77: Cannabinoids

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

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

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

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

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

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

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

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

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

Pain

Acute Pain.

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

Chronic Pain.

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

Nausea and Vomiting

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

Glaucoma

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

Summary of Medical Use

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

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

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

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

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

CB₁ Receptors and the Psychogenic Effects of Cannabis

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

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

Mechanism of Cellular Signaling

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

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

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

Absorption

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

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

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

Distribution

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

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

Metabolism

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

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

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

Excretion

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

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

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

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

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

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

Psychological Effects

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

Physiologic Effects

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Acute Use

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

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

Chronic Use

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

Immune System.

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

Respiratory System.

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

Cardiovascular System.

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

Reproductive System.

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

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

Endocrine System.

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

Neurobehavioral Effects.

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

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

Abuse, Dependence, and Withdrawal.

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

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

Cannabinoid Hyperemesis Syndrome.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Acknowledgment

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

References