similar to MDMA.^{9,25,26,108,130} Reported complications include compartment syndrome, acute kidney injury, and sudden cardiac death.^{101,118,139,144,179} An irreversible Parkinson syndrome was also described in chronic users of intravenous methcathinone, particularly in Europe and Russia. The methcathinone was manufactured with the use of potassium permanganate to oxidize ephedrine or pseudoephedrine. In one case series, T1-weighted magnetic resonance imaging showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all active methcathinone users, suggestive of manganese poisoning, which was also confirmed with elevated whole blood concentrations.¹⁵⁹

Synthetic cathinones are often sold as “bath salts” or “plant food” and labeled as “not for human consumption” in an attempt to circumvent controlled substances legislation. The legal status differs among countries and changes over time. In the United States, the synthetic cathinones were initially unscheduled, but they are illegal for human consumption under the Federal Analogue Act of 1986. However, on September 7, 2011, the Drug Enforcement Administration used its emergency scheduling authority to enact temporary control, making possession or sale of methylenedioxypyrovalerone, methylone, and mephedrone illegal until recently, when permanent law has been enacted.

Bromo-dragonFLY

1-(8-Bromobenzo[1,2-b;4,5-b′]difuran-4-yl)-2-aminopropane, also known as Bromo-dragonFLY (BDF), was first synthesized in 1998. BDF was named after its superficial structural resemblance to a dragonfly, similar to earlier and the less potent dihydrofuran series of compounds nicknamed FLY. BDF is a member of a new class of benzodifurans, which have been used as a potent research tools for investigation of the serotonin receptor family and for a time as potential antidepressants.

Structurally, BDF is closely related to other phenylethylamines suchas DOB and 2C-B. BDF contains two furan rings on either side of the benzene ring, creating a fully aromatic tricyclic structure. There are a number of similar compounds to BDF, differing by substitution of the bromide atom with other entities. BDF exists as R- and S-enantiomers, which are both biologically active. The R-enantiomer is considered more potent, with its potent hallucinogenic effect mediated through the 5-HT_2A serotonin receptor (also with affinity for the 5-HT_2B and 5-HT_2C serotonin receptors).¹²⁷

BDF is associated with deaths in Europe and the United States. Reports demonstrate delayed complications from severe peripheral vasoconstriction and limb ischemia that likely result from the potent serotonergic properties of BDF.^4,37,166,175

2,5-Dimethoxy-4-Methylamphetamine (DOM) and 2,5-Dimethoxy-4-Iodoamphetamine (DOI)

2,5-Dimethoxy-4-methylamphetamine (DOM), also known as STP, which stands for “Serenity, Tranquility, and Peace,” emerged in the 1960s as a hallucinogen. It was noted for its delayed onset of action and duration of effect that quickly led to its short-lived appearance. 2,5-Dimethoxy-4-iodoamphetamine (DOI) is another potent hallucinogen, previously sold as a substitute for lysergic acid diethylamide, or LSD.

Dimethoxy amphetamine derivatives are structurally characterized by methoxy ring substitution at the 2 and 5 positions on the aromatic ring, with varying additional substitution of hydrophobic moieties at the 4 position. DOM and DOI are both serotonin receptor agonists with selectivity at the 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor subtypes. Due to this selectivity, DOM and DOI are often used in scientific research involving study of the 5-HT₂ receptor subfamily. DOM exists as a chiral molecule, with the R-(-)-enantiomer considered the more potent.¹³

Potent hallucinogenic effects and dysphoria characterize the use of DOB and DOI, with minimal sympathomimetic effects. These symptoms can often be delayed with a prolonged duration of effect, sometimes refractory to the use of benzodiazepines. There is also report of reversible vasospasm with the use of these dimethoxy amphetamine derivatives.^8,19

SUMMARY

• Amphetamines, often created to evade designer drug laws, continue to increase dramatically throughout the United States.

• The extensive knowledge with regard to the modifications to the existing phenylethylamine backbone allows clinicians to predict the effects of the amphetamines. These effects are attributed to variable degrees of selectivity affecting dopamine, norepinephrine and serotonin.

• Many complications associated with amphetamines are similar to those of cocaine, such as agitation, hyperthermia, rhabdomyolysis, myocardial ischemia, and cerebral infarction.

• The management of acute amphetamine toxicity includes supportive care, with the judicious use of benzodiazepines and anticipation of complications of adrenergic toxicity such as hyperthermia and rhabdomyolysis.

Acknowledgment

William K. Chiang, MD, contributed to this chapter in previous editions.

References

HISTORY AND EPIDEMIOLOGY

Cannabis has been used for more than 4000 years. The earliest documentation of the therapeutic use of marijuana is the fourth century b.c. in China.¹⁵⁶ Cannabis use spread from China to India to North Africa, reaching Europe around a.d. 500.¹²⁶ In colonial North America, cannabis was cultivated as a source of fiber. Like cocaine and morphine, cannabis was the focus of research efforts in the 19th century. Although the active chemical constituents of the former were isolated during this time, that of cannabis remained elusive.⁹¹ This is due to the fact that the active compounds of morphine and cocaine are both alkaloids and were possible to extract with the technological means of the time, whereas the methods to isolate the active terpenes in cannabis were not available to researchers until several decades later.

The first pure phytocannabinoid to be isolated was cannabinol, in 1898. Synthesis of its structural isomers yielded the first synthetic cannabinoid years later—Δ⁹-tetrahydrocannabinol (THC). Cannabinol was previously shown to lack psychoactive effects, but this new compound demonstrated similar effects to cannabis in a model of ataxia in dogs. Pure Δ⁹-THC was subsequently isolated from hashish extract in 1964, and the structure was elucidated in 1967.⁹²

Marijuana was used as an intoxicant from the 1850s until the 1930s when the US Federal Bureau of Narcotics began to portray marijuana as a powerful, addicting substance. Despite this, marijuana was listed in the US Pharmacopoeia from 1850–1942. In 1970, the Controlled Substances Act classified marijuana as a Schedule I drug.

In all populations, cannabis use by males exceeds use by females. Currently, marijuana is the most commonly used illicit xenobiotic in the United States, yet it is legal in states such as Colorado and Washington. A study by the Substance Abuse and Mental Health Services Administration reported that in 2006 in the United States, 6.0% (14.8 million persons) 12 years of age or older used marijuana in the month prior to the survey; this prevalence is unchanged from previous years. The prevalence of past-month users aged 12 to 17 years was 6.7% (down from 8.2% in 2002). The number of first-time users was estimated to be 2.1 million, with 63.3% younger than 18 years of age.

Interest in synthetic cannabinoid receptor agonists (SCRAs) as potential therapeutics increased following the progress of the late 1960’s, and ­several SCRAs similar in structure to THC were created. These semisynthetic compounds were based on the dibenzopyran ring structure of THC and had varying cannabinoid receptor binding affinity relative to THC. The search for a nonopioid analgesic sparked research and development efforts by pharmaceutical companies, most notably Pfizer, from the 1960s to 1980s.⁶³ Despite its efforts, no drugs came to market; new agents retained unwanted psychoactive side effects. During this period, extensive structure activity relationships for cannabinoids were developed.⁶²

Subsequent synthetic compounds were developed as cannabinoid research tools and were important in the discovery of central and peripheral cannabinoid receptors (CB₁ and CB₂) in the 1980s.³² Many of these did not retain chemical similarity to THC but remained potent and efficacious agonists at CB₁ and CB₂.⁶² In the 1990s, the endogenous cannabinoids were discovered and have been since synthesized.⁸⁰ These free fatty acids are quickly hydrolyzed in vivo, a fact that previously limited potential for pharmaceutical development. More recently stable versions of endocannabinoids have been made (Fig. 77–1).

In 2004, SCRA–laced herbal incense blends began to be available over the Internet and through smoke shops in Western Europe.⁸⁴ Popular use and subsequent publicity increased resulting in several users presenting to emergency departments in Germany. As the result of efforts by the German government and THC Pharma, JWH-018 was isolated as the psychoactive ingredient present in these early incense blends. The discovery led to legislative action and subsequent ban of herbal incense–containing JWH-018 in Germany, but almost as soon as the ban took effect, incense manufacturers simply switched to a different SCRA—JWH-073. Since that time, many Western European countries have further legislated control of SCRAs.

Incidence of exposure in the United States has been increasing over the past 3 years, and in November 2010, the Drug Enforcement Administration (DEA) began the process of declaring selected SCRAs to be Schedule I substances on a temporary basis. As of March 2011, the DEA has listed several nonclassical cannabinoids as Schedule I, but as was the case in Germany, manufacturers have switched to other SCRAs not yet scheduled and even marketed the products as such.

MEDICAL USES

Marijuana has been used medicinally for thousands of years to treat a seemingly endless array of conditions. However, modern medicine is burdened by an evidence-based system rather than the belief-based medicine of old. Therefore, potential medicinals must be proven through rigorous investigation to be not only safe but efficacious in the treatment of a targeted malady. While smoked marijuana and THC preparations have not proved overly dangerous in published studies, questionable efficacy has been demonstrated. Several issues must be considered when examining the body of evidence both for and against the medical use of cannabinoids. Marijuana is not the same entity as, nor is interchangeable with, Δ⁹-THC. While the latter may be the chief psychoactive constituent of marijuana, the multiple additional cannabinoids present in marijuana are biologically active and must be considered. Secondly, significant study design flaws limit the conclusions that can be drawn from existing studies. Finally, poor overall understanding of cannabinoid physiology may hamper future study design. Proposed uses for medical marijuana and the available evidence supporting that use are reviewed below.

Pain

Acute Pain.

Studies examining the efficacy of THC in the setting of induced acute pain showed no improvement. These studies were limited by the lack of a positive control and examined only extremes of induced pain.²⁹ Smoked marijuana failed to attenuate thermal pain in volunteers, and an oral THC analog had no effect on postsurgical pain.⁶⁹

Chronic Pain.

When used for the treatment of chronic and neuropathic pain, cannabinoids have had more favorable outcomes in published studies although design flaws severely limit the quality of evidence for medical use.¹⁰⁹ Initial trials of combined cannabinoid opioid therapy have been encouraging, and the principle may have mechanistic merit based on the knowledge that opioid and cannabinoid receptors can form heterodimers,¹²⁰ but lack of proper controls and the presence of confounders limit the accepted clinical applicability of cannabinoids as analgesics at this time.

Nausea and Vomiting

Trials of cannabinoids for treatment of chemotherapy-induced nausea and vomiting have repeatedly shown that serotonin antagonists such as ondansetron are superior compared to smoked marijuana or oral synthetic preparations.

Glaucoma

Trials investigating the efficacy of cannabinoids for the treatment of glaucoma have demonstrated their inferiority to longer acting traditional therapeutics, which have more significant effects on intraocular pressure and longer durations of effect.

Summary of Medical Use

In 2003, the Institute of Medicine undertook an extensive review of the evidence supporting the medical use of marijuana. It concluded that in some circumstances, cannabinoids show promise for use as therapeutics but the quality of current studies necessitated further research specifically for the treatment of chronic pain. In addition, smoked marijuana is a crude and unpredictable delivery mechanism, and safer, more precise methods of administration are needed.¹⁵² No data reviewed since that publication is sufficient to reverse that opinion.

Pharmaceutical cannabinoids are proposed for use in the management of many clinical conditions (Table 77–1) but have generally been approved only for the control of chemotherapy-related nausea and vomiting that are resistant to conventional antiemetics, for breakthrough postoperative nausea and vomiting, and for appetite stimulation in human immunodeficiency virus (HIV) patients with anorexia-cachexia syndrome.⁵⁵ The claims of benefit in the other medical conditions in Table 77–1 are not supported by evidence.^6,154

PHARMACOLOGY AND PATHOPHYSIOLOGY

The term “cannabinoid” refers to compounds that bind to and agonize the cannabinoid receptors regardless of whether they are derived from plants (phytocannabinoids), synthetic processes (synthetic cannabinoid receptor agonists), or endogenously existing neuromodulators (endocannabinoids). At one time the term may have been used to delineate a structural similarity to Δ⁹-THC, but this naming convention has largely been abandoned during the past 30 years of cannabinoid research as new compounds have been discovered and synthesized. The structural diversity of cannabinoid ligands and the absence of a true pharmacophore make nomenclature based purely on structure cumbersome and inconsistent. It is preferable then to use the term cannabinoid to denote receptor agonism and subclassify cannabinoids further based on origin and structure (Fig. 77–1).

Cannabis is a collective term referring to the bioactive substances from the Cannabis plant. The Cannabis genus (species sativa and indica) produces more than 60 chemicals (C21 group) called cannabinoids. In this chapter, the term “cannabis” encompasses all cannabis products. The major cannabinoids are cannabinol, cannabidiol (CBD), and tetrahydrocannabinol. The principal psychoactive cannabinoid is THC, or Δ⁹-tetrahydrocannabinol. Marijuana is the common name for a mixture of dried leaves and flowers of the C. sativa plant. Hashish and hashish oil are the pressed resin and the oil expressed from the pressed resin, respectively. The concentration of THC varies from 1% in low-grade marijuana up to 50% in hash oil. THC extracted from marijuana using butane (butane hash oil or BHO) can approach THC concentrations of 100%. Pure THC and a SCRA are available by prescription with the generic names of dronabinol and nabilone, respectively. Nabiximols is the generic name for an oral mucosal spray containing THC and cannabidiol, which is approved for medical use in Canada, the United Kingdom, and parts of Europe. Unregulated SCRAs originally designed as research chemicals have emerged as designer drugs of abuse over the past 6 years.

Cannabinoid receptors are G protein linked neuromodulators that inhibit adenylate cyclase in a dose-dependent and stereospecific manner. While historically the cannabinoid receptor system is described as having a central CB₁ and a peripheral CB₂ receptor, recent evidence points to the central nervous system (CNS) presence of CB₂ receptors.¹³⁴ The two currently identified cannabinoid receptors are labeled CB₁ and CB₂ and are distinguished largely by their anatomic distribution and mechanisms of cellular messaging (Fig. 77–2).

CB₁ Receptors and the Psychogenic Effects of Cannabis

CB₁ receptors are the most numerous G protein coupled receptors in the mammalian brain accounting for the multiple and varied effects of Cannabis on behavior, learning, and mood as well as suggesting the enormous ­complexity of the endocannabinoid system.⁵⁴ The highest concentration of CB₁ receptors are located in areas of the brain associated with movement and higher functions of cognition and emotions. Relative lack of CB₁ receptors in the brainstem also explains lack of coma and respiratory depression seen with Cannabis use. CB₁ receptors are structurally comprised of seven transmembrane protein units coupled to pertussis-sensitive (decrease aden­ylate cyclase) G proteins. They exhibit genetic variation via splice variants and are found as heterodimers with a multitude of other receptor types.⁶³

CB₂ receptors have traditionally been thought of as existing in the periphery and mainly affecting immune response, although evidence now exists of their activity in the CNS. Isolated agonism of CB₂ receptors has been the target for novel pharmaceutical candidates as antiinflammatory agents with minimal success as psychoactive effects of CB₁ agonism were still evident.

Mechanism of Cellular Signaling

Cannabinoid receptors both in the CNS and in the periphery exist on the presynaptic terminus of various neurons. Depolarization in postsynaptic portion of the neuron and subsequent increase in intracellular Ca²⁺ leads to on-demand synthesis and release of endocannabioids.¹⁰⁸ These free fatty acid–based messengers diffuse into the synapse and bind to the presynaptic cannabinoid receptor. Ligand binding causes conformational change in the G protein subunits and inhibition of adenylate cyclase, resulting in decreased intracellular cAMP concentrations, decreased activity of voltage-gated Ca²⁺ channels, and ultimately decreased neurotransmitter release (Fig. 77–2). Exogenous cannabinoids act in much the same way compared to endogenous compounds after receptor binding, except that binding affinity will vary among ligands and endogenous cannabinoids are rapidly metabolized by hydrolases.⁸⁰ Interestingly, some online chemical suppliers offer fatty acid amide hydrolase inhibitors for sale, along with various SCRAs, perhaps providing a glimpse into future products more closely related to endocannabinoids coming to market.

Both receptors inhibit adenylyl cyclase and stimulate K⁺ channel conductance.¹¹² CB₁ receptors are located either presynaptically or postsynaptically and their activation can inhibit or enhance the release of acetylcholine, L-glutamate, γ-aminobutyric acid, noradrenaline, dopamine, and 5-hydroxytryptamine.^67,73,127

The neuropharmacologic mechanisms by which cannabinoids produce their psychoactive effects have not been fully elucidated.^56,67,112 Nevertheless, activity at the CB₁ receptors is believed to be responsible for the clinical effects of cannabinoids,^12,37,67,140 including the regulation of cognition, memory, motor activities, nociception, and nausea and vomiting. Chronic administration of a cannabinoid agonist reduces CB₁ receptor density in several regions of the rat brain.¹³

PHARMACOKINETICS AND TOXICOKINETICS

Absorption

The pharmacokinetics of phytocannabinoids have been extensively reviewed.⁴⁷ The rate and completeness of absorption of cannabinoids depend on the route of administration and the type of cannabis product.

Inhalation of smoke containing THC results in the onset of psychoactive effects within minutes. From 10% to 35% of available THC is absorbed during smoking, and peak serum THC concentrations occur an average of 8 minutes (range, 3–10 minutes) after the onset of smoking marijuana. Peak serum concentrations depend on the dose. A marijuana cigarette containing 1.75% THC produces a peak serum THC concentration of approximately 85 ng/mL.⁵⁹

Ingestion of cannabis results in an unpredictable onset of psychoactive effects in 1 to 3 hours. Only 5% to 20% of available THC reaches the systemic circulation following ingestion. Peak serum THC concentrations usually occur 2 to 4 hours after ingestion, but delays up to 6 hours are described.⁸² Dronabinol has an oral bioavailability of approximately 10% with high interindividual variability.^44,103 THC is detectable in serum 1.5 to 4.5 hours after ingestion of dronabinol; peak serum concentrations occur within 4 hours after ingestion.⁴³ Nabilone has an oral bioavailability estimated to be greater than 90% and reaches peak serum concentrations 2 hours after ingestion.¹²⁵ The therapeutic serum THC concentration for the treatment of nausea and vomiting is greater than 10 ng/mL.²²

Distribution

THC has a steady-state volume of distribution of approximately 2.5 to 3.5 L/kg.⁴⁷ Cannabinoids are lipid soluble and accumulate in fatty tissue in a biphasic pattern. Initially, THC is distributed to highly vascularized tissues such as the liver, kidneys, heart, and muscle. Following smoking or intravenous administration, the distribution half-life is less than 10 minutes.⁶⁰ After the initial distribution phase, THC accumulates more slowly in less vascularized tissues and body fat. Repeated administration of Δ⁸-THC (an isomer of Δ⁹-THC) to rats over 2 weeks resulted in steadily increasing concentrations of Δ⁸-THC in body fat and liver but not in brain tissue. Once administration of Δ⁸-THC stopped, the cannabinoids were slowly released from fat stores as adipose tissue turned over.¹⁰⁷

THC crosses the placenta and enters the breast milk. Concentrations in fetal serum are 10% to 30% of maternal concentrations. Daily marijuana smoking by a nursing mother resulted in concentrations of THC in breast milk eightfold higher than concomitant maternal serum concentrations; THC metabolites do not accumulate in breast milk.¹¹⁴

Metabolism

THC is nearly completely metabolized by hepatic microsomal hydroxylation and oxidation (primarily CYP2C9 and CYP3A4).⁴⁷ The primary metabolite (11-hydroxy-Δ⁹-THC or 11-OH-THC) is active and is subsequently oxidized to the inactive 11-nor-Δ⁹-THC carboxylic acid metabolite (THC-COOH) and many other inactive metabolites.^1,4,118

The serum concentrations of THC and its metabolites change over time. Smoking a marijuana cigarette results in peak serum THC concentrations before finishing the cigarette. In six volunteers, peak serum THC concentrations occurred at 8 minutes (range, 6–10 minutes) after onset of smoking, peak 11-OH-THC at 13 minutes (range, 9–23 minutes), and peak THC-COOH at 120 minutes (range, 48–240 minutes) (Fig. 77–3).⁵⁹ Approximately 1 hour after beginning to smoke a marijuana cigarette, the THC to 11-OH-THC ratio is 3:1, and the THC to THC-COOH ratio is 1:2; at approximately 2 hours the ratios are 2.5:1 and 1:8, respectively; and at 3 hours the ratios are 2:1 and 1:16, respectively.⁵⁹ Ingestion of cannabis results in much more variable concentrations and time courses of THC and metabolites (Fig. 77–3). Nonetheless, at 2 to 3 hours postingestion, the ratios are similar to those after smoking: THC to 11-OH-THC is 2:1 and THC to THC-COOH ranges from 1:7 to 1:14.¹⁵⁰

Of the many aminoalkylindole (AAI) SCRAs isolated in “Spice” incense blends, human metabolic analyses have been published for JWH-018, JWH-073, and AM 2201.^14,15 In contrast to THC, these cannabinoids are metabolized largely through hydroxylation and oxidation by CYP2C9 and CYP1A2 (with minor contributions of CYP2D6) to active metabolites that retain affinity for and in most are agonists at both CB₁ and CB₂ receptors.^26,27 These metabolites undergo glucuronic acid conjugation in phase II metabolism.

Excretion

Reported elimination half-lives of THC and its major metabolites vary considerably. Following intravenous doses of THC, the mean elimination half-life ranges from 1.6 to 57 hours.⁴⁷ Elimination half-lives are expected to be similar following inhalation.^47,59 The elimination half-life of 11-OH-THC is 12 to 36 hours, and the elimination half-life of THC-COOH ranges from 1 to 6 days.^75,150

THC and its metabolites are excreted in the urine and the feces. In the 72 hours following ingestion, approximately 15% of a THC dose is excreted in the urine and roughly 50% is excreted in the feces.^1,20,153 Following intravenous administration, approximately 15% of a THC dose is excreted in the urine and only 25% to 35% is excreted in the feces.¹⁵⁰ Inhalation is expected to produce results similar to intravenous administration.^47,59 In 5 days, 80% to 90% of a THC dose is excreted from the body.^51,64

Cannabinoids were measured in the urine following smoking a marijuana cigarette containing 27 mg of THC (Fig. 77–3).⁸⁸ THC urine concentrations peaked at 2 hours (mean, 21.5 ng/mL; range, 3.2–53.3 ng/mL) after smoking and were undetectable (<1.5 ng/mL) in five of the eight subjects by 6 hours after smoking. Urine concentrations of 11-OH-THC peaked at 3 hours (77.3 ± 29.7 ng/mL). The primary urinary metabolite is the glucur­onidate conjugate of THC-COOH.¹⁵⁴ THC-COOH urine concentrations peak at 4 hours (179.4 ± 146.9 ng/mL),⁸⁹ and it has an average urinary excretion half-life of 2 to 3 days (range: 0.9–9.8 days).⁴⁷ Both 11-OH-THC and THC-COOH remained detectable in the urine of all eight subjects for the 8 hours of the study.⁸⁸

Following discontinuation of use, metabolites may be detected in the urine of chronic users for several weeks.^36,70 Factors such as age, weight, and frequency of use only partially explained the long excretion period.³⁶

Primary urinary metabolites of nonclassical SCRAs are summarized in Fig. 77–4.

CLINICAL MANIFESTATIONS

The clinical effects of THC use, including time of onset and duration of effect, vary with the dose, the route of administration (ingestion is slower in onset than inhalation), the experience of the user, the vulnerability of the user to psychoactive effects, and the setting in which the drug is used. The concomitant use of CNS depressants such as ethanol, or stimulants such as cocaine, alters the psychological and physiologic effects of marijuana.

Psychological Effects

Use of marijuana produces variable psychological effects.³⁷ The variation, which occurs both between and within users, may be a result of drug tolerance, level or phase of clinical effects, strain of cannabis, physical and social settings, or user expectations or cognitive set. The most commonly self-reported effect is relaxation. Other commonly reported effects are perceptual alterations (heightened sensory awareness, slowing of time), a feeling of well-being (including giddiness or laughter), and increased appetite.⁴⁶

Physiologic Effects

Use of cannabis is associated with physiologic effects on cerebral blood flow, the heart, the lungs, and the eyes. In a controlled, double-blind positron emission tomography study,⁸⁹ intravenous THC increased cerebral blood flow, particularly in the frontal cortex, insula, cingulate gyrus, and subcortical regions. These increases in cerebral blood flow occurred 30 to 60 minutes after use and were still elevated at 120 minutes.⁹⁰ Similar blood flow changes result from smoking marijuana.¹¹¹

Common acute cardiovascular effects of cannabis use include increases in heart rate and decreases in vascular resistance.^71,135 Cannabis produces dose-dependent increases in heart rate within 15 minutes of starting a marijuana cigarette (from a baseline mean of 66 beats/min to a mean of 89 beats/min) that reach a maximum (mean, 92 beats/min) 10 to 15 minutes after peak serum THC concentrations. These changes last for 2 to 3 hours.⁸ Increases in blood pressure may occur with cannabis use. In a study of six subjects, an increase in blood pressure from a baseline mean of 119/74 mm Hg to a mean of 129/81 mm Hg occurred but was not statistically significant.⁸ In a double-blind, controlled study of men being investigated for angina pectoris, smoking a marijuana cigarette resulted in statistically significant changes in blood pressure from a baseline mean of 123/79 mm Hg to a peak mean of 132/84 mm Hg.¹¹⁹ In contrast, repeated THC use resulted in significant slowing of heart rate (from a mean of 68 beats/min to a low of 62 beats/min) and lowering of blood pressure (from a mean of 116/62 mm Hg to a low of 108/53 mm Hg).¹⁰ Decreased vascular tone may cause postural hypotension accompanied by dizziness and syncope.

Inhalation or ingestion of THC produces a dose-related short-term decrease in airway resistance and an increase in airway conductance in both normal and asthmatic individuals.¹⁴² Smoking marijuana results in an immediate increase in airway conductance, which peaks at 15 minutes and lasts 60 minutes. Ingestion of cannabis produces a significant increase in airway conductance at 30 minutes, which peaks at 3 hours and lasts 4 to 6 hours.^143,144,147 The mechanism for this effect is unclear.

The principal ocular effects of cannabis are conjunctival injection and decreased intraocular pressure. Cannabinoids, applied topically to a rabbit eye, resulted in hyperemia of the conjunctival blood vessels 2 hours after application.⁹⁶ Regardless of route of administration, cannabis causes a fall in intraocular pressure in 60% of users⁴⁵ by acting on CB₁ receptors in the ciliary body.¹¹⁷ The mean reduction in intraocular pressure is 25% and lasts 3 to 4 hours.

Physiological effects of novel SCRAs have not been studied in any ­controlled settings.

ACUTE TOXICITY

In addition to the physiologic and psychological effects described above, acute toxicity may include decreases in coordination, muscle strength, and hand steadiness. Lethargy, sedation, postural hypotension, inability to concentrate, decreased psychomotor activity, slurred speech, and slow reaction time also may occur.^106,153

In young children, the acute ingestion of cannabis is potentially life threatening.⁸⁷ Ingestion of estimated amounts of 250 to 1000 mg of hashish resulted in obtundation in 30 to 75 minutes. Tachycardia (>150 beats/min) was found in one third of the children. Less commonly reported findings include apnea, cyanosis, bradycardia, hypotonia, and opisthotonus.

The acute toxicity profile of nonclassical SCRAs stands in stark contrast to the relatively mild effects of smoked or ingested phytocannabinoid products and surprised both users and clinicians, who expected effects to be largely identical to marijuana and hashish. This is likely a result of AAI cannabinoids found in incense blends being more potent and efficacious at cannabinoid receptors as well as having active metabolites. Moreover, these products are unregulated, and the presence of additional contaminating xenobiotics, such as designer cathinones, methylxanthines, and long-acting β-adrenergic agonists such as clenbuterol must be considered.

Deciphering the recent case literature of SCRA toxicity is fraught with challenges as many of the published reports lack laboratory confirmation of exposure. In addition, cases involving spice blends carry the possibility that some adverse effects could result from the plant matter found with the SCRAs. Finally, the concentration of SCRAs varies by incense package, even of the same brand and lot, making dose estimation difficult if not impossible.

Agitation¹²⁹ and seizures are reported.^81,128 In one report with laboratory confirmation, a patient experienced multiple seizures within 30 minutes after ingesting JWH-018 in powder form.⁸¹ The sample was confirmed as pure JWH-018, and it was later further analyzed, as was the patient’s blood and urine, for the presence of cathinones or other xenobiotic contaminants, with none detected.

Psychosis (new onset, acute exacerbation of existing psychiatric disorders, and increased risk of psychosis relapse) and anxiety have resulted even after single doses.^53,65,115

Tachycardia was a common finding detailed in one series, and tachydysrhythmia requiring cardioversion has been described.⁸¹ Chest pain and increased troponin concentrations were observed in three patients who claimed to have smoked spice several days before presenting to hospital, but laboratory confirmation of SCRA exposure was not performed.⁹⁷

Diffuse pulmonary infiltrates and dyspnea requiring intubation and mechanical ventilation were reported in a habitual spice user. Laboratory confirmation revealed three parent SCRAs (AM2201, JWH-122, and JWH-210).²

Accounts of acute kidney injury are described in a case series of 16 previously healthy patients. All patients reported smoking spice incense blends prior to presentation. The patients had flank pain, nausea, and vomiting with elevated serum creatinine concentrations. Laboratory confirmation was achieved in eight of the patients and a previously unreported SCRA was isolated (XLR-11). Several of the patients required hemodialysis, but all eventually recovered.¹⁰¹

ADVERSE REACTIONS

Acute Use

Cannabis users occasionally may experience distrust, dysphoria, fear, or panic reactions. Transient psychotic episodes are associated with cannabis use. Commonly reported adverse reactions at the prescribed dose of dronabinol or nabilone include postural hypotension, dizziness, sedation, xerostomia, abdominal discomfort, nausea, and vomiting. One case of acute pancreatitis (serum amylase concentration up to 3200 IU/mL) following a period of heavy cannabis use is reported, but the causal relationship is unclear.⁴⁴

Life-threatening ventricular tachycardia (200 beats/min) has been reported.¹²¹ In six individuals with acute cardiovascular deaths, postmortem whole-blood THC concentrations ranged from 2 to 22 ng/mL (mean, 7.2 ng/mL; median, 5 ng/mL).⁵ While the temporal association is clear, causality is less clear because three of the six people had significant preexisting cardiac pathology. The risk of myocardial infarction is increased five times over baseline in the 60 minutes after marijuana use but subsequently declines rapidly to baseline risk levels.⁹⁸ Atrial fibrillation with palpitations, nausea, and dizziness was temporally associated with smoking marijuana in four patients.^38,79,138

Chronic Use

Long-term use of cannabis is associated with a number of adverse effects.

Immune System.

Cannabinoids affect host resistance to infection by modulating the secondary immune response (macrophages, T and B lymphocytes, acute phase and immune cytokines). However, an immune-mediated health risk from using cannabis has not been documented.⁷⁷

Respiratory System.

Chronic use of marijuana is associated with clinical findings compatible with obstructive lung disease.¹⁴⁷ Smoking marijuana delivers more particulates to the lower respiratory tract than does smoking tobacco,¹⁵⁵ and marijuana smoke contains carcinogens similar to tobacco smoke. Case reports and a hospital-based case-control study suggest that cancers of the respiratory tract (mouth, larynx, sinuses, lung) are associated with daily or near daily smoking of marijuana, although exposure to tobacco smoke and ethanol may be confounding factors.^21,142,145 A systematic review and a cohort study with 8 years of follow-up demonstrated no association between marijuana smoking and smoking-related cancers,^49,93 and a population-based case-control study found that marijuana use was not associated with an increased risk of developing oral squamous cell carcinoma.¹²⁴

Cardiovascular System.

Marijuana use may be a risk for individuals with coronary artery disease. An exploratory prospective study of self-reported marijuana use among patients admitted for myocardial infarction found that patients who used marijuana were at significantly increased risk for cardiovascular and noncardiovascular mortality compared with nonusers.^98,103

Reproductive System.

Reduced fertility in chronic users is a result of oligospermia, abnormal menstruation, and decreased ovulation.¹⁷ Cannabis is a class C drug in pregnancy¹⁶ and affects birth weight and length but does not cause fetal malformations. Statistically significant reductions in birth weight (mean, 79 g less than nonusers) and length (mean, 0.5 cm shorter than nonusers) are reported in women who had urine assays positive for cannabis during pregnancy.¹⁵⁷ The results of three other studies are difficult to interpret because marijuana use in pregnancy was poorly documented.^50,157 Epidemiologic studies based on self-reporting of cannabis use do not support an association between the use of cannabis during pregnancy and teratogenesis.^78,85,157

The effect of maternal use of cannabis during pregnancy on neurobehavioral development in the offspring has been studied. No detrimental effects are reported in children born to women who smoked marijuana daily (more than 21 cigarettes per week) in rural Jamaica.³⁴ Tremors and increased startling are reported in infants younger than 1 week of age whose mothers used cannabis during pregnancy.⁴⁰ These findings, which persisted beyond 3 days, were not associated with other signs of a withdrawal syndrome. There were no abnormalities in the children of parents who used greater than five cigarettes per week in Ottawa, Canada, at 12, 24, and 36 months of age, but lower scores in verbal and memory domains at 48 months of age are reported.^39,41,51 The results of studies evaluating the effect of in utero exposure to cannabis on postnatal neurobehavioral development are equivocal because of methodologic concerns regarding exposure assessment and control of covariates,³¹ including the continued parental use of cannabis during the postnatal and early childhood periods. The role of second hand exposure to cannabis on postnatal and early childhood development of neurobehavioral problems has not been evaluated.

Endocrine System.

In experimental animals, cannabis exposure is associated with suppression of gonadal steroids, growth hormone, prolactin, and thyroid hormone. In addition, cannabis alters the activity of the hypothalamic-pituitary-adrenal axis.¹⁷ In human studies, the results are inconsistent, long-term effects have not been convincingly demonstrated, and clinical consequences are undefined.¹⁷

Neurobehavioral Effects.

There is a concern that chronic cannabis use results in deficits in cognition and learning that last well after cannabis use has stopped. Neuropsychological tests administered to 10 cannabis-dependent adolescents, eight adolescent noncannabis drug abusers, and nine nondrug users showed significant differences that persisted for the duration of the study (6 weeks of abstinence) between the cannabis group and the other groups in a visual retention test and a memory test.¹³² In a study of three experienced marijuana smokers, cannabis impaired arithmetic and recall tasks up to 24 hours after smoking.⁵² Adults who used cannabis more than seven times per week had impairments in math skills, verbal expression, and memory retrieval processes; people who used cannabis one to six times per week showed no impairments.¹¹ After 1 day of abstinence, 65 heavy marijuana users (median, use on 29 of past 30 days) showed greater impairment on neuropsychological tests of attention and executive functions than light marijuana users (median, use on 1 day of past 30 days).¹¹⁶ (The authors were uncertain whether this difference was caused by residual THC in the brain, a withdrawal effect from the drug, or a direct neurotoxic effect of cannabis.)

There is little evidence that adverse cognitive effects persist after stopping the use of cannabis⁶⁸ or that cannabis use causes psychosocial harm to the user.⁸⁶ The hypothesis that there is a causal association between cannabis use and psychosis has not been proven unequivocally.⁹ An “amotivational syndrome” is attributed to cannabis use. The syndrome is a poorly defined complex of characteristics such as apathy, underachievement, and lack of energy.^25,131 The association of the syndrome with cannabis use is based primarily on anecdotal, uncontrolled observations.⁵⁶ Anthropologic field studies, evaluations of US college students, and controlled laboratory experiments have failed to identify a causal relationship between cannabis use and the amotivational syndrome.⁵⁶ A study evaluating the role of depression in the amotivational syndrome found significantly lower scores on “need for achievement” scales in heavy users (median, daily use for 6 years) with depressive symptoms compared with heavy users without depressive symptoms and light users (median, several times per month for 4.5 years) with or without depressive symptoms.¹⁰⁵ These data suggest that symptoms attributed to an amotivational syndrome are caused by depression, not cannabis. Another study found that behavior that could be interpreted as amotivation was inversely related to the perceived size of the reward.²⁵

Abuse, Dependence, and Withdrawal.

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, defines marijuana abuse as repeated instances of use under hazardous conditions; repeated, clinically meaningful impairment in social/occupational/educational functioning; or legal problems related to marijuana use. Marijuana dependence is defined as tolerance, compulsive use, impaired control, and continued use despite physical and psychological problems caused or exacerbated by use. The amount, frequency, and duration of cannabis use required to develop dependence are not well established.^24,141 Much of the support for cannabis dependence is based on the existence of a withdrawal syndrome. In animals repeatedly given cannabis, the administration of a CB₁ receptor antagonist produced signs of withdrawal.^83,139 In humans, chronic users experience unpleasant effects when abstaining from cannabis.¹⁸ The time of onset of withdrawal symptoms is not well characterized.¹⁷ The most reliably reported effects are irritability, restlessness, and nervousness as well as appetite and sleep disturbances.¹³⁹ Other reported acute withdrawal manifestations include tremor, diaphoresis, fever, and nausea. These symptoms and signs are reversed by the oral administration of THC.^9,48 The duration of withdrawal manifestations, without treatment, is not clearly established.^19,139

There is a single report of a withdrawal syndrome observed after heavy and prolonged nonclassical SCRA use.

Cannabinoid Hyperemesis Syndrome.

Chronic, heavy marijuana use is associated with a clinical syndrome comprised of abdominal discomfort, nausea, and hyperemesis. Symptoms are often refractory to opioids and antiemetics.¹⁵¹ The hallmark of the syndrome is almost immediate relief of symptoms with bathing or showering in hot water, and a major diagnostic feature is compulsive bathing. The pathophysiology of this syndrome is unclear. However, relief with hot water may indicate dysfunction of pain perception, excess substance P release, and activation of TRPV1 (a G protein receptor that has been shown to interact with the endocannabinoid system and is the only known capsaicin receptor); these may play a role in elucidating the mechanism for this syndrome as well as providing new treatment modalities. Ultimately, successful treatment of the cannabinoid hyperemesis syndrome depends on cessation of marijuana use.^{3,23,33,42,136,137,151}

CANNABIS AND DRIVING

The perceptual alterations caused by cannabis suggest that its recent use should be associated with automobile crashes. However, neither experimental nor epidemiologic studies have provided definitive answers about the effects cannabis use has on driving ability. The published analytical ­studies of the relationship between cannabis and driving behavior and motor vehicle crashes have been reviewed.⁷ In experimental driving studies, cannabis impairs driving ability, but cannabis-using drivers recognize their impairment and compensate for it by driving at slower speeds and increasing following distance. However, the slower reaction time caused by cannabis results in impaired emergency response behavior.

The epidemiologic studies evaluating the association of cannabis use and traffic crashes provide no evidence that cannabis alone increases the risk of causing fatal crashes or serious injuries.^7,110 A recent study comparing past driving records of subjects entering a drug treatment center with controls found that a self-reported history of cannabis use was associated with a statistically significant increase in adjusted relative risk for all crashes (relative risk, 1.49; 95% confidence interval, 1.17–1.89) and for “at fault” crashes (relative risk, 1.68; 95% confidence interval, 1.21–2.34).²⁸

DIAGNOSTIC TESTING

Cannabinoids can be detected in plasma or urine. Enzyme-multiplied immunoassay technique (EMIT) and radioimmunoassay (RIA) are routinely available; gas chromatography–mass spectrometry (GC-MS) is the most specific assay and is used as the reference method.

EMIT is a qualitative urine test that is often used for screening purposes. EMIT identifies the metabolites of THC. In these tests, the concentrations of all metabolites present are additive. For the EMIT II Cannabinoid 20 ng Assay, the cutoff concentration for distinguishing positive from negative samples is 20 ng/mL. A positive test means that the total concentration of all the metabolites present in the urine was at least 20 ng/mL. A positive urine test for cannabis only indicates the presence of cannabinoids, and it does not identify which metabolites are present or in what concentrations. Qualitative urine test results do not indicate or measure intoxication or degree of exposure. The National Institute on Drug Abuse guidelines for urine testing specify test cutoff concentrations of 50 ng/mL for screening and 15 ng/mL for confirmation.

Variables affecting the duration of detection of urinary metabolites include dose, duration of use, acute versus chronic use, route of exposure, and sensitivity of the method. In addition, factors affecting the quantitative values of urine THC and metabolites include urine volume, concentration, and pH. Using GC/MS, metabolites may be detected in the urine up to7 days following a single marijuana cigarette.^60,61

The length of time between stopping cannabis use and a negative EMIT urine test (<20 ng/mL) depends on the extent of use. Release of THC from adipose tissue is important in drug testing because chronic users may release cannabinoids in quantities sufficient to result in positive urine tests for several weeks. In addition, vigorous exercise may stimulate the release of cannabinoids from fat depots. In light users being tested daily under observed abstinence, the mean time to the first negative urine test is 8.5 days (range, 3–18 days) and the mean time to the last positive urine is 18.2 days (range, 7–34 days).³⁶ In heavy users (mean, 9 years of using at least once a day) being tested under the same conditions, the mean time to the first negative urine test result (EMIT assay <20 ng/mL) was 19.1 days (range, 3–46 days) and the mean time to the last positive urine sample was 31.5 days (range, 4–77 days).³⁶

Standard laboratory analyses identify THC and its metabolites but cannot identify the source of the THC (eg, marijuana, hashish, dronabinol). EMIT will not identify nabilone because it is not THC; however, nabilone can be specifically identified using high-performance liquid chromatography–tandem mass spectrometry.¹²²

Immunoassays may give false-negative and false-positive test results (Table 77–2). To help identify evidence tampering, negative urine immunoassays should be accompanied by examining the urine for clarity and measuring urinary specific gravity, pH, temperature, and creatinine.^133,148

EMIT will not detect nonclassical SCRA metabolites. Commercial urine immunoassays are available but generally need to be directed to a specific SCRAs. High-performance liquid chromatography–tandem mass spectrometry or gas chromatography mass spectrometry are currently the mainstay of laboratory confirmation for SCRAs, but their clinical utility is limited in all but retrospective instances. Further challenges are presented by the multitude of known nonclassical cannabinoids and doubly so by the rate new SCRAs are introduced to the illegal high market.^{46,66,72,74,99,100,123,146,149}

PASSIVE INHALATION

Studies of passive exposure to marijuana smoke and the urinary excretion of cannabinoids have used enclosed spaces with nonsmokers present during and after active smoking.^{30,82,102,110,113} In an unventilated 6.9 × 8.2 × 7.9-foot room (12,225.8 L of air), five adult volunteers were exposed to the side stream smoke of 4 or 16 marijuana cigarettes (THC, 25 mg/cigarette) smoked simultaneously over one hour on each of six consecutive days.³¹ After being exposed to four marijuana cigarettes, four of the volunteers had at least one positive urine by EMIT assay (cutoff, 20 ng/mL) at some unspecified time during the six study days; exposure to 16 marijuana cigarettes resulted in positive EMIT assays only after the ­second day of exposure.

In a car (1650 L of air), three adult volunteers were exposed to the smoke from 12 marijuana cigarettes smoked by two people over 30 minutes.¹⁰² EMIT analyses of urine samples from one passive inhaler were positive at time 0 to 4 hours and on days 2 and 3; a second passive inhaler had one positive urine test at time 4 to 24 hours after exposure.

Three adult volunteers in a 10 × 10 × 8-foot unventilated room (21,600 Lof air) were exposed to the side stream smoke of four marijuana cigarettes (THC, 27 mg/cigarette) smoked simultaneously over one hour.¹⁰⁴ The concentrations of cannabinoids in urine samples taken 20 to 24 hours after exposure were less than 6 ng/mL when analyzed using RIA methodology. Another study used an unventilated room (total volume of 27,950 L) containing three desks and a filing cabinet.⁸² Over 10 to 34 minutes, each of six volunteers smoked a marijuana cigarette (THC, 17.1 mg/cigarette) and left the room. Four nonsmoking adult males were in the study room for 3 hours from the start of smoking. The door was opened and closed 18 times during the study. The maximum urine cannabinoid concentration (measured by RIA) in the nonsmokers was 6.8 ng/mL at 6 hours after the start of smoking.

Another study used a closed 8 × 8 × 10-foot room (15,500 L of air) with each of four subjects smoking two marijuana cigarettes containing 2.5% THC on one occasion and 2.8% THC on a second occasion.¹¹³ On each occasion, two nonsmoking subjects were in the room for one hour from the onset of smoking. None of the nonsmokers’ urine samples (0–24 hours) from either exposure period tested positive on an EMIT assay with a cutoff of 20 ng/mL. An identical experiment in a closed car (approximately 3500 Lof air) resulted in one of 23 urine specimens testing positive at 6 hours.

Therefore, passive inhalation of marijuana smoke is unlikely to result in positive urine test results unless the exposure has been extreme.

SALIVA

Saliva samples may be used to establish the presence of cannabinoids and time of cannabis consumption. Cannabinoids (THC, THC-COOH, 11-OH-THC) in saliva may be from the smoke of the marijuana or hashish or from a preliminary metabolism in the mouth.¹³⁰ Saliva THC concentrations above 10 ng/mL are consistent with recent use and correlate with subjective intoxication and heart rate changes.⁹⁴

HAIR

Hair sample analysis is not useful in identifying THC or its metabolites. Only small quantities of non–nitrogen-containing substances, such as cannabinoids, are found in hair pigments.^35,76,95

SWEAT

The analysis of perspiration to test for cannabinoids is a recent development. Perspiration deposits drug metabolites on the skin, and these are renewed even after the skin is washed. Detection threshold is reported to be 10 ng/mL, but forensic confirmation by alternative means is required.⁷⁶

ESTIMATING TIME OF EXPOSURE

A measurable serum concentration of THC is consistent with recent exposure and toxicity, but there is poor correlation between serum THC concentrations and actual clinical effects.⁵⁷ The ratio of THC to THC-COOH has been used to estimate time of smoking marijuana. Similar concentrations of each indicate cannabis use within 20 to 40 minutes and imply intoxication. In naive users, a concentration of THC-COOH that is greater than THC indicates that use probably occurred more than 30 minutes ago. The high background concentrations of THC-COOH in habitual users make estimations of time of exposure unreliable in this population.

Serum concentrations of THC and THC-COOH were used in a logarithmic equation to predict the time since smoking a marijuana cigarette.⁸⁸ The ratio provided acceptable results up to 3 hours after smoking (predicted time of exposure averaged 27 minutes longer than actual exposure time), but more than 3 hours after smoking the predicted exposure time was overestimated by 3 hours. Mean overestimations of predicted exposure time of 2.5 to 4.2 hours for smoking and of 1.6 hours for ingestions are reported when serum samples are taken more than 4 hours after exposure.⁵⁹

Chronic use or oral administration of cannabis increases the concentration of 11-OH-THC relative to the concentrations of THC or THC-COOH. In these cases, estimating time of exposure based on relative concentrations is problematic.⁵⁸ In four subjects, ingestion of cannabis produced total serum metabolite concentrations less than 20 times the serum THC concentration for 3 hours after ingestion, suggesting that a ratio of this magnitude is consistent with recent oral consumption.⁸²

MANAGEMENT

Gastrointestinal decontamination is not recommended for patients who ingest cannabis products, nabilone, or dronabinol because clinical toxicity is rarely serious and responds to supportive care. In addition, a patient with a significantly altered mental status, such as somnolence, agitation, or anxiety, has risks associated with gastrointestinal decontamination that outweigh the potential benefits of the intervention.

Agitation, anxiety, or transient psychotic episodes should be treated with quiet reassurance and benzodiazepines (midazolam 1–2 mg intramuscularly or diazepam 5–10 mg intravenously) as needed.

The toxicity of SCRAs should not be expected to mirror that of THC or prescription THC-based cannabinoids. Aggressive supportive care may be necessary.

Psychomotor agitation, anxiety, and convulsions should be treated with benzodiazepines as above. Laboratory evaluation should be initiated for signs of electrolyte disturbances and direct toxicity of the CNS, cardiovascular, renal, and musculoskeletal systems. Aggressive crystalloid fluid resuscitation should be given for rhabdomyolysis and acute kidney injury.

Antipsychotics should be avoided during any phase of undifferentiated agitated delirium. Should psychotic features persist into a subacute time frame after the resolution of sympathomimetic features, antipsychotic medications can be considered. Patients should be observed until asymptomatic.

If available, drug samples along with the patient’s blood and urine, while not clinically useful, may aid in unknown designer SCRA identification and understanding of clinical effects.

There are no specific antidotes for cannabis or SCRA toxicity. Coingestants, such as cocaine, ethanol, designer amphetamines, methylxanthines, and long-acting β-adrenergic agonists should be identified and their effects anticipated and treated as indicated.

SUMMARY

• Phytocannabinoids have been used for centuries both as medicinal substances and as intoxicants.

• Despite the collective human history with cannabinoids, we are only now beginning to understand the endocannabinoid system and the consequences of alterations to that system.

• Medical use of THC and smoked marijuana have long existed, and while the safety profile of these xenobiotics are established, evidence of the efficacy of medical marijuana over the gamut of currently prescribed maladies is sparse. Still, the cannabinoid system provides an attractive target system for treatment of chronic pain and appetite modulation, but more rigorous and properly designed investigations are needed.

• The toxicity profile of traditional cannabinoids and designer SCRAs used as drugs of abuse and research chemicals are as different as their chemical structures. Clinicians, users, and public health policy makers alike would do well to separate these groups of cannabinoids in both thought and practice.

Acknowledgment

Michael A. McGuigan, MD, contributed to this chapter in previous editions.

References

HISTORY AND EPIDEMIOLOGY

Cocaine is contained in the leaves of Erythroxylum coca, a shrub that grows abundantly in Colombia, Peru, Bolivia, the West Indies, and Indonesia. As early as the 6th century, the inhabitants of Peru chewed or sucked on the leaves for social and religious reasons. In the 1100s, the Incas used cocaine-filled saliva as local anesthesia for ritual trephinations of the skull.⁶⁸

In 1859, Albert Niemann isolated cocaine as the active ingredient of the plant. By 1879, Vassili von Anrep demonstrated that cocaine could numb the tongue.¹⁰⁸ However, Europeans knew little about cocaine until 1884, when the Austrian ophthalmologist Karl Koller introduced cocaine as an effective local anesthetic for eye surgery and Koller’s colleague, Sigmund Freud, wrote extensively on the psychoactive properties of cocaine.⁵⁵ Following these revelations, Merck, Europe’s main cocaine producer, increased production from less than 0.75 pounds in 1883 to more than 150,000 pounds in 1886.¹⁰⁴

Simultaneously, reports of complications from the therapeutic use of cocaine began to appear. In 1886, a 25 year-old man had a “pulseless” syncope after cocaine was applied to his eye to remove a foreign body.²¹¹ By 1887, more than 30 cases of severe toxicity were reported,¹⁸¹ and by 1895 at least eight fatalities resulting from a variety of doses and routes of administration were summarized in one article.⁵⁷ Recreational cocaine use was legal in the United States until the passage of the Harrison Narcotic Act of 1914, when cocaine was restricted to medical use. Not until 1982, however, was the first cocaine-associated myocardial infarction reported in the United States.²⁸

Currently, cocaine is an approved pharmaceutical. It is used primarily for topical anesthesia of cutaneous lacerations or during otolaryngology procedures as a vasoconstrictor and topical anesthetic. Although multiple factors have fostered a decline in the medicinal use of cocaine,^18,63,130 the recreational use of cocaine remains a significant problem.

The United Nations office on Drugs and Crime estimates that there are 13 to 19 million cocaine users worldwide.³⁴ In the United States, it is estimated that there are 1.5 million cocaine users.⁴³

PHARMACOLOGY

The alkaloid form of cocaine, benzoylmethylecgonine, is a weak base that is relatively insoluble in water. It is extracted from the leaf by mechanical degradation in the presence of a hydrocarbon. The resulting product is converted into a hydrochloride salt to yield a white powder, cocaine hydrochloride, which is very water soluble. Cocaine hydrochloride can be insufflated, applied topically to mucous membranes, dissolved in water and injected, or ingested; however, it degrades rapidly when pyrolyzed. Smokable cocaine (crack) is formed by dissolving cocaine hydrochloride in water and adding a strong base. A hydrocarbon solvent is added, the cocaine base is extracted into the organic phase, and then evaporated. The term “free-base” refers to the use of cocaine base in solution.

Cocaine is rapidly absorbed following all routes of exposure; however, when applied to mucous membranes or ingested, its vasoconstrictive properties slow the rate of absorption and delay the peak effect. Bioavailability for smoking cocaine exceeds 90%, and is approximately 80% following nasal ­application.¹⁰⁰ Data for ingested cocaine and application to other mucous membranes such as the urethra, vagina, or rectum are inadequately documented. Table 78–1 lists the typical onsets and durations of action for various routes of cocaine exposure.

Following absorption cocaine is approximately 90% bound to plasma proteins, primarily α₁-acid glycoprotein.¹⁶⁴ Based on human volunteer studies with small doses of cocaine, the volume of distribution is reported to be about 2.7 L/kg,¹⁰⁰ but it is unclear if the volume of distribution changes with overdose.