H: SUBSTANCES OF ABUSE

INTRODUCTION

HISTORY AND EPIDEMIOLOGY

Amphetamine was first synthesized in 1887 but was essentially lost until the 1920s, when concerns arose regarding the supply of ephedrine for asthma therapy.⁶⁷ The attempt to synthesize ephedrine lead to the rediscovery of dextroamphetamine in the United States and methamphetamine (d-phenylisopropylmethylamine hydrochloride) in Japan. Amphetamine was first marketed by Smith, Kline, and French in 1932 as the nasal decongestant Benzedrine. Both amphetamine and methamphetamine were supplied as stimulants for soldiers and prisoners of war during World War II. Amphetamine tablets were later available in 1935 for the treatment of narcolepsy and were advocated as anorexiants in 1938.¹⁷

The stimulant and euphoric effects of amphetamine were immediately recognized, with abuse reported as early as 1940.⁷⁴ 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 and early 1970s, various amphetamines such as methylenedioxyamphetamine (MDA), para-methoxyamphetamine (PMA), and para-methoxymethamphetamine (PMMA) were popularized as hallucinogens.^97,127 The Controlled Substance Act of 1970 placed amphetamines in Schedule II to prevent the diversion of pharmaceutical amphetamines for nonmedicinal uses. Abuse of amphetamines subsequently declined.¹³⁶

In the 1980s, use of methylenedioxy derivatives of amphetamine and methamphetamine surfaced and circumvented existing regulations. The best known of these derivatives were 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethamphetamine (MDEA).⁶ 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 illegally marketed in a large crystalline form termed “ice” by abusers.⁴⁶ Methamphetamine-related deaths in the United States increased through the 1990s, initially at several hundred per year. From 2010 to 2014, deaths involving methamphetamine doubled from 1,388 to 3,728 per year.¹⁷¹ Men who have sex with men in New York City (and perhaps elsewhere) remain a specific population at risk, with a persistently high prevalence of methamphetamine use.⁷² The ease and low cost of methamphetamine synthesis encourage establishment of illegal clandestine laboratories in the United States.⁷² Since the mid-1990s, MDMA has been widely used by college students and teenagers in large gatherings, known as “rave” or “techno” parties, in Europe and the United States.¹³⁴ Methcathinone (a khat-derived substance) and 4-bromo-2,5-methoxyphenylethylamine (2CB) were popular in dance clubs in the Midwestern United States in the 1990s, but use was not widespread.^59,62 Synthetic cathinones are currently sold as “bath salts” or “legal highs” to circumvent existing laws, resulting in serious toxicity and deaths.³¹ Recently, older amphetamines such as PMA and PMMA made a resurgence, with new reports of toxicity and deaths.¹⁰²

PHARMACOLOGY

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

The pharmacologic effects of amphetamines are complex, but their primary mechanism of action is the release of biogenic amines. Release of catecholamines from the presynaptic terminals, particularly dopamine and norepinephrine, leads to a hyperadrenergic condition, but release of serotonin favors a serotonergic condition. Although there are conflicting mechanistic models of amphetamine induction of catecholamine release, these variable results are directly correlated with the different concentrations of amphetamine used in experimental models. Our understanding of the mechanism of action of amphetamines is 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–dependent active proton transport system.^115,145

Amphetamines 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 enter the cell by exchange diffusion at the dopamine reuptake transporter and cause the release of dopamine from the cytoplasmic pool. At moderate concentrations, amphetamines passively 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.^145,170 At high concentrations, an additional mechanism is invoked as amphetamines diffuse through the cellular and vesicular membranes. Because amphetamines are bases, they alkalinize the vesicles, reducing the pH gradient necessary for vesicle integrity, resulting in dopamine release from the vesicles and delivery into the synapse by reverse transport (Chap. 13 and Fig. 73–1).^161,162 Amphetamines also block the reuptake of biogenic amines by competitive inhibition.^68,181 However, the contribution of this to the ultimate clinical effects are likely minor. Amphetamine’s structural similarity to amphetamine derived monoamine oxidase inhibitors (MAOIs) such as tranylcypromine explains their weak MAOI effect, the clinical significance of which is unclear.¹³¹

Binding selectivity to the neurotransmitter transporters largely determines the range of pharmacologic effects for a particular amphetamine. The affinity of MDMA for serotonin transporters, for example, is 10 times greater than that for dopamine and norepinephrine transporters. With this high affinity for serotonin transporters, MDMA produces primarily serotonergic effects.⁶⁴ Other predominantly serotonergic amphetamines include paramethoxyamphetamine and bromo-dragonFLY (Table 73–1).

The most identifiable effects of amphetamines are those caused by excessive biogenic amine release and the resultant stimulation of various receptors including α-adrenergic, β-adrenergic, dopamine, and serotonin receptors. The majority of serotonergic neurons in the central nervous system (CNS) are located in the raphe nuclei, which connects the brainstem to the rest of the CNS via serotonergic projections. Within the CNS, serotonin regulates a wide variety of functions, including, but not limited to, mood, memory, temperature regulation, sleep, and pain.⁶⁷ Serotonin is also involved in the release of antidiuretic hormone, the excessive release of which leads to hyponatremia. This is particularly associated with amphetamines with potent serotonergic effects such as MDMA.⁷³ Additional effects of serotonin include regulation of fluid secretion and peristalsis, as well as regulation of many vascular beds, predominantly via vasoconstriction. Peripherally, serotonergic actions of amphetamines can result in carcinoidlike effects.^103,144

Norepinephrine is another important neurotransmitter central to the action of amphetamines. Norepinephrine is found in the CNS and is also released peripherally from postganglionic sympathetic fibers. The main noradrenergic nucleus in the CNS is the locus ceruleus. Amphetamine induced excessive release of norepinephrine within the CNS results in decreased fatigue and increased attentiveness. Peripherally, norepinephrine acts on the adrenergic receptors (α and β), which mediate vasoconstriction and increased cardiac activity, resulting in hypertension and tachycardia.

The increase in CNS dopamine, particularly in the neostriatum, mediates stereotypical behavior and other locomotor activities as well as reward pathways.³⁶ The activity of dopamine in the neostriatum appears to be linked to glutamate release and inhibition of γ-aminobutyric acid (GABA) efferent neurons.⁸⁶ Stimulation of the glutamatergic system contributes significantly to the stereotypical behavior, locomotor activity, and neurotoxicity of amphetamines.^86,152,153 The effects of serotonin and dopamine on the mesolimbic system alter perception, cause psychotic behavior and anorexia.^76,160

Structure Modification

Phenylethylamines are chemical structures 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 later. 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 of the amphetamine but allows retention of 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).⁶⁰ Although these generalizations enable an understanding of the effects of amphetamines, there are many exceptions, and such generalizations do not necessarily apply after exposure to large doses of a particular molecule. There is a broad spectrum of clinical effects that derive from the various amphetamines: methamphetamine results in the most potent cardiovascular effects, and 2,5-dimethoxy-4-bromoamphetamine (DOB) results in the most consequential hallucinogenic and serotonergic effects.^60,117 Table 73–2 further describes the pharmacology of specific substitutions.

Other specific substitutions are worth noting. The addition of an extra methyl group to the terminal amine in amphetamine produces methamphetamine, greatly increasing 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. The addition of an α-methyl group results in strong stimulant, cardiovascular, and anorectic properties.^60,117 This is largely due to resistance to metabolism by monoamine oxidase conferred by the addition of this group. 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. With few notable exceptions including MDMA, the d-enantiomer is typically 4 to 10 times more potent than the l form of amphetamine. 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 (eg, iodine or bromine), which increases the potency and neurotoxicity of the compound compared to nonhalogenated compounds. Neurotoxicity is thought to be due to significant serotonin depletion, leading to irreversible neuron damage.⁷⁶ The ability of amphetamines to directly interact with neurotransmitter transporters enable minor modifications of the molecule to significantly alter its pharmacologic profile.⁸⁰ The addition of a ketone group at the β position results in a group of compounds known as the synthetic cathinones. Specifically, the addition of this group to amphetamine results in cathinone. The β-ketone group is responsible for increased polarity, which decreases penetration of the blood–brain barrier.

PHARMACOKINETICS AND TOXICOKINETICS

Absorption

Amphetamines can be absorbed by intravenous, oral, intranasal, and inhalational routes. Amphetamines are rapidly absorbed, with bioavailability that ranges between 60% and 90% depending on the route of administration. Peak serum concentrations are variable and are substance and route dependent. Methamphetamine has peak serum concentrations in less than 15 minutes when used via an intravenous (IV) or intranasal route and up to 180 minutes when taken orally.

Distribution

After 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 transformation and 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 are formed. N-demethylation of methamphetamine and MDMA result in the formation of amphetamine and MDA, respectively.¹⁰⁸ Dealkylation and demethylation are mainly performed by CYP1A2, CYP2D6, and CYP3A4, as well as flavin monooxygenase. Polymorphism of CYP2D6 in humans was recognized because of 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.¹⁴⁶ Increased toxicity of amphetamines 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.¹²¹ In general, because multiple enzymes and elimination 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.¹⁴ 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, leads to drug accumulation and prolongation of the apparent half-life and duration of effect.^13,108

PATHOPHYSIOLOGY

Most complications associated with amphetamines are a result of an uncontrolled hyperadrenergic condition similar to that which occurs with other sympathomimetics such as cocaine, except the duration of effect is typically longer (Table 73–3). 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. Additional organ-specific pathophysiologic effects are described later.

Central Nervous System

Anxiety, agitation, and hallucinations are typical CNS findings that result from adrenergic stimulation. Choreoathetoid movements, often described as irregular jerking or twisting movements, are related to increased dopaminergic stimulation in the striatal area.^88,101,107 Seizures are the direct result of amphetamine or occur secondarily to hyponatremia as reported with MDMA and certain synthetic cathinones.¹⁹ Psychosis, often a finding with acute use, is likely to recur with subsequent use, even after periods of prolonged abstinence. This phenomenon of recurrent psychosis on reexposure is likely related to a kindling phenomenon.¹¹²

Cardiac

Cardiomyopathy is reported in chronic amphetamine users. Excessive catecholamine exposure is likely responsible for their associated cardiomyopathies, similar to that occurring in patients with pheochromocytomas or chronic cocaine use.^85,177 Some postulate that polymorphisms in CYP2D6 activity influences the risk of developing cardiomyopathy; however, a clear association is not demonstrated.¹⁶⁴ Valvular heart disease and pulmonary hypertension are associated with amphetamines taken for diet suppression. The mechanism of toxicity is incompletely understood but is likely do to serotonergic activity occurs in carcinoid pathology. Specifically, alterations in serotonin reuptake transporter (SERT) activity is thought to play a significant role in the pathophysiology of both diseases, and drug effect at the 5HT_2B receptor is implicated in the development of valvular heart disease.^103,144

Vascular

Necrotizing vasculitis of small- and medium-sized arteries occurs in association with amphetamine use and affects multiple organ systems as described later. 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 IV amphetamine administration is also associated with vasculitis, suggesting that this is a direct amphetamine effect.^18,32,165

Chronic Central Nervous System Toxicity

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.^{16,56,139,140,145,180} The cause of neuronal toxicity is 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 affect toxicity. Intact dopamine or serotonin transporters are necessary to produce neurologic injury. Xenobiotics that inhibit transporter function appear to prevent neurologic injuries in animals.⁶⁴ Although not as well studied as MDMA, studies of former methamphetamine users demonstrate impaired memory and psychomotor functions, as well as corresponding dopamine transporter dysfunction and abnormal glucose metabolism on positron emission tomography scans. However, species-specific susceptibility to neurologic injuries, the duration of effects in primates and humans, and functional consequences of neurotoxicity in humans remain unclear and require further study.

CLINICAL MANIFESTATIONS

Acute and chronic toxicity of amphetamines are described next. Refer to the section Individual Amphetamines for effects specific to each individual molecule.

Acute Toxicity

Central nervous system effects from acute amphetamine use include anxiety, agitation, hallucinations, seizures, mydriasis, diaphoresis, and hyperthermia.^47,48,143 The pathophysiology of amphetamine-induced hyperthermia is multifactorial and includes increased catecholamine release, increased metabolic and psychomotor activity, and vasoconstriction-mediated impaired heat dissipation.¹⁰⁶ Psychosis appears to be a more prominent feature after amphetamine than after cocaine use.² Intracerebral hemorrhage and cerebral infarction are also reported with amphetamine use.^{49,84,110,129}

Cardiovascular toxicity from acute amphetamine use involves hypertension, tachycardia, and dysrhythmias. Reported dysrhythmias range from premature ventricular complexes to ventricular tachycardia and ventricular fibrillation.⁷⁸ Other vascular complications reported with acute use include myocardial ischemia or infarction,^113,173 aortic dissection,¹⁷⁶ acute respiratory distress syndrome,^166,175 obstetric complications, fetal death,^63,99 and ischemic colitis.^77,82 Additional acute complications include metabolic acidosis, rhabdomyolysis,⁵⁰ acute kidney injury (AKI); acute tubular necrosis), and coagulopathy, often from uncontrolled agitation and hyperthermia.^39,70,170 Unless these systemic signs and symptoms are rapidly reversed, multiorgan failure and death ensue.

Chronic Toxicity

Amphetamine users seeking intense “highs” 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.¹⁵⁰ Acute psychosis resembling paranoid schizophrenia occurs during these binges and has contributed to both amphetamine-related suicides and homicides.⁵¹ A normal sensorium usually returns within a few days after discontinuation of the drug. Typically, after such binges, patients sleep for prolonged periods of time, feel hungry and depressed when awake, and often have amphetamine cravings.^89,93

Compulsive repetitive behavior patterns from the use of amphetamines are reported in humans and animals. Individuals pick at their skin, grind their teeth (bruxism), or perform repetitive tasks, such as constantly cleaning the house or car. 3,4-Methylenedioxymethamphetamine users often carry pacifiers to relieve bruxism and prevent tooth damage. Choreoathetoid movements, although uncommon, are reported with acute and chronic amphetamine use.^88,101,107

Necrotizing vasculitis is associated with amphetamine abuse. Angiography typically demonstrates beading and narrowing of the small- and medium-sized arteries (Fig. 8–29). Progressive necrotizing arteritis involves multiple organ systems, including the brain, heart, gut, and kidney.^18,32,92,165 Complications include cerebral infarction and hemorrhage, coronary artery disease, pancreatitis, and AKI. Cardiomyopathy is also reported with acute and chronic amphetamine abuse.^156,182 Valvular disease and pulmonary hypertension are reported when amphetamines such as fenfluramine, dexfenfluramine, and phentermine are used for dieting.^144,163

Finally, complications can result from IV drug use and from the associated contaminants. Contamination with microbials leads to human immunodeficiency virus infection, hepatitis, and malaria. Bacterial and foreign body contamination results in endocarditis, tetanus, wound botulism, osteomyelitis, and pulmonary and soft tissue abscesses.¹⁰⁰

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 patients to screen for tachydysrhythmias and coingestants, and continuous cardiac monitoring should be initiated. A complete blood count, urinalysis, coagulation profile, creatine phosphokinase, chest radiograph, computed tomography scan of the head, echocardiogram of the heart, and lumbar puncture will 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. Although point-of-care urine tests are available, these tests rarely contribute to management in the acute setting. A major limitation is the high rate of false-positive and false-negative results common to the amphetamine immunoassay. For example, many cold preparations contain pseudoephedrine, which is structurally similar and cross-reacts with the immunoassay.^33,53 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 results include bupropion, trazodone, amantadine, and certain antihistamines.^21,119,123 Even a true-positive result only means that 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.^33,155 Utilization of such tests is often misleading and rarely directly contributes 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.¹⁰ 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 determination, 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^24,58 (Chap. 29). 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 result in rhabdomyolysis and continued heat generation. IV access should be obtained so that IV sedation can be initiated. If IV access cannot be obtained, it is necessary to attempt to administer intramuscular benzodiazepines such as midazolam until definitive access is accomplished.

The most appropriate choice of chemical sedation is a benzodiazepine because of the characteristic high therapeutic index, good antiepileptic activity, and predictable pharmacokinetic properties. 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: A26).^44,61,122 Sedation should be titrated rapidly until the patient is calm. In our clinical experience, cumulative benzodiazepine doses required in the initial 30 minutes to achieve adequate sedation will periodically exceed 100 mg of diazepam or its equivalent (Table 73–4).

Antipsychotics, particularly potent dopamine antagonists such as haloperidol and droperidol, are frequently recommended as adjuncts for amphetamine-induced delirium. Potent blockade of dopamine receptors functions to antagonize the psychiatric and psychomotor effects of amphetamines. In experimental models, antipsychotics are not always as effective as benzodiazepines in treatment of amphetamine toxicity; however, results are mixed regarding their safety and efficacy.^40,45,61 Very little clinical data are available evaluating antipsychotics in the management of amphetamine toxicity, but at least one study in children demonstrates safety when antipsychotics are used adjunctively with benzodiazepines.^40,142 In our clinical experience, antipsychotics are very effective for benzodiazepine-resistant methamphetamine toxicity in children, particularly for symptoms of psychomotor agitation. However, antipsychotics have several negative effects that must be taken into consideration. Antipsychotics lower the seizure threshold, alter temperature regulation, cause acute dystonia, and precipitate cardiac dysrhythmias. Hyperthermia and seizures are potential life-threatening complications of amphetamine toxicity, and the use of antipsychotics could worsen these outcomes. Additionally, they do not interact with the benzodiazepine–GABA–chloride channel receptor complex, which could aggravate the clinical outcomes related to occult or concomitant cocaine toxicity and ethanol withdrawal.^61,65,122 Based on these concerns, benzodiazepines are recommended as first-line treatments in the management of acute toxicity from amphetamines. In a patient without hyperthermia or seizure activity, in whom psychomotor or psychiatric agitation is a predominant feature, adjunctive use of antipsychotics after benzodiazepine administration is reasonable, particularly in children.

Rhabdomyolysis from amphetamines usually results from psychomotor agitation and hyperthermia.¹⁴¹ Sedation, typically with benzodiazepines, prevents further muscle contraction and heat production. External cooling should be instituted for hyperthermia.⁹⁵ Although some promote dantrolene as potential treatment option for amphetamine-induced hyperthermia, evidence is limited to case reports, predominantly involving MDMA.⁶⁹ Strong evidence to support the use of dantrolene is limited to cases of malignant hyperthermia, and side effects, including significant respiratory muscle weakness, are reported.⁹⁰ Given the potential harms of dantrolene and limited supportive evidence, in contrast to known efficacy of supportive measures, we do not currently recommended its use for amphetamine-induced hyperthermia. Adequate IV 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,^13,14 urinary pH manipulation does not decrease toxicity and instead increases the risk of AKI from rhabdomyolysis by precipitating ferrihemate in the renal tubules.³⁷ Some patients with AKI, acidemia, and hyperkalemia 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.¹⁷² Intravenous fluids, benzodiazepines, intubation, and external cooling are often 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.¹³⁵ 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 that initially use pseudoephedrine, ephedrine, or phenyl-2-propanone (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.^46,132 Phenyl-2-propanone, as an alternative ingredient, can be methylated into ephedrine and then transformed into methamphetamine.²³ Because of the strict control of ephedrine and P2P, illicit chemists use phenylacetic acid to synthesize P2P.^23,38 Lead acetate, which is used as a substrate for the reaction, resulted in an epidemic of lead poisoning associated with methamphetamine abuse in Oregon.^3,120 Mercury contamination was also documented, although clinical mercury toxicity has not been reported.²³ Methamphetamine laboratories use many potentially toxic xenobiotics, including phosphine gas, methylamine gas, chloroform, and hydrochloric acid.^4,79 These laboratories therefore pose a significant health risk to law enforcement officers and the general public, causing respiratory and ophthalmic irritation, headaches, and burns.^29,154 Currently, the sale of other potential amphetamine synthetic ingredients, such as hydrochloric acid, hydrogen chloride, anhydrous ammonia, red phosphorus, and iodine, is also monitored and restricted in the United States.^23,30

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 solely responsible for the 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.⁴⁶

3,4-Methylenedioxymethamphetamine

3,4-Methylenedioxymethamphetamine, also known as MDMA, was first synthesized in 1912 and was rediscovered in 1965 by Shulgin. 3,4-Methylenedioxymethamphetamine is known as “ecstasy,” “E,” “Adam,” “XTC,” “Molly,” and “MDM,” and it is commonly abused.^128,174,178 Other amphetamines similar to MDMA include MDEA (“Eve”) and MDA (“love drug”). With similar clinical effects, these xenobiotics are also used or distributed as MDMA in areas of MDMA popularity. Amphetamines sold as MDMA include 2CB, 2,4-dimethoxy-4-(n)-propylthiophenylethylamine (2C-T7), and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB).^28,59 Typically, MDMA is available in 50- to 200-mg colorful and branded tablets.

3,4-Methylenedioxymethamphetamine and similar analogs are so-called entactogens (meaning “touching within”), capable of producing euphoria, inner peace, and a desire to socialize.¹⁵¹ 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.¹²⁷ People who use MDMA report that it enhances pleasure, heightens sexuality, and expands consciousness without the loss of control.⁶⁶ Negative effects reported with acute use included ataxia, restlessness, confusion, poor concentration, and impaired memory.¹⁵¹ 3,4-Methylenedioxymethamphetamine has about one-tenth the CNS stimulant effect of amphetamine. Unlike amphetamine and methamphetamine, MDMA is a potent stimulus for the release of serotonin.^25,41,68 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.²⁵

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. Dysrhythmias, hyperthermia, rhabdomyolysis, disseminated intravascular coagulation (DIC), and deaths are reported.^57,87,137 Significant hyponatremia is also reported with MDMA use.^1,22,73 3,4-Methylenedioxymethamphetamine and its metabolites increase the release of vasopressin (antidiuretic hormone), and this is thought to be related to the serotonergic effects.⁵² Furthermore, substantial free water intake combined with sodium loss from physical exertion in dance clubs increases the risk of the development of hyponatremia.

Molly is a purified or crystallized form of MDMA that is typically sold as a powder rather than a pill and is taken orally. It gained popularity because of 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 because it is erroneously believed by users to contain no adulterants. The use of Molly is associated with typical amphetamine adverse effects.⁸³ Although Molly is often sold on the street as pure MDMA, Molly may contain various compounds including members of the 2C series, amphetamines that have two methoxy groups and a halogen such as iodine (2C-I) or bromide (2C-B).

A major concern with MDMA is its long-term effects on the brain. In numerous animal models, acute administration of MDMA leads to the decrease in SERT function and number. Recovery of SERT function takes 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.^109,139 Some regeneration of synaptic terminals occurs 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.¹⁴⁷ 3,4-Methylenedioxymethamphetamine itself is not the ultimate neurotoxin; rather, its metabolites 3-methyldopamine and N-methyl-α-methyldopamine appear to be responsible in animals.¹¹⁴ When antioxidants are depleted, neuronal damage occurs.

Para-methoxyamphetamine and Para-methoxymethamphetamine-Monomethoxy Derivatives

Para-methoxyamphetamine (PMA) is the 4-methoxylated analog of amphetamine, and para-methoxy-N-methylamphetamine (PMMA; methyl-MA) is the 4-methoxy analog of methamphetamine. Para-methoxyamphetamine was first produced in 1973 and sold as a hallucinogen for a short period of time and then reemerged in the 1990s. Para-methoxy-N-methylamphetamine soon appeared after PMA, with multiple reports of death also emerging during that time.^12,81,91 Para-methoxyamphetamine and PMMA are commonly found as tablets or capsules sold as MDMA or “ecstasy.” Although the effects of PMA and PMMA mimic some aspects of MDMA and methamphetamine, unique properties of PMA and PMMA make them considerably more lethal, earning the street name “death.” More than 100 fatalities and severe poisonings attributed to PMMA and PMA are reported in North America, Australia, and Europe.^{94,98,102,105}

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.^35,158 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.^8,54

Para-methoxyamphetamine and PMMA poisoning results in autonomic hyperactivity similar to that observed with other amphetamines, namely, hypertension, tachycardia, and agitation. Poor blood–brain barrier penetration results in a delayed onset of CNS effects and overall a comparatively weak euphoric effect. These properties often lead users to repeat doses, resulting in severe toxicity and the seemingly high mortality rate.

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

Cathinone (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 the Middle East. The plant form contains numerous amphetamines in minute quantities, but 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, or much of its potency is lost. The primary effects of khat are increased alertness, insomnia, euphoria, anxiety, and hyperactivity. Khat chewing is linked to cardiac and gastrointestinal (GI) disease.^124,125

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 was used recreationally, historically most often in countries formerly part of the Soviet Union. Various synthetic cathinones, including mephedrone and methylenedioxypyrovalerone (MDPV), have gained popularity in both the United States and Europe in recent years.⁷ Increased popularity of synthetic cathinones is likely be due to a combination of media attention and widespread Internet availability.^133,149 Many other synthetic cathinones produced include methylone, mephedrone, butylone, MDPV, dimethylcathinone, ethcathinone, ethylone, 3-,4-fluoromethcathinone, and α-pyrrolidinovalerophenone. α-Pyrrolidinovalerophenone (1-phenyl-2-(pyrrolidin-1)-ylpentan-1-one), sold on the street as “flakka,” in particular is a popular drug of abuse.¹⁶⁸ Bupropion, a popular pharmaceutical licensed for treatment of depression and smoking cessation, is the only medicinally used cathinone.¹¹¹ Sustained-release bupropion overdoses are associated with delayed toxicity. Serious toxicity in overdose, including seizures and refractory dysrhythmias requiring extracorporeal membrane oxygenation as well as fatalities, are reported.^75,157

The synthetic cathinones differ structurally from other amphetamines by the addition of a ketone at the β position. The β-ketone group is responsible for increased polarity, which decreases penetration of the blood–brain barrier. Cathinones possess amphetamine-like properties and have sympathomimetic effects, although as a group, they are considered less potent. Both the US Poison Control Centers and the Toxicology Investigator’s Consortium Registry (ToxIC) data report common adverse effects to include agitation, tachycardia, hallucinations, and a general sympathomimetic toxidrome.^55,155 Some synthetic cathinones cause hyponatremia, although the mechanism is not clear and may differ from that of MDMA.^{11,26,27,104,130} Reported complications include compartment syndrome, DIC, AKI, cardiomyopathy, myocardial infarction, seizures, and sudden cardiac death.^{55,96,116,138,148,183} An irreversible Parkinson syndrome was also described in chronic users of IV methcathinone that was manufactured with the use of potassium permanganate as an oxidizing agent. In one case series, T1-weighted magnetic resonance imaging showed symmetric hyperintensity in the globus pallidus, substantia nigra, and innominata in all active methcathinone users, characteristic of manganese poisoning. These cases were also confirmed with elevated whole-blood manganese concentrations.¹⁵⁹

Synthetic cathinones are often sold as “bath salts” or “plant food” and labeled as “not for human consumption” 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 were made illegal for human consumption under the Federal Analogue Act of 1986. In 2011, the Drug Enforcement Administration used its emergency scheduling authority to enact temporary control, making possession or sale of methylenedioxypyrovalerone, methylone, and mephedrone illegal. This was later written into permanent law. In 2014, an additional 10 synthetic cathinones were given temporary Schedule I status.

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. Bromo-dragonFLY was named after its superficial structural resemblance to a dragonfly, similar to its less potent predecessor, the dihydrofuran series nicknamed FLY. Bromo-dragonFLY is a member of a new class of benzodifurans, which were used as potent tools for investigation of the serotonin receptor family. Benzodifurans were also briefly investigated as potential antidepressants.¹⁷⁹

Structurally, BDF is closely related to other phenylethylamines such as DOB and 2C-B but contains two furan rings on either side of the benzene ring, creating a fully aromatic tricyclic structure. There are several similar compounds to BDF, differing by substitution of the bromine atom with other entities. Bromo-dragonFLY exists as R- and S-enantiomers, which are both biologically active. The R-enantiomer is considered more potent, with a significant hallucinogenic effect mediated primarily through the 5-HT_2A serotonin receptor (also with affinity for the 5-HT_2B and 5-HT_2C serotonin receptors).¹²⁶

Bromo-dragonFLY use is associated with deaths in Europe and the United States. Reports demonstrate delayed complications owing to severe peripheral vasoconstriction and limb ischemia. Such complications likely result from BDF’s potent serotonergic properties.^{5,34,41,167,179}

2,5-Dimethoxy-4-Methylamphetamine and 2,5-Dimethoxy-4-Iodoamphetamine

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, which resulted in a 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 substitution of hydrophobic moieties at the 4 position. 2,5-Dimethoxy-4-methylamphetamine and DOI are both serotonin receptor agonists with selectivity at the 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor subtypes. Because of this selectivity, DOM and DOI are often used in scientific research involving study of the 5-HT₂ receptor subfamily. 2,5-Dimethoxy-4-methylamphetamine exists as a chiral molecule, with the R-(-)-enantiomer considered the more potent.¹⁵

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. Reversible vasospasm with the use of dimethoxy amphetamine derivatives is reported.^9,20

The 2C-Series and N-2-methoxybenzylphenylethylamines

The 2C-series and its derivatives are similar in structure and function DOM and DOI as all are dimethoxy phenylethylamine derivatives with potent hallucinogenic properties. The 2C series differs in that they lack an α-carbon methyl group and are thus not true amphetamines in structure.

The first of this series 2C-B was initially intended for psychotherapy, however, it fell out of favor because of GI side effects and limited entactogenic effects. Multiple other 2C compounds have been developed by altering substitutions at positions 2,4 and 5 on the phenyl ring. The compound 2C-I is an iodo-substituted dimethoxy phenylethylamine popularized in recent years as “smiles.” Reported clinical effects of this series include sympathomimetic effects, delirium, hallucinations, and psychosis.⁴²

2-(4-Iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (2C-I-NBOMe, N-Bomb) was discovered in 2003, along with other similar NBOMe compounds. It possesses strong 5-HT_2A agonism and was initially used as a pharmacologic tool to study 5-HT_2A receptors. 2C-I-NBOMe is synthesized by N-benzyl substitution of 2C-I and is currently used recreationally as an LSD alternative. The high potency of NBOMe compounds compared with 2C-I allow efficacy in microgram doses, with subsequent potential for accidental overdose. NBOMes are used by all routes, but poor oral bioavailability limits oral use.^71,118 Reported clinical effects include euphoria, hallucinations, and sympathomimetic effects. Deaths are reported.^118,169

SUMMARY

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

• The extensive knowledge of 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 patients with acute toxicity of any of the amphetamines includes supportive care, with the judicious use of benzodiazepines and anticipation of complications of adrenergic and serotonergic 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 4,000 years. The earliest documentation of the therapeutic use of marijuana is the fourth century B.C. in China.¹⁷² Cannabis use spread from China to India to North Africa, reaching Europe around A.D. 500.¹³⁸ In colonial North America, cannabis was cultivated as a source of fiber. Similar to 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.⁹⁷ This was because the active compounds of opium poppy and coca leaf 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 (SC) 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 1967.⁹⁸

Cannabis was used in the United States as a substance of abuse from the 1850s until the 1930s when the US Federal Bureau of Narcotics began to portray marijuana as a powerful, addictive substance. Despite this, marijuana was listed in the US Pharmacopoeia from 1850 to 1942. In 1970, the Controlled Substances Act classified marijuana as a Schedule I drug.

In all populations, cannabis use by men exceeds use by women. Currently, marijuana is the most commonly used illicit xenobiotic in the United States; however, it is legal for recreational use in an increasing number of states, including at the time of this writing Colorado, Washington, California, Oregon, and Alaska. In 2015 in the United States, 8.2% (22 million persons) 12 years of age or older used marijuana in the month before the survey; this prevalence is increased from 6% in previous years. The prevalence of past-month users aged 12 to 17 years was 7% (increased from 6.8% in 2006). The number of first-time users was estimated to be 2.1 million, with 63.3% younger than 18 years of age.¹²⁸

Interest in SCs as potential therapeutics increased after the progress of the late 1960s, and several SCs 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 affinities 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.⁶⁷ Despite its efforts, no medications came to market; new analgesics retained unwanted psychoactive side effects. During this period, an extensive understanding of structure activity relationships for cannabinoids developed.⁶⁶

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.³⁴ Many of these did not retain structural similarity to THC but remained potent and efficacious agonists at CB₁ and CB₂.⁶⁶ In the 1990s, the endogenous cannabinoids were discovered and were subsequently synthesized.⁸⁴ These free fatty acids are quickly hydrolyzed in vivo, a fact that previously limited potential for pharmaceutical development. Researchers have since synthesized stable versions of endocannabinoids (Fig. 74–1).

In 2004, SC-laced herbal incense blends became available over the Internet and through smoke shops in Western Europe.⁸⁸ 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, manufacturers substituted a different SC—JWH-073. Since that time, many Western European countries have legislated further control of SCs.

The incidence of SC exposure in the United States increased, and in November 2010, the Drug Enforcement Administration (DEA) began the process of listing selected SCs as Schedule I drugs on a temporary basis. By March 2011, the DEA listed several nonclassical SCs as Schedule I, but as was the case in Germany, manufacturers of herbal incense blends in the United States switched to other unscheduled SCs. Second- and third-generation SCs, such as AM-2201, XLR-11, and the indazole derivatives, have since emerged and further complicate the clinical, regulatory, and public health efforts.

Toxicologists face a new era in the field of cannabinoids: Research continues to advance understanding of the cannabinoid system, a myriad of new and discrete SCs emerge ever year, and even the familiar marijuana is found with higher potency and changing phytocannabinoid ratios that may affect patients in unanticipated ways.

MEDICAL USES

Cannabis has been used medicinally for thousands of years to treat a seemingly endless array of conditions. However, modern medicine is supported by an evidence-based system rather than the belief-based medicine of the past. Therefore, potential medicinals must be proven through rigorous investigation to be not only safe but effective in the treatment of a targeted malady. Although smoked marijuana and THC preparations have not typically proven acutely dangerous, efficacy is questionable. 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. Although the latter is the chief psychoactive constituent of marijuana, the multiple additional cannabinoids present in marijuana are biologically active and must be considered. Second, 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 cannabis and the available evidence supporting that use are reviewed next.

Pain

Acute Pain

Studies examining the efficacy of cannabis 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.³⁰ Smoked marijuana failed to attenuate thermal pain in volunteers, and an oral THC analog had no effect on postsurgical pain.⁷³

Chronic Pain

When used for the treatment of chronic and neuropathic pain, cannabinoids have had some favorable outcomes, although design flaws severely limit the quality of medical evidence.¹¹⁸ Initial trials of combined cannabinoid and opioid therapy are encouraging, and the principle may have mechanistic merit based on the knowledge that opioid and cannabinoid receptors can form heterodimers,¹³¹ but lack of proper controls and the presence of confounders limit the clinical applicability of cannabinoids as analgesics at this time.

Nausea and Vomiting

Trials of cannabinoids for treatment of chemotherapy-induced nausea and vomiting demonstrate superiority over placebo but compared with serotonin and dopamine antagonists, this difference is not statistically significant.^{17,38,90,100,169} Dronabinol is currently FDA approved for this indication.

Glaucoma

Trials investigating the efficacy of cannabinoids for the treatment of glaucoma demonstrate the inferiority to longer acting traditional therapeutics, which have more significant effects on intraocular pressure (IOP) and longer durations of effect. One small trial found no difference between the effect of cannabinoids and placebo on IOP.¹⁶²

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, smoking marijuana provides a crude and unpredictable delivery mechanism, and safer, more precise methods of administration are needed.¹⁶⁷

Similarly, a meta-analysis in 2015 composed of randomized clinical trials (RCTs) showed only moderate evidence to support the efficacy of cannabinoids in treating chronic pain and spasticity related to multiple sclerosis.¹⁶⁹ A Cochrane review of 23 RCTs found that pharmaceutical cannabinoids for use in the management of many clinical conditions but are only currently FDA approved 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 patients with human immunodeficiency virus (HIV) patients with anorexia-cachexia syndrome.⁵⁹ The claims of benefit in the other medical conditions are not clearly supported by evidence.^6,170

PHARMACOLOGY AND PATHOPHYSIOLOGY

The term cannabinoid refers to compounds that bind to the cannabinoid receptors regardless of whether they are derived from plants (phytocannabinoids), synthetic processes (SCs), or endogenous sources (endocannabinoids). At one time, the term may have been used to delineate a structural similarity to Δ⁹-THC, but this naming convention was largely abandoned during the past 30 years of cannabinoid research as new compounds were discovered and synthesized. The structural diversity of cannabinoid receptor 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 binding and subclassify cannabinoids further based on origin and structure (Fig. 74–1). The terms cannabinoid, cannabinometic, and cannabinoid receptor agonist are interchangeable.

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. The major cannabinoids are cannabinol, cannabidiol (CBD), and tetrahydrocannabinol. The principal psychoactive cannabinoid is THC, also known as 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-potency marijuana up to 50% in hash oil. Δ⁹-Tetrahydrocannabinol extracted from marijuana using butane (butane hash oil or BHO) approaches THC concentrations of 100%. Pure THC and several pharmaceutical SCs are available by prescription with the generic names of dronabinol and nabilone, respectively. Nabiximol 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 SCs originally designed as research chemicals have emerged as designer drugs of abuse over the past several years.

Cannabinoid receptors are G protein–linked neuromodulators that inhibit adenyl cyclase in a dose-dependent and stereospecific manner. Although historically the cannabinoid receptor system is described as having a central CB₁ and a peripheral CB₂ receptor, the available evidence points to the central nervous system (CNS) presence of CB₂ receptors.¹⁴⁷ 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. 74–2).

CB₁ Receptors and the Psychogenic Effects of Cannabis

The CB₁ receptors are structurally composed of seven transmembrane protein units coupled to pertussis-sensitive (decrease adenyl cyclase) G proteins. They exhibit genetic variation via splice variants and are found as heterodimers with a multitude of other receptor types.⁶⁷

Isolated agonism of CB₂ receptors was the target for novel pharmaceutical candidates as antiinflammatory agents with minimal success as the psychoactive effects of CB₁ agonism persisted.

The CB₁ receptors are the most numerous G protein–coupled receptors in the mammalian brain, accounting for the multiple and varied effects of cannabinoids on behavior, learning, and mood as well as suggesting the enormous complexity of the endocannabinoid system.⁵⁸ The highest concentration of CB₁ receptors is located in areas of the brain associated with movement and higher functions of cognition and emotions. A relative lack of CB₁ receptors in the brainstem also explains lack of coma and respiratory depression that occurs with Cannabis use.

Mechanism of Cellular Signaling

Cannabinoid receptors both in the CNS and in the periphery exist on the presynaptic terminus of various neurons. Depolarization in the postsynaptic portion of the neuron and subsequent increase in intracellular Ca²⁺ leads to on-demand synthesis and release of endocannabioids.¹¹⁷ 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 adenyl cyclase, resulting in decreased intracellular cyclic adenosine monophosphate (cAMP) concentrations, decreased activity of voltage-gated Ca²⁺ channels, and ultimately decreased neurotransmitter release (Fig. 74–2). Exogenous cannabinoids act similarly to endogenous cannabinoids upon receptor binding, except that binding affinity will vary among exogenous ligands and endogenous cannabinoids, which are rapidly metabolized by fatty acid amide hydrolases.⁸⁴ Interestingly, some online chemical suppliers offer fatty acid amide hydrolase inhibitors for sale, along with various SCs, perhaps providing a glimpse into future products more closely related to endocannabinoids coming to market.

Both receptors inhibit adenyl cyclase and stimulate K⁺ channel conductance.¹²¹ 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.^71,77,140

The neuropharmacologic mechanisms by which cannabinoids produce their psychoactive effects are not fully elucidated.^60,71,121 Nevertheless, activity at the CB₁ receptors is believed to be responsible for the clinical effects of cannabinoids,^12,40,71,153 including the regulation of cognition, memory, motor activities, nociception, 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 was extensively reviewed.⁵⁰ 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 typically reaching peak serum concentration before finishing the cigarette. From 10% to 35% of available THC is absorbed during smoking, and peak serum. 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.⁶³

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 after ingestion. Peak serum THC concentrations usually occur 2 to 4 hours after ingestion, but delays up to 6 hours are described.⁸⁶ Dronabinol has an oral bioavailability of approximately 10% with high interindividual variability.^47,111 Nabilone has an oral bioavailability estimated to be greater than 90% and reaches peak serum concentrations 2 hours after ingestion.¹³⁷

Distribution

Δ⁹-Tetrahydrocannabinol 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. After smoking or intravenous (IV) administration, the distribution half-life is less than 10 minutes.⁶⁴ 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. After administration of Δ⁸-THC stopped, the cannabinoids are slowly released from fat stores during adipose tissue turnover.¹¹⁶

Δ⁹-Tetrahydrocannabinol crosses the placenta and enters the breast milk. Concentrations in fetal serum are 10% to 30% of maternal concentrations. Daily cannabis 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.¹²³

Metabolism

Δ⁹-Tetrahydrocannabinol is nearly completely metabolized by hepatic microsomal hydroxylation and oxidation (primarily CYP2C9 and CYP3A4).⁵⁰ 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.^1,4,127

In six volunteers, peak serum THC concentrations occurred at 8 minutes (range, 6–10 minutes) after the 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. 74–3).⁶³ 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.⁶³ Ingestion of cannabis results in much more variable concentrations and time courses of THC and metabolites (Fig. 74–3). Nonetheless, at 2 to 3 hours after ingestion, 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 1:14.¹⁶⁵ Δ⁹-Tetrahydrocannabinol is detectable in serum 1.5 to 4.5 hours after ingestion of dronabinol.⁴⁶

Of the many aminoalkylindole (AAI) SCs isolated in “Spice” incense blends, human metabolic analyses are only 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.^27,28 These metabolites undergo glucuronic acid conjugation in phase II metabolism.

Excretion

Reported elimination half-lives of THC and its major metabolites vary considerably. After IV doses of THC, the mean elimination half-life ranges from 1.6 to 57 hours.⁵⁰ Elimination half-lives are expected to be similar after inhalation.^50,63 The elimination half-life of 11-OH-THC is 12 to 36 hours, and that of THC-COOH ranges from 1 to 6 days.^79,165

Δ⁹-Tetrahydrocannabinol and its metabolites are excreted in the urine and the feces. In the 72 hours after ingestion, approximately 15% of a THC dose is excreted in the urine, and roughly 50% is excreted in the feces.^1,21,168 After IV administration, approximately 15% of a THC dose is excreted in the urine, and only 25% to 35% is excreted in the feces.¹⁶⁵ Inhalation is expected to produce results similar to IV administration.^50,63 Within 5 days, 80% to 90% of a THC dose is excreted from the body.^55,68

Cannabinoids were measured in the urine after smoking a marijuana cigarette containing 27 mg of THC (Fig. 74–3).⁹⁴ After smoking THC, urine concentrations peaked at 2 hours (mean, 21.5 ng/mL; range, 3.2–53.3 ng/mL) and were undetectable (<1.5 ng/mL) in five of the eight participants by 6 hours. Urine concentrations of 11-OH-THC peaked at 3 hours (77.3 ± 29.7 ng/mL). The primary urinary metabolite is the glucuronide conjugate of THC-COOH.¹⁷⁰ The urine concentration of THC-COOH peaks at 4 hours (179.4 ± 146.9 ng/mL),⁹⁵ and it has an average urinary excretion half-life of 2 to 3 days (range, 0.9–9.8 days).⁵⁰ Both 11-OH-THC and THC-COOH remained detectable in the urine of all eight participants for the 8 hours of the study.⁹⁴

After discontinuation of use, metabolites are often detected in the urine of chronic users for several weeks.^39,74 Factors such as age, weight, and frequency of use only partially explained the long excretion period.³⁹ Primary urinary metabolites of nonclassical SCs are summarized in Fig. 74–4.

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 THC is used. The concomitant use of CNS depressants such as ethanol or stimulants such as cocaine alters the psychological and physiological effects of marijuana. The therapeutic serum THC concentration for the treatment of nausea and vomiting is greater than 10 ng/mL.²³

Psychological Effects

Use of marijuana produces variable psychological effects.⁴⁰ The variation, which occurs both between and within users, is likely the result of drug tolerance, phase of clinical effects, strain of cannabis, physical and social settings, or user expectations or cognitive capacity. 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.⁴⁹

Physiological 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,⁹⁵ 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.⁹⁶ Similar blood flow changes result from smoking marijuana.¹²⁰

Common acute cardiovascular effects of cannabis use include increases in heart rate and decreases in vascular resistance.^75,148 Cannabis produces dose-dependent increases in heart rate within 15 minutes of using 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 occur with cannabis use. In a study of six participants, 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.¹²⁹ In contrast, in one study, 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 causes 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 individuals and individuals with asthma.¹⁵⁶ 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.^157,158,161 The mechanism for this effect is unclear.

The principal ocular effects of cannabis are conjunctival injection and a transient decrease in IOP. Cannabinoids, applied topically to a rabbit eye, resulted in hyperemia of the conjunctival blood vessels for 2 hours after application.¹⁰³ Regardless of route of administration, cannabis causes a fall in IOP in 60% of users⁴⁸ by acting on CB₁ receptors in the ciliary body.¹²⁶ The mean reduction in IOP is 25% and lasts 3 to 4 hours.

Physiological effects of novel SCs are not yet studied in any controlled settings.

ACUTE TOXICITY

In addition to the physiological and psychological effects described, acute toxicity includes 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 occur.^115,168

In young children, the acute ingestion of cannabis is potentially consequential.⁹³ Ingestion of estimated amounts of 250 to 1,000 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 SCs stands in stark contrast to the relatively mild effects of smoked or ingested phytocannabinoid products. Given the general similarity in receptor binding, both users and clinicians initially expected the effects to be largely identical to marijuana and hashish. The significant differences are 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 xenobiotics, such as cathinones, methylxanthines, and long-acting β-adrenergic agonists such as clenbuterol must be considered.

The recent published reports of presumed SC toxicity are challenging to interpret because many lack laboratory confirmation of exposure. In addition, in cases involving “spice” blends, adverse effects may result from the plant matter or adulterants. Finally, the concentration of SCs varies by incense package, even of the same brand and lot, making dose estimation difficult if not impossible.

Agitation¹⁴² and seizures are reported.^85,141 In one report with laboratory confirmation, a patient experienced multiple seizures within 30 minutes after ingesting JWH-018 in powder form.⁸⁵ The sample was confirmed as pure JWH-018.

Psychosis (new onset, acute exacerbation of existing psychiatric disorders, and increased risk of psychosis relapse) and anxiety have resulted after a single dose.^57,69,124

Tachycardia was a common finding detailed in one series, and tachydysrhythmias requiring cardioversion are reported.⁸⁵ Chest pain and increased troponin concentrations were observed in three patients who claimed to have smoked spice several days before presenting to the hospital, but laboratory confirmation of SC exposure was not performed.¹⁰⁴

Diffuse pulmonary infiltrates and dyspnea requiring intubation and mechanical ventilation were reported in a habitual spice user. Laboratory confirmation revealed three parent SCs (AM-2201, JWH-122, and JWH-210).²

Accounts of acute kidney injury are described in a case series of 16 previously healthy participants. All patients reported smoking spice incense blends before 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 SC was isolated (XLR-11). Several of the patients required hemodialysis, but all eventually recovered.¹

Cerebral ischemia was reported in a patient using a product confirmed to contain XLR-11. The patient presented after smoking SC with right-sided weakness and later had CT of the brain confirming a left insular stroke. Forensic testing of the product revealed XLR-11, but neither the parent or metabolites could not be identified in the patient’s urine, suggesting rapid metabolism.¹⁵⁵

The fourth-generation indazole derivative SCs were likely responsible for several recent outbreaks of somnolence and bradycardia in suspected users. This stands in contrast to earlier generations of SCs users who presented with sympathomimetic-like symptoms. Patients using nonclassical SCs respond to supportive care.¹⁰⁶

ADVERSE REACTIONS

Acute Use

Cannabis users occasionally experience distrust, dysphoria, fear, panic reactions, or transient psychoses. Commonly reported adverse reactions at the prescribed dose of dronabinol or nabilone include postural hypotension, dizziness, sedation, xerostomia, abdominal discomfort, nausea, and vomiting. Acute pancreatitis (serum amylase concentration up to 3,200 IU/mL) after a period of heavy cannabis use is reported, but the causal relationship is unclear.⁴⁷

Life-threatening ventricular tachycardia is reported.¹³² 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 Although 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.¹⁰⁵ Atrial fibrillation with palpitations, nausea, and dizziness was temporally associated with smoking marijuana in four patients.^41,83,151

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 was not documented.⁸¹

Respiratory System

Chronic use of smoked marijuana is associated with clinical findings compatible with obstructive lung disease.¹⁶¹ Smoking marijuana delivers more particulates to the lower respiratory tract than does smoking tobacco,¹⁷¹ 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.^22,156,159 By contrast a systematic review and a cohort study with 8 years of follow-up demonstrated no association between marijuana smoking and smoking-related cancers,^53,99 and a population-based case-control study found that marijuana use was not associated with an increased risk of developing oral squamous cell carcinoma.¹³⁶

Cardiovascular System

Marijuana use is 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.^105,111

Reproductive System

Reduced fertility in chronic users is a result of oligospermia, abnormal menstruation, and decreased ovulation.¹⁸ Cannabis is probably the most common illicit drug of abuse during the reproductive age. No definitive patterns of malformations are recognized.¹⁶ 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.¹⁶³ The results of three other studies are difficult to interpret because marijuana use in pregnancy was poorly documented.^54,173 Epidemiologic studies based on self-reporting of cannabis use do not support an association between the use of cannabis during pregnancy and teratogenesis.^82,89,173

The effect of maternal use of cannabis during pregnancy on neurobehavioral development in the offspring was studied. No detrimental effects were reported in children born to women who smoked marijuana daily (more than 21 cigarettes per week) in rural Jamaica.³⁶ Tremors and increased startling were reported in infants younger than 1 week of age whose mothers used cannabis during pregnancy.⁴³ 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 more than five marijuana 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.^42,44,55 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,³³ including the continued parental use of cannabis during the postnatal and early childhood periods. The role of secondhand exposure to cannabis on postnatal and early childhood development of neurobehavioral problems remains unstudied.

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.¹⁸ In human studies, the results are inconsistent, long term effects are not demonstrated, and clinical consequences are undefined.¹⁸

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 were administered to 27 adolescents:10 cannabis abusers, 8 infrequent cannabis abusers, and 9 who used no psychoactive substances 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.¹⁴⁵ In a study of three experienced marijuana smokers, arithmetic and recall tasks were impaired for up to 24 hours after smoking.⁵⁶ 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).¹²⁵ 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 cannabis⁷² or that cannabis use causes psychosocial harm to the user.⁹² Patients using cannabinoids at younger ages, those using potent cannabinoids such as SCs, and those who have underlying psychiatric disorders are more likely to exhibit psychotic features after cannabinoid exposure.^9,130 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.^26,144 The association of the syndrome with cannabis use is based primarily on anecdotal, uncontrolled observations.⁶⁰ 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.⁶⁰ 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.¹¹³ 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.²⁶

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, or educational functioning; or legal problems related to marijuana use. The amount, frequency, and duration of cannabis use required to develop dependence are not well established.^25,154 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.^87,152 In humans, chronic users experience unpleasant effects when abstaining from cannabis.¹⁹ The time of onset of withdrawal symptoms is not well characterized.¹⁸ The most reliably reported effects are irritability, restlessness, and nervousness as well as appetite and sleep disturbances.¹⁵² Other reported acute withdrawal manifestations include tremor, diaphoresis, fever, and nausea. These symptoms and signs are reversed by the oral administration of THC.^9,51 The duration of withdrawal manifestations, without treatment, is not clearly established.^20,152 There are reports of a withdrawal syndrome observed after heavy and prolonged nonclassical SC use.^{32, 91,114,139}

Cannabinoid Hyperemesis Syndrome

Chronic, heavy marijuana use is associated with a clinical syndrome (CHS) composed of abdominal discomfort, nausea, and hyperemesis. Symptoms are often refractory to opioids and antiemetics.¹⁶⁶ Patients typically have multiple visits to the emergency department and are subjected to a host of diagnostic and therapeutic modalities ranging from CT scans and endoscopy to cholecystectomy. 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. In animal models, excessive cannabinoid administration results in downregulation of CB₁ receptors. Endogenous cannabinoids, such as anandamide, demonstrate increased binding affinity for other G protein receptors such as transient receptor potential cation channel subfamily V member 1 (TPRV1).

Relief with hot water may indicate dysfunction of pain perception, excess substance P release, and involvement of TRPV1 which these factors may assist in elucidating the mechanism for this syndrome as well as providing new treatment modalities.¹³³ This hypothesis is supported by reports of successful treatment of CHS treatment with topical capsaicin. Ultimately, resolution of this syndrome depends on cessation of marijuana use.^{3,24,35,45,149,150,166}

Reports also exist of successful CHS treatment with, benzodiazepines, dopamine antagonists, and substance P inhibitors. Opioids are not shown to be effective and are not indicated. Upon discharge, patients should be educated that the syndrome will likely return if the individual continues to use exogenous cannabinoids, and full resolution of symptoms should take place in 10 to 14 days.

CANNABIS AND DRIVING

The perceptual alterations caused by cannabis suggest that its recent use could be associated with automobile crashes. Experimental and epidemiologic studies have provided limited evidence with regard to the effects of cannabis use on driving ability. The published analytical studies of the relationship between cannabis and driving behavior and motor vehicle crashes were reviewed elsewhere.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.^7,119 Regardless, cannabis use decreases reaction times and results in significant driving impairment.⁵² One study comparing past driving records of subjects entering a drug treatment center with control participants 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 {CI}, 1.17–1.89) and for “at fault” crashes (relative risk, 1.68; 95%CI, 1.21–2.34).²⁹

DIAGNOSTIC TESTING

Cannabinoids can be detected in plasma or urine. Immunoassays are routinely available; gas chromatography–mass spectrometry (GC-MS) is the most specific assay and is considered the reference method.

Enzyme-multiplied immunoassay technique (EMIT) is a qualitative urine test that is often used for screening purposes. Enzyme-multiplied immunoassay technique identifies the metabolites of THC. In these tests, the concentrations of all metabolites present are additive. For the EMIT II Cannabinoid Assay, the cutoff concentration for distinguishing positive from negative samples is 20 ng/mL. A positive test result means that the total concentration of all the assayed metabolites present in the urine is at least 20 ng/mL. A positive urine test result for cannabis only indicates the presence of cannabinoids, and it does not identify which metabolites are present or at what concentrations. Qualitative urine test results do not indicate or measure toxicity 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 are typically detected in the urine up to 7 days after the use of single marijuana cigarette.^64,65

The length of time between stopping cannabis use and a negative EMIT urine test result (<20 ng/mL) depends on the extent of use. Release of THC from adipose tissue is important in drug test interpretation because many chronic users release cannabinoids in quantities sufficient to result in positive urine test results for several weeks. In addition, vigorous exercise stimulates 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 result 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).³⁹ 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 less than 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).³⁹

Standard laboratory analyses identify THC and its metabolites but cannot identify the source of the THC (eg, marijuana, hashish, dronabinol). Immunoassays for THC will not identify nabilone because it is not THC; however, nabilone can be specifically identified using high-performance liquid chromatography–tandem mass spectrometry.¹⁴⁶

Immunoassays give false-negative and false-positive test results (Table 74–1). 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^146,163 (Chap. 7).

Immunoassays for THC will not detect nonclassical SCs or their metabolites. Commercial urine immunoassays are available but need to be directed toward a specific nonclassical SCs. High-performance liquid chromatography–tandem mass spectrometry or gas chromatography mass spectrometry are currently the gold standard for laboratory confirmation for SCs, but their clinical utility is limited retrospective confirmation. Further challenges are presented by the multitude of known nonclassical SCs and the rate at which new illicit SCs are introduced to the illegal high market.^{49,70,76,78,107,108,135,160,164}

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 by others.^{31,86,110,119,122} In an unventilated 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 1 hour on each of 6 consecutive days.³³ 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 (1,650 L of air), three adult volunteers were exposed to the smoke from 12 marijuana cigarettes smoked by two people over 30 minutes.¹¹⁰ Enzyme-multiplied immunoassay technique 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 result at time 4 to 24 hours after exposure.

Three adult volunteers in an unventilated room (21,600 L of air) were exposed to the side stream smoke of four marijuana cigarettes (THC, 27 mg/cigarette) smoked simultaneously over 1 hour.¹¹² The concentrations of cannabinoids in urine samples taken 20 to 24 hours after exposure were less than 6 ng/mL when analyzed using radioimmunoassay (RIA) methodology. Another study used an unventilated room (total volume of 27,950 L) containing three desks and a filing cabinet.⁸⁶ Over 10 to 34 minutes, each of six volunteers smoked a marijuana cigarette (THC, 17.1 mg/cigarette) and left the room. Four nonsmoking men 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 room (15,500 L of air) with each of four participants smoking two marijuana cigarettes containing 2.5% THC on one occasion and 2.8% THC on a second occasion.¹²² On each occasion, two nonsmoking participants were in the room for 1 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 (∼3,500 L of air) resulted in 1 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 is substantial.

Saliva

Saliva samples are used to establish the presence of cannabinoids and time of cannabis consumption. Cannabinoids (THC, THC-COOH, 11-OH-THC) in saliva are derived from either the smoke of the marijuana or hashish or from a preliminary metabolism in the mouth.¹⁴³ Saliva THC concentrations above 10 ng/mL are consistent with recent use and correlate with subjective toxicity and heart rate changes.¹⁰¹

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.^37,80,102

Sweat

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.⁸⁰

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.⁶¹ The ratio of THC to THC-COOH is used to estimate time of smoking marijuana. Similar concentrations of each indicate cannabis use within 20 to 40 minutes and imply toxicity. In naïve 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.⁹⁴ 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.⁶³

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.⁶² In four participants, 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.⁸⁶

MANAGEMENT

Gastrointestinal (GI) decontamination is not recommended for patients who ingest cannabis products, nabilone, dronabinol, or nonclassical SCs 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 GI decontamination that outweigh the potential benefits of the intervention.

We recommend that agitation, anxiety seizures or transient psychotic episodes be treated with quiet reassurance and benzodiazepines (midazolam 1–2 mg intramuscularly or diazepam 5–10 mg intravenously) as needed. The management of patients exposed to SCs should not be expected to mirror that of THC or prescription THC-based cannabinoids. Symptomatic and supportive care is often necessary.

Laboratory evaluation should be initiated for signs of electrolyte disturbances and direct toxicity of the CNS, cardiovascular, renal, and musculoskeletal systems. Appropriate crystalloid fluid resuscitation should be given for rhabdomyolysis and acute kidney injury.

Antipsychotics are not recommended at this time during any phase of undifferentiated agitated delirium. If psychotic features persist after the resolution of sympathomimetic features, a quiet space with close observation is indicated, and antipsychotic medications are reasonable if resolution is prolonged. Patients should be observed until asymptomatic.

If available, drug samples in addition to the patient’s blood and urine, although not clinically useful, may aid in unknown designer SC identification and understanding of clinical effects.

There are no specific antidotes for cannabis or SC 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 were used for centuries both as medicinal substances and as intoxicants.

• Despite the collective human history with cannabinoids, we are only 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 although the safety profile of these xenobiotics is 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 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 SCs 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

INTRODUCTION

HISTORY AND EPIDEMIOLOGY

Cocaine is contained in the leaves of Erythroxylum coca (coca plant), a shrub that grows abundantly in Colombia, Peru, Bolivia, the West Indies, and Indonesia. As early as the sixth 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.⁷⁸

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.¹¹⁸ 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.⁶³ Following these revelations, Merck, the main cocaine producer in Europe, increased production from less than 0.75 pounds in 1883 to more than 150,000 pounds in 1886.¹¹⁴

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.²²⁹ By 1887, more than 30 cases of severe toxicity were reported,¹⁹⁸ and by 1895, at least eight fatalities resulting from a variety of doses and routes of administration were summarized in one article.⁶⁶ Recreational cocaine use was legal in the United States until the passage of the Harrison Narcotics Act of 1914, when cocaine was restricted to medicinal use. Not until 1982, however, was the first cocaine-associated myocardial infarction (MI) reported in the United States.³⁶

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 fostered a decline in the medicinal use of cocaine,^24,73,142 the recreational use of cocaine remains a significant problem.

The United Nations office on Drugs and Crime estimates that there are 19 million cocaine users worldwide.²³³ In the United States, it was estimated that in 2015, there were 1.9 million cocaine users,⁵¹ and in 2011, cocaine was the most common illicit xenobiotic resulting in emergency department (ED) visits.⁵² The dramatic evolution of the cannabinoid and opioid epidemics will probably change the profile of the ED patients using illicit xenobiotics (Chaps. 36 and 74).

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 is used by insufflation, application topically to mucous membranes, injection after dissolution in water, or ingestion; 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 after 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 when smoking cocaine exceeds 90% and is approximately 80% after nasal application.¹¹⁰ Data for ingested cocaine and application to other mucous membranes such as the urethra, vagina, or rectum are inadequately documented. Table 75–1 lists the typical onsets and durations of action for various routes of cocaine use.

After absorption, cocaine is approximately 90% bound to plasma proteins, primarily α₁-acid glycoprotein.¹⁷⁸ Based on human volunteer studies with small doses of cocaine, the volume of distribution is reported to range from 1.6 to 2.7 L/kg,^11,32,110 but it is unclear if the volume of distribution changes with overdose.

The metabolism of cocaine is complex and dependent on both genetic and acquired factors. Three major pathways of cocaine metabolism are well described (Fig. 75–1). Cocaine undergoes N-demethylation in the liver to form norcocaine, a minor metabolite that rarely accounts for more than 5% of drug.^106,223 However, norcocaine readily crosses the blood–brain barrier and produces clinical effects in animals that are quite similar to cocaine.^17,113,210 Nearly half of a dose of cocaine is both nonenzymatically²²² and enzymatically hydrolyzed⁴⁸ to form benzoylecgonine (BE). When BE is injected into animals, some reports suggest that it is virtually inactive,^115,218 but other studies demonstrate cerebral vasoconstriction⁴¹ and seizures.^122,160 When either injected directly into the cerebral ventricles^161,210 or applied to the surface of cerebral arteries,¹⁴⁵ BE is a potent vasoconstrictor. Although BE traverses the blood–brain barrier poorly,¹⁶² the potential effects are of concern as some BE is probably formed from cocaine that has already entered the central nervous system (CNS). In vitro, BE has little or no effect on cardiac sodium or potassium channels.^41,58 Finally, plasma cholinesterase (PChE) and other esterases metabolize cocaine to ecgonine methyl ester (EME). In normal individuals, between 32% and 49% of cocaine is metabolized to EME.^4,106 Similar to BE, EME crosses the blood–brain barrier poorly.¹⁶¹ Although many authors state that EME has little or no pharmacologic activity,^160,161,207 diverse animal models demonstrate contradictory results, concluding that EME is a vasodilator,^145,176,208 sedative, anticonvulsant,²¹⁰ and protective metabolite against lethal doses of cocaine.⁹⁰

Genetic or acquired alterations in PChE activity modulate the effects of cocaine. Early in vitro studies showed that cocaine was poorly metabolized in serum from patients with succinylcholine sensitivity (low PChE activity). In subsequent studies and case series, patients with low PChE activity demonstrate increased sensitivity to cocaine,^89,174 findings that are corroborated in multiple animal models.^26,90,143

Multiple other metabolites of cocaine are well characterized.³⁹ Several have clinical or diagnostic importance. In 1990, a unique metabolite was identified in patients who smoke cocaine, now known either as anhydroecgonine methyl ester (AEME) or methylecgonide.¹⁰⁸ The presence of this compound and its metabolite, ecgonidine, are useful to help determine the route of administration in cocaine users.²⁰⁶ Additionally, AEME has demonstrable agonism and antagonism at various muscarinic receptor subtypes, which has important clinical implications.^65,250 Animal models also suggest that AEME has greater neurotoxic potential compared with cocaine.⁶⁵

Ethanol has a unique pharmacologic interaction with cocaine. A transesterification reaction between the two drugs produces ethylbenzoylecognine, which is also called “ethyl cocaine” or “cocaethylene” (CE).¹⁷ In human volunteers given cocaine and ethanol, CE accounted for approximately 17% of the metabolites, producing a decrease in the amount of BE and an increase in the amount of EME formed.^82,83 Cocaethylene has a longer duration of action than cocaine and similar neurotoxic and cardiotoxic effects.

PATHOPHYSIOLOGY

Neurotransmitter Effects

Cocaine blocks the reuptake of biogenic amines. Specifically, these effects are described on serotonin and the catecholamines dopamine, norepinephrine, and epinephrine. Several animal investigations elucidated the particular roles of each neurotransmitter. Mice lacking the dopamine transporter are relatively insensitive to the locomotor effects of cocaine.⁶⁸ Whereas tachycardia emanates from adrenally derived epinephrine, hypertension results from neuronally derived norepinephrine.^227,228 Serotonin is an important modulator of dopamine and has a role in cocaine addiction, reward, and seizures.^80,133,153

Although much emphasis is placed on the reuptake blockade of these biogenic amines, it is clear that this effect is insufficient to account for the clinical manifestations of cocaine toxicity. Other xenobiotics that block the reuptake of biogenic amines, such as cyclic antidepressants, produce quite distinct clinical manifestations²³⁰ (Chap. 68). Xenobiotics that block the effects of dopamine, epinephrine, and norepinephrine not only fail to protect against cocaine toxicity but actually exacerbate toxicity.^{29,75,142,201} Although this results in part from an unopposed α-adrenergic effect, hypertension and vasospasm fail to explain the increase in psychomotor agitation, seizures, and hyperthermia that result.^29,75 These effects most likely result from an interaction between cocaine and excitatory amino acids. Cocaine increases excitatory amino acid concentrations in the brain,²¹⁷ and excitatory amino acid antagonists prevent both seizures and death in experimental animals.^18,192 Finally, because experimental evidence in animals^28,75,211 and clinical experience in humans demonstrate that sedation treats both the central effects of cocaine and the peripheral effects of biogenic amines, a newer model was proposed (Fig. 75–2). This model emphasizes the necessity of diffuse CNS excitation as a prerequisite for cocaine toxicity, explains experimental and clinical observations, and provides insight into the treatment of acute toxicity.

Cardiovascular Effects

Cocaine use is associated with myocardial ischemia and MI. The increased risk of MI results from several different mechanisms, including hypertension and tachycardia with resultant increase in myocardial oxygen demand, vasospasm resulting in decrease coronary artery blood flow, accelerated atherogenesis, and hypercoagulability. In addition, chronic exposure to high concentrations of catecholamines results in mitochondrial disruption and oxidative stress on a cellular level with direct myocardial injury.¹³⁸

Vasospasm

Although increased myocardial oxygen demand is sufficient to cause ischemia in some individuals, it is clear that cocaine also produces profound vasoconstriction. Evidence suggests that cocaine-induced vasoconstriction is mediated through both neuronal norepinephrine and BE.^127,144 Benzoylecgonine has a direct effect on vessels that is calcium mediated.¹⁴⁴ Additionally nicotine, which is simultaneously used by many substance users, has additive, if not synergistic, effects with cocaine.¹⁶⁶

Oxidative Stress