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).
Cannabinoid structural classes.
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.
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
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.
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.
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.
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
TABLE 77–1.Medical Conditions Proposed for Cannabinoid Use ||Download (.pdf) TABLE 77–1. Medical Conditions Proposed for Cannabinoid Use
|Anorexia-cachexia syndrome secondary to HIV infectiona |
|Head injury |
|Migraine headaches |
|Multiple sclerosis |
|Muscle spasticity and spasms |
|Nausea and vomiting (resistant)a |
|Neurologic disorders |
|Parkinson disease |
|Tourette syndrome |
PHARMACOLOGY AND PATHOPHYSIOLOGY
The term “cannabinoid” refers to compounds that bind to and agonize the cannabinoid receptors regardless of whether they are derived from plants (phytocannabinoids), synthetic processes (synthetic cannabinoid receptor agonists), or endogenously existing neuromodulators (endocannabinoids). At one time the term may have been used to delineate a structural similarity to Δ9-THC, but this naming convention has largely been abandoned during the past 30 years of cannabinoid research as new compounds have been discovered and synthesized. The structural diversity of cannabinoid ligands and the absence of a true pharmacophore make nomenclature based purely on structure cumbersome and inconsistent. It is preferable then to use the term cannabinoid to denote receptor agonism and subclassify cannabinoids further based on origin and structure (Fig. 77–1).
Cannabis is a collective term referring to the bioactive substances from the Cannabis plant. The Cannabis genus (species sativa and indica) produces more than 60 chemicals (C21 group) called cannabinoids. In this chapter, the term “cannabis” encompasses all cannabis products. The major cannabinoids are cannabinol, cannabidiol (CBD), and tetrahydrocannabinol. The principal psychoactive cannabinoid is THC, or Δ9-tetrahydrocannabinol. Marijuana is the common name for a mixture of dried leaves and flowers of the C. sativa plant. Hashish and hashish oil are the pressed resin and the oil expressed from the pressed resin, respectively. The concentration of THC varies from 1% in low-grade marijuana up to 50% in hash oil. THC extracted from marijuana using butane (butane hash oil or BHO) can approach THC concentrations of 100%. Pure THC and a SCRA are available by prescription with the generic names of dronabinol and nabilone, respectively. Nabiximols is the generic name for an oral mucosal spray containing THC and cannabidiol, which is approved for medical use in Canada, the United Kingdom, and parts of Europe. Unregulated SCRAs originally designed as research chemicals have emerged as designer drugs of abuse over the past 6 years.
Cannabinoid receptors are G protein linked neuromodulators that inhibit adenylate cyclase in a dose-dependent and stereospecific manner. While historically the cannabinoid receptor system is described as having a central CB1 and a peripheral CB2 receptor, recent evidence points to the central nervous system (CNS) presence of CB2 receptors.134 The two currently identified cannabinoid receptors are labeled CB1 and CB2 and are distinguished largely by their anatomic distribution and mechanisms of cellular messaging (Fig. 77–2).
Endocannabinoids act as allosteric cellular messengers. In response to presynaptic γ-aminobutyric acid (GABA) release and postsynaptic binding resulting in increased cyclic AMP, endocannabinoids are synthesized on demand and bind to presynaptic cannabinoid receptors. Activation of these G protein receptors results in decreased presynaptic adenylyl cyclase, decreased cAMP, decreased calcium ion influx and increased potassium efflux. The net result is hyperpolarization of the presynaptic cell and decreased neurotransmitter release. After binding, endocannabinoids diffuse back to the post synaptic area where they undergo degradation by MAG lipase and fatty acid amide hydrolase. CB1R = cannabinoid type 1 receptor; MPAK = mitogen-activated protein kinase; MAG lipase = monoaceylglycerol lipase; DAG lipase = diaceylglycerol lipase. (Adapted with permission from Seely KA, Prather PL, James LP, Moran JH: Marijuana-based drugs: innovative therapeutics or designer drugs of abuse? Mol Interv. 2011;11:36–51.)
CB1 Receptors and the Psychogenic Effects of Cannabis
CB1 receptors are the most numerous G protein coupled receptors in the mammalian brain accounting for the multiple and varied effects of Cannabis on behavior, learning, and mood as well as suggesting the enormous complexity of the endocannabinoid system.54 The highest concentration of CB1 receptors are located in areas of the brain associated with movement and higher functions of cognition and emotions. Relative lack of CB1 receptors in the brainstem also explains lack of coma and respiratory depression seen with Cannabis use. CB1 receptors are structurally comprised of seven transmembrane protein units coupled to pertussis-sensitive (decrease adenylate cyclase) G proteins. They exhibit genetic variation via splice variants and are found as heterodimers with a multitude of other receptor types.63
CB2 receptors have traditionally been thought of as existing in the periphery and mainly affecting immune response, although evidence now exists of their activity in the CNS. Isolated agonism of CB2 receptors has been the target for novel pharmaceutical candidates as antiinflammatory agents with minimal success as psychoactive effects of CB1 agonism were still evident.
Mechanism of Cellular Signaling
Cannabinoid receptors both in the CNS and in the periphery exist on the presynaptic terminus of various neurons. Depolarization in postsynaptic portion of the neuron and subsequent increase in intracellular Ca2+ leads to on-demand synthesis and release of endocannabioids.108 These free fatty acid–based messengers diffuse into the synapse and bind to the presynaptic cannabinoid receptor. Ligand binding causes conformational change in the G protein subunits and inhibition of adenylate cyclase, resulting in decreased intracellular cAMP concentrations, decreased activity of voltage-gated Ca2+ channels, and ultimately decreased neurotransmitter release (Fig. 77–2). Exogenous cannabinoids act in much the same way compared to endogenous compounds after receptor binding, except that binding affinity will vary among ligands and endogenous cannabinoids are rapidly metabolized by hydrolases.80 Interestingly, some online chemical suppliers offer fatty acid amide hydrolase inhibitors for sale, along with various SCRAs, perhaps providing a glimpse into future products more closely related to endocannabinoids coming to market.
Both receptors inhibit adenylyl cyclase and stimulate K+ channel conductance.112 CB1 receptors are located either presynaptically or postsynaptically and their activation can inhibit or enhance the release of acetylcholine, L-glutamate, γ-aminobutyric acid, noradrenaline, dopamine, and 5-hydroxytryptamine.67,73,127
The neuropharmacologic mechanisms by which cannabinoids produce their psychoactive effects have not been fully elucidated.56,67,112 Nevertheless, activity at the CB1 receptors is believed to be responsible for the clinical effects of cannabinoids,12,37,67,140 including the regulation of cognition, memory, motor activities, nociception, and nausea and vomiting. Chronic administration of a cannabinoid agonist reduces CB1 receptor density in several regions of the rat brain.13
PHARMACOKINETICS AND TOXICOKINETICS
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
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
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
Estimated relative time course of THC and its major metabolite in the urine based on the route of exposure. THC = Δ9 tetrahydrocannabinol; THC-COOH = Δ9 THC carboxylic acid.
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.
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.
JWH-018 and AM2201 metabolism. Aminoalkylindole synthetic cannabinoid JWH-018 and its omega fluorinated analog AM2201 undergo oxidation by CYP2C9 and CYP1A9 to primary metabolites that retain affinity and ability to bind with cannabinoid receptors. One JWH-018 primary metabolite, acts as a antagonist at CB1. Secondary metabolites are formed by conjugation. These metabolites may retain ability to bind to cannabinoid receptors but at this time it is clear which do so and in what capacity (agonist, antagonist, or inverse agonist). (Adapted with permission from Chimalakonda KC, Seely KA, Bratton SM, et al.: Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos. 2012;40:2174–2184.)
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.
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
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
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
Long-term use of cannabis is associated with a number of adverse effects.
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
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
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
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.
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
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
TABLE 77–2.Xenobiotics or Conditions Reported to Produce Inaccurate Screening Test Results for Tetrahydrocannabinol ||Download (.pdf) TABLE 77–2. Xenobiotics or Conditions Reported to Produce Inaccurate Screening Test Results for Tetrahydrocannabinol
|False Negativea ||False Positive |
|Bleach (NaOCl) ||Dronabinol |
|Citric acid ||Efavirenz |
|Detergent additives ||Ethacrynic acid |
|Dettol ||Hemp seed oil |
|Dilution ||Nonsteroidal antiinflammatory drugs |
|Glutaraldehyde ||Promethazine |
|Lemon juice ||Riboflavin |
|Potassium nitrite (KNO2) || |
|Table salt (NaCl) || |
|Tetrahydrozoline || |
|Vinegar (acetic acid) || |
|Water || |
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
ESTIMATING TIME OF EXPOSURE
A measurable serum concentration of THC is consistent with recent exposure and toxicity, but there is poor correlation between serum THC concentrations and actual clinical effects.57 The ratio of THC to THC-COOH has been used to estimate time of smoking marijuana. Similar concentrations of each indicate cannabis use within 20 to 40 minutes and imply intoxication. In naive users, a concentration of THC-COOH that is greater than THC indicates that use probably occurred more than 30 minutes ago. The high background concentrations of THC-COOH in habitual users make estimations of time of exposure unreliable in this population.
Serum concentrations of THC and THC-COOH were used in a logarithmic equation to predict the time since smoking a marijuana cigarette.88 The ratio provided acceptable results up to 3 hours after smoking (predicted time of exposure averaged 27 minutes longer than actual exposure time), but more than 3 hours after smoking the predicted exposure time was overestimated by 3 hours. Mean overestimations of predicted exposure time of 2.5 to 4.2 hours for smoking and of 1.6 hours for ingestions are reported when serum samples are taken more than 4 hours after exposure.59
Chronic use or oral administration of cannabis increases the concentration of 11-OH-THC relative to the concentrations of THC or THC-COOH. In these cases, estimating time of exposure based on relative concentrations is problematic.58 In four subjects, ingestion of cannabis produced total serum metabolite concentrations less than 20 times the serum THC concentration for 3 hours after ingestion, suggesting that a ratio of this magnitude is consistent with recent oral consumption.82
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.
Michael A. McGuigan, MD, contributed to this chapter in previous editions.
et al.: Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev. 1986;38:21–43.
et al.: High times, low sats: diffuse pulmonary infiltrates associated with chronic synthetic cannabinoid use. J Med Toxicol. 2013;9:199–206.CrossRef
JH, De Moore
JC: Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut. 2004;53:1566–1570.CrossRef
GG: Delta-9-tetrahydrocannabinol as an antiemetic. Am J Hosp Pharm. 1981;38:639–646.
H: Acute cardiovascular fatalities following cannabis use. Forensic Sci Int. 2001;124:200–203.CrossRef
NA: Medical efficacy of cannabinoids and marijuana: a comprehensive review of the literature. J Palliat Care. 2002;18:111–122.
R: Marihuana smoking. Cardiovascular effects in man and possible mechanisms. N Engl J Med. 1972;287:209–212.CrossRef
S: Cannabis and psychosis: what is the link? J Psychoactive Drugs. 2007;39:131–142.CrossRef
RT: Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol Ther. 1975;18:287–297.
MM: Effects of chronic marijuana use on human cognition. Psychopharmacology (Berl). 1993;110:219–228.CrossRef
SR: The functional neuroanatomy of brain cannabinoid receptors. Neurobiol Dis. 1998;5:417–431.CrossRef
et al.: Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J Neurochem. 1999;73:2447–2459.CrossRef
et al.: Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem Pharmacol. 2012;83:952–961.CrossRef
et al.: Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One. 2011;6:e21917.CrossRef
SJ: Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Philadelphia: Lippincott Williams & Wilkins; 2012.
BA: Development and consequences of cannabis dependence.J Clin Pharmacol. 2002;42:28S–33S.CrossRef
EM: Clinical pharmacokinetics of non-opiate abused drugs. Clin Pharmacokinet. 1989;16:1–26.CrossRef
GA: Marihuana and mouth cancer. J Royal Soc Med. 1991;84:386.
et al.: Delata-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate
. A prospective, randomized evaluation. Ann Intern Med. 1979;91:819–824.CrossRef
DM: Cannabinoid hyperemesis relieved by compulsive bathing. Mayo Clin Proc.
M: Relationships between frequency and quantity of marijuana use and last year proxy dependence among adolescents and adults in the United States. Drug Alcohol
DM: Possible amotivational effects following marijuana smoking under laboratory conditions. Exp Clin Psychopharmacol. 2002;10:26–38.CrossRef
et al.: Conjugation of synthetic cannabinoids JWH-018 and JWH-073, metabolites by human UDP-glucuronosyltransferases. Drug Metab Dispos. 2011;39:1967–1976.CrossRef
et al.: Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos. 2012;40:2174–2184.CrossRef
GG: Effects of moderate and high doses of marihuana on thermal pain: a sensory decision theory analysis. J Clin Pharmacol. 1981;21:299S–310S.CrossRef
et al.: Passive inhalation of marijuana smoke: urinalysis and room air levels of delta-9-tetrahydrocannabinol. J Anal Toxicol. 1987;11:89–96.CrossRef
GA: Prenatal marijuana use: epidemiology, methodologic issues, and infant outcome. Clin Perinatol. 1991;18:77–91.
et al.: Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–613.
J: Cannabinoid hyperemesis: a case series. J Emerg Med. 2011;40:e63–e66.CrossRef
R: Prenatal marijuana exposure and neonatal outcomes in Jamaica: an ethnographic study. Pediatrics. 1994;93:254–260.
WA: Drug testing by urine and hair analysis: complementary features and scientific issues. Forensic Sci Int. 1995;70:63–76.CrossRef
et al.: Excretion patterns of cannabinoid metabolites after last use in a group of chronic users. Clin Pharmacol Ther. 1985;38:572–578.CrossRef
M: Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol. 1998;38:179–200.CrossRef
TF: Cardiovascular complications induced by cannabis smoking: a case report and review of the literature. Emerg Med J. 2005;22:679–680.CrossRef
PA: Behavioral outcomes in preschool and school-age children exposed prenatally to marijuana: a review and speculative interpretation. NIDA Res Monogr. 1996;164:242–260.
JE: Neonatal behavioural correlates of prenatal exposure to marihuana, cigarettes and alcohol
in a low risk population. Neurotoxicol Teratol. 1987;9:1–7.CrossRef
B: 36-and 48-month neurobehavioral follow-up of children prenatally exposed to marijuana, cigarettes, and alcohol
. J Dev Behav Pediatr. 1990;11:49–58.CrossRef
FK: Cannabinoid hyperemesis syndrome. Curr Drug Abuse Rev. 2011;4:241.CrossRef
et al.: Delta(9)-tetrahydrocannabinol, 11-hydroxy-delta(9)-tetrahydrocannabinol and 11-nor-9-carboxy-delta(9)-tetrahydrocannabinol in human plasma after controlled oral administration of cannabinoids. Ther Drug Monit. 2006;28:545–551.CrossRef
P: A case of cannabis-induced pancreatitis. JOP. 2004;5:41–43.
K: Marijuana smoking vs cannabinoids for glaucoma therapy. Arch Ophthalmol. 1998;116:1433–1437.CrossRef
et al.: Chromatography–mass spectrometry studies on the metabolism of synthetic cannabinoids JWH-018 and JWH-073, psychoactive components of smoking mixtures. J Chromatography B. 2011;879:1126–1136.CrossRef
F: Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42:327–360.CrossRef
et al.: Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacology. 2004;29:158–170.CrossRef
ZF: Marijuana smoking and head and neck cancer. J Clin Pharmacol. 2002;42:103S–107S.CrossRef
MB: Effect of marijuana use in pregnancy on fetal growth. Am J Epidemiol. 1986;124:986–993.
RL: The constituents of cannabis and the disposition and metabolism of cannabinoids. NIDA Res Monogr. 1982;42:125–137.
EJ: Acute and residual effects of marijuana: profiles of plasma THC levels, physiological, subjective, and performance measures. Pharmacol Biochem Behav. 1990;37:561–565.CrossRef
TR: Psychosis associated with synthetic cannabinoid agonists: a case series. Am J Psychiatry. 2011;168:10.
et al.: Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study.J Neurosci. 1991;11:563–583.
WG: Pharmacology and potential therapeutic uses of cannabis. Br J Anaesth. 1998;81:77–84.CrossRef
LE: Health aspects of cannabis. Pharmacol Rev. 1986;38:1–20.
et al.: Do plasma concentrations of delta 9-tetrahydrocannabinol reflect the degree of intoxication? J Clin Pharmacol. 1981;21:171S–177S.CrossRef
et al.: Estimating time of last oral ingestion of cannabis from plasma THC and THCCOOH concentrations. Ther Drug Monit. 2006;28:540–544.CrossRef
EJ: Blood cannabinoids. II. Models for the prediction of time of marijuana exposure from plasma concentrations of Δ9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH). J Anal Toxicol. 1992;16:283–290.CrossRef
EJ: Detection times of marijuana metabolites in urine by immunoassay and GC-MS. J Anal Toxicol. 1995;19:443–449.CrossRef
EJ: Urinary excretion profiles of 11-nor-9-carboxy-delta 9-tetrahydrocannabinol in humans after single smoked doses of marijuana.J Anal Toxicol. 1996;20:441–452.CrossRef
JW: Cannabimimetic indoles, pyrroles and indenes. Curr Med Chem. 1999;6:705–720.
LW: Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes. Curr Med Chem. 2005;12:1395–1411.CrossRef
RT: Tolerance and disposition of tetrahydrocannabinol in man.J Pharmacol Exp Ther. 1980;215:35–44.
R: Psychosis associated with synthetic cannabinoid agonists: a case series. Am J Psychiatry. 2011;168:1119.CrossRef
V: Identification of the major urinary metabolites in man of seven synthetic cannabinoids of the aminoalkylindole type present as adulterants in “herbal mixtures” using LC–MS/MS techniques. J Mass Spectrom. 2012;47:54–65.CrossRef
G: Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol. 1981;21:320S–326S.CrossRef
MM: Urinary excretion half-life of delta 1-tetrahydrocannabinol-7-oic acid in heavy marijuana users after smoking. J Anal Toxicol. 1989;13:218–223.CrossRef
et al.: Development and validation of a liquid chromatography-tandem mass spectrometry method for the identification and quantification of JWH-018, JWH-073, JWH-019, and JWH-250 in human whole blood. J Anal Toxicol. 2011;35:386–393.CrossRef
et al.: GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus. Neuroscience. 2000;100:797–804.CrossRef
A: The Identification of the urinary metabolites of 3-(4-Methoxybenzoyl)-1-Pentylindole (RCS-4), a novel cannabimimetic, by gas chromatography–mass spectrometry. J Anal Toxicol. 2012;36:303–311.CrossRef
RT: Metabolism of tetrahydrocannabinol in frequent and infrequent marijuana users. J Anal Toxicol. 1992;16:228–235.CrossRef
S: Testing for drugs of abuse in saliva and sweat. J Chromatogr B Biomed Sci Appl. 1998;713:111–135.CrossRef
S: Marijuana, immunity and infection.J Neuroimmunol. 1998;83:102–115.CrossRef
et al.: Marijuana and spontaneous abortion of known karyotype. Paediatr Perinat Epidemiol. 1991;5:320–332.CrossRef
G: Paroxysmal atrial fibrillation following marijuana intoxication: a two-case report of possible association. Int J Cardiol. 2001;78:183–184.CrossRef
CJ: The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications. J Med Chem. 2005;48:5059–5087.CrossRef
et al.: Severe toxicity following synthetic cannabinoid ingestion. Clin Toxicol. 2011;49:760–764.CrossRef
et al.: Passive inhalation of cannabis smoke. J Pharm Pharmacol. 1984;36:578–581.CrossRef
BR: Marijuana withdrawal syndrome in the animal model.J Clin Pharmacol. 2002;42:20S–27S.CrossRef
et al.: Spice: a never ending story? Forensic Sci Int. 2009;191:58–63.CrossRef
et al.: The association of marijuana use with outcome of pregnancy. Am J Public Health. 1983;73:1161–1164.CrossRef
et al.: Psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies. Lancet. 2004;363:1579–1588.CrossRef
L: Ingestion of cannabis: a cause of coma in children. Pediatr Emerg Care. 1989;5:238–239.CrossRef
et al.: Temporal indication of marijuana use can be estimated from plasma and urine concentrations of delta9-tetrahydrocannabinol, 11-hydroxy-delta9-tetrahydrocannabinol, and 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid. J Anal Toxicol. 2001;25:538–549.CrossRef
et al.: Marijuana intoxication and brain activation in marijuana smokers. Life Sci. 1997;60:2075–2089.CrossRef
et al.: Time course of tetrahydrocannabinol-induced changes in regional cerebral blood flow measured with positron emission tomography. Psychiatry Res. 2002;116:173–185.CrossRef
R: A historical overview of chemical research on cannabinoids. Chem Physics Lipids.
Y: The absolute configuration of delta-1-tetrahydrocannabinol, the major active constituent of hashish. Tetrahedron Lett. 1967;12:1109–1111.CrossRef
et al.: The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. 2006;166:1359–1367.CrossRef
ER: Salivary THC following cannabis smoking correlates with subjective intoxication and heart rate. Psychopharmacology. 1991;103:277–279.CrossRef
T: A research note: the outcome of GC/MS/MS confirmation of hair assays on 93 cannabinoid (+) cases. Forensic Sci Int. 1995;70:83–91.CrossRef
et al.: Ocular activity of topically administered anandamide in the rabbit. Jap J Ophthalmol. 1997;41:217–220.CrossRef
C: Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics. 2011;128:e1622–e1627.CrossRef
et al.: Triggering myocardial infarction by marijuana. Circulation. 2001;103:2805–2809.CrossRef
et al.: A fast and inexpensive procedure for the isolation of synthetic cannabinoids from “Spice” products using a flash chromatography system. Anal Bioanal Chem. 2012:1–7.
et al.: Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine. Anal Chem. 2011;83:4228–4236.CrossRef
Morbidity and Mortality Weekly Report: Acute kidney injury associated with synthetic cannabinoid use–multiple states, 2012. MMWR Morb Mortal Wkly Rep. 2013;62:93–98.
et al.: Cannabinoids in blood and urine after passive inhalation of Cannabis smoke. J Forensic Sci. 1985;30:997–1002.
MA: An exploratory prospective study of marijuana use and mortality following acute myocardial infarction.Am Heart J. 2008;155:465–470.CrossRef
SJ: Active and realistic passive marijuana exposure tested by three immunoassays and GC/MS in urine. J Anal Toxicol. 1988;12:113–116.CrossRef
L: Relationships between motivation and depression in chronic marijuana users. Life Sci. 1995;56:2151–2158.CrossRef
H: The kinetics of cannabinoid distribution and storage with special reference to the brain and testis. J Clin Pharmacol. 1981;21:208S–214S.CrossRef
GG: Lethal cannabis intoxication. N Engl J Med. 1971;284:792.
AA: Cannabis and cannabinoid receptors. Fitoterapia.
: The analgesic properties of delta-9-tetrahydrocannabinol and codeine
. Clin Pharmacol Ther. 1975;18:84–89.
LA: Cannabis and driving: a new perspective. Emerg Med (Fremantle). 2002;14:296–303.CrossRef
et al.: Effects of smoking marijuana on brain perfusion and cognition. Neuropsychopharmacology. 2002;26:802–816.CrossRef
et al.: Endocannabinoids and cannabinoid receptor genetics. Prog Neurobiol. 2002;66:307–344.CrossRef
M, Di Guiseppi
KH: Passive inhalation of marihuana smoke and urinary excretion of cannabinoids. Clin Pharmacol Ther. 1983;34:36–41.CrossRef
ME: Presence of delta9-tetrahydrocannabinol in human milk.N Engl J Med. 1982;307:819–820.CrossRef
JM: Cannabis, synthetic cannabinoids, and psychosis risk: what the evidence says. Curr Psychiatry. 2011;10.
D: The residual cognitive effects of heavy marijuana use in college students. JAMA. 1996;275:521–527.CrossRef
L: The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies. Eur J Neurosci. 2001;13:409–412.CrossRef
JS: delta 9-tetrahydrocannabinol in clinical oncology. JAMA. 1981;245:2047–2051.CrossRef
et al.: Effects of marihuana and placebo marihuana smoking on hemodynamics in coronary disease. Clin Pharmacol Ther. 1975;18:90–95.
et al.: Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice. J Pharmacol Exp Ther. 2011;339:173–185.CrossRef
RA: Coronary no-flow and ventricular tachycardia associated with habitual marijuana use. Ann Emerg Med. 2003;42:365–369.CrossRef
R: Determination of nabilone
in bulk powders and capsules by high-performance liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2004;18:128–130.CrossRef
KM: Here today, gone tomorrow… and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol. 2012;8:15–32.CrossRef
et al.: Marijuana use and risk of oral squamous cell carcinoma. Cancer Res. 2004;64:4049–4054.CrossRef
et al.: Physiologic disposition of nabilone
, a cannabinol derivative, in man. Clin Pharmacol Ther. 1977;22:85–91.
EB: History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007;4:1614–1648.CrossRef
M: Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci. 2001;22:565–572.CrossRef
T: Convulsions associated with the use of a synthetic cannabinoid product. J Med Toxicol. 2012;8:62–64.CrossRef
BT: “Spice” girls: synthetic cannabinoid intoxication. J Emerg Med. 2011;40:296–299.CrossRef
DA: Drugs of abuse in saliva: a review.J Anal Toxicol. 1992;16:1–9.CrossRef
RH: Marijuana: an overview. Pediatr Clin North Am. 1987;34:305–317.
P: Short-term memory impairment in cannabis-dependent adolescents. Am J Dis Child. 1989;143:1214–1219.
JH: Marijuana-based drugs: innovative therapeutics or designer drugs of abuse? Mol Interv. 2011;11:36–51.CrossRef
JH: Cannabinoid hyperemesis: a case series of 98 patients. Mayo Clin Proc.
NT: A review of the published literature into cannabis withdrawal symptoms in human users. Addiction. 2002;97:621–632.CrossRef
J: One year follow-up of cannabis dependence among long-term users in Sydney, Australia. Drug Alcohol
IM: Acute effects of smoked marijuana and oral delta9-tetrahydrocannabinol on specific airway conductance in asthmatic subjects. Am Rev Respir Dis. 1974;109:420–428.
IM: Acute pulmonary physiologic effects of smoked marijuana and oral 9-tetrahydrocannabinol in healthy young men. N Engl J Med. 1973;289:336–341.CrossRef
F3: Marijuana as a potential respiratory tract carcinogen: a retrospective analysis of a community hospital population. South Med J. 1988;81:1213–1216.CrossRef
et al.: Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) in human serum by liquid chromatography–tandem mass spectrometry. J Chromatogr B. 2010;878:2659–2663.CrossRef
et al.: Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. 2007;167:221–228.CrossRef
CA: Toxicological screening for drugs of abuse in samples adulterated with household chemicals. S Afr Med J. 2002;92:547–549.
C: Spice drugs as a new trend: mode of action, identification and legislation. Toxicol Lett. 2010;197:157–162.CrossRef
et al.: Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther. 1983;34:352–363.CrossRef
MJ: Cannabinoid hyperemesis syndrome: literature review and proposed diagnosis and treatment algorithm. South Med J. 2011;104:659–664.CrossRef
JE: Marijuana and medicine: assessing the science base: a summary of the 1999 Institute of Medicine report. Arch Gen Psychiatry. 2000;57:547–552.CrossRef
AT: Adverse reactions to marihuana. Classification and suggested treatment.N Engl J Med. 1970;282:997–1000.CrossRef
JE: Pulmonary hazards of smoking marijuana as compared with tobacco. N Engl J Med. 1988;318:347–351.CrossRef
et al.: Effects of maternal marijuana and cocaine
use on fetal growth. N Engl J Med. 1989;320:762–768.CrossRef