Adverse Reactions to Cannabis and Cannabinoids

EXECUTIVE SUMMARY

• Adverse effects of cannabis correlate with increasing tetrahydrocannabinol (THC) concentration.
• Drugs derived from cannabis or synthetic cannabinoids are approved by the FDA to treat three conditions: chemotherapy-related nausea and vomiting; anorexia and weight loss in AIDS; and seizures due to Lennox-Gastaut or Dravet syndrome.
• Consider cannabis hyperemesis syndrome in patients with recurrent attacks of abdominal pain with severe nausea and vomiting.
• Synthetic cannabinoids possess greater affinity than THC at the cannabinoid receptors, producing more intense effects.
• The adverse effects of the synthetic cannabinoids vary according to their ability to interact with other neuroreceptors.
• Common features of a severe reaction to most synthetic cannabinoids include tachycardia, hyperthermia, agitation, and delirium.

Introduction

Marijuana, or cannabis, has been used in the United States since the 1800s. Today, it is the most widely used illicit substance in the United States. Many people see the use of cannabis as a good experience, as it enhances the sense of physical and mental well-being (the “high”). Cannabis consumption improves taste responsiveness and enhances the sensory appeal of food.¹ However, in some people, it can cause dysphoria, anxiety, and paranoia. Cannabis also impairs the ability to learn and memorize and impairs motor skills and cognitive performance.²

Cannabis components, such as cannabidiol (CBD), also are used for medicinal purposes. Nausea and vomiting with chemotherapy was one of the first indications.³ Other conditions thought to benefit from these agents include glaucoma, anorexia with weight loss in AIDS,⁴ chronic pain,⁵ inflammation,⁶ multiple sclerosis,⁷ and epilepsy in children.⁸

Reports of recreational synthetic cannabinoid (SC) use started appearing in the medical literature in the 2000s. Since then, SCs have flooded markets around the world. This has resulted in more calls to U.S. poison centers and more visits to emergency departments (EDs), particularly in the younger population.⁹

Changes in the formulation and concentrations of Δ-9-tetrahydrocannabinol (THC) in marijuana products also have resulted in more frequent adverse effects of cannabis. SCs have broadened the profile of negative effects seen with the use of cannabis and cannabinoids.

Historically, cannabis has been smoked, as a joint or a blunt (when mixed with tobacco), or used with a bong (a water filter). However, other forms of use include drinking teas, consuming edibles, vaping (inhaling the vapors of heated e-liquids, like using an e-cigarette), dabbing (inhaling vapors from heating highly concentrated forms of cannabis or hashish, such as “honey,” “budder,” or “shatter”), and rosin (use of the concentrated resin).^9,10

Epidemiology

Demographic studies show increased cannabis use in the United States, along with increased potency of the products. Cannabis potency, defined by the THC content, has more than doubled in the last two decades, from 3.4% in cannabis tested in 1993 to 8.8% in 2008.¹¹ Correspondingly, the concentration of CBD has decreased, from 0.5% in 1995 to 0.2% in 2014.¹² This is meaningful, as adverse effects from cannabis are related to THC content. The lower concentration of CBD is important as well, because CBD helps prevent or ameliorate some of the adverse effects of THC, including the risk of addiction.^6,13,14

Since 2012, eight states have passed recreational marijuana laws (RMLs). These RMLs allow individuals to sell, possess, and use cannabis without a medical reason or authorization.¹⁰

In addition, the use of SCs has increased since their first appearance.¹⁵ Since SCs are not detected on routine drug screens, many users gravitate to these products to avoid detection.¹⁶

Pharmacology

The human cannabinoid system consists of specific receptors and their endogenous ligands.² They are all G-protein-coupled receptors and inhibit the production of cAMP in the cell.¹⁷

There are two cannabinoid receptors: CB1 (cloned in 1990) and CB2 (cloned in 1993). CB1 is found mostly in the brain, spinal cord, and the peripheral nervous system. To some extent, CB1 receptors also are found in the spleen, leukocytes, heart, and parts of the reproductive, gastrointestinal, and urinary tracts. These receptors are involved mainly in motor control, memory processing, and pain modulation via modulation of GABA and glutamate.^2,18 CB2 receptors are found mainly in leukocytes, the spleen, and tonsils. They are involved in the modulation of cytokine and chemokine production.^2,18

Endocannabinoids

The endogenous ligands at the CB receptors are called endocannabinoids, five of which are well understood. (See Table 1.) They all serve as neurotransmitters and neuromodulators of the nervous and immune systems.

Phytocannabinoids

About 65 cannabinoids have been identified in the cannabis plant. These are all partial agonists at the CB receptors. The primary psychoactive component in cannabis is THC, which was identified in 1964.¹⁹ The manufactured form of THC, dronabinol, is available for medicinal uses in the United States and Canada under the trade names Marinol™ and Syndros™ (liquid). Other phytocannabinoids include cannabigerol (CBG), cannabinol (CBN), and cannabidiol (CBD). (See Table 2.) Cannabidiol, in particular, has no psychoactive activity.

Synthetic Cannabinoids

Many of the SCs being used today were developed at Clemson University in the 1990s by scientists investigating potential medicinal uses of cannabinoids. There are several “series” of these agents: the JWH, HU, CP, and AM, among others. (See Table 3.) They are all full agonists at both the CB1 and CB2 receptors.²⁰ They also have greater receptor affinity than THC, and some have receptor affinity as much as 100 times greater.^21,22 SCs also have a longer half-life than THC.²³ All of these factors lead to higher frequency of adverse effects. The SCs are metabolized by the liver via poorly understood p450 pathways, resulting in active metabolites. Therefore, drug-drug interactions can be expected.²⁴

These synthetics began appearing in the medical literature as drugs of abuse in 2008, starting in Europe. Since then, more than 500 have been identified in the market, with steep increases seen in the past few years.²⁵ They are marketed under the names “spice,” “incense, “potpourri,” “fake weed,” or “K2.” Most consist of vegetable material sprayed with the liquid synthetic. They also are sold as tablets, capsules, or powder.²⁶ Recently, they have been found as liquids that can be used in e-cigarettes (vaping).²⁷ Most are manufactured by chemical companies based in Asia and are relatively inexpensive.^25,28

DEA and Drug Scheduling

In 1970, the Drug Enforcement Administration (DEA) classified cannabis as a Schedule I drug, which is a drug that has no medical uses and high abuse potential. Rules in the United States have been changing since 1996, with states developing both recreational and medicinal marijuana laws (RMLs and MMLs, respectively). Because of the 1970 DEA classification, users in states with MMLs and RMLs still could be prosecuted under federal law. As a result of this discrepancy, in 2009, and subsequently in 2011 and 2013, the U.S. Attorney General issued memoranda that clarified the federal government’s position on states’ MMLs.²⁹

MMLs all permit the possession and use of cannabis for the treatment of medical conditions after the user has obtained medical authorization. However, they vary in which medical conditions are allowed, how the cannabis is dispensed, and what amounts are permitted per patient.^10,30 California was the first state to have MMLs, and since then, 29 states, the District of Columbia, and two U.S. territories have followed suit.¹⁰ In Canada, marijuana has been legal since 2001.³¹

Medical Uses

Several pharmaceuticals that are either marijuana derivatives or SCs now are available. Three conditions have been listed as FDA-approved indications for marijuana-derived drugs: nausea/vomiting related to cancer treated with chemotherapy; anorexia associated with weight loss in AIDS; and seizures due to Lennox-Gastaut syndrome or Dravet syndrome.^32-34 Although some report benefits for other conditions, such as glaucoma, pain, and multiple sclerosis, no cannabinoids are FDA-approved for these indications in the United States.

Nausea and Vomiting With Chemotherapy

In 1985, both dronabinol (Marinol™) and nabilone (Cesamet™) received FDA approval for nausea/vomiting related to cancer treated with chemotherapy. In 2017, dronabinol also was approved in a liquid form, known by the trade name Syndros™. In a 2008 meta-analysis, dronabinol showed better control of nausea and vomiting than conventional antiemetics.³⁵ In another study from 2015, researchers noted that both dronabinol and nabilone demonstrated statistically significant improvement in nausea and vomiting compared to placebo, but did not achieve significance compared to other agents.³⁶

Anorexia and Weight Loss With AIDS

The FDA approved dronabinol for the additional indication of “treatment for anorexia associated with weight loss in AIDS” in 1991. A systematic review and meta-analysis found some evidence that dronabinol is associated with increased weight gain and possibly increased appetite, body fat, and functional status. The authors of this analysis commented that the reviewed studies were at high risk for bias.³⁶

Seizures

In June 2018, the FDA approved the drug Epidiolex™, which is isolated cannabidiol, for the treatment of seizures due to Lennox-Gastaut syndrome or Dravet syndrome.³² Seizures with these syndromes are difficult to control. It is unclear precisely how cannabidiol controls seizures in these two conditions. Studies have shown a statistically significant decrease in convulsive seizure frequency with treatment of either condition with CBD.^37-39

Non-FDA Approved Uses

Nabiximols (Sativex™) is a combination CBD/THC product available in Canada and many other countries. It is approved by agencies outside the United States for treatment of spasticity related to multiple sclerosis and neuropathic pain related to cancer. This product has not received FDA approval for use in the United States.

Dose Adjustment

Patients taking dronabinol and nabilone can experience a sense of disorientation or euphoria similar to the high described with smoking marijuana. It is recommended to decrease the dose if these effects are experienced.^33,40

Adverse Reactions to Cannabis

Although in general marijuana is safer than other recreationally used Schedule I agents, there are some immediate and long-term undesirable effects. Problems include issues after prenatal and early childhood exposures, a decline in educational and occupational performance in the younger population, motor vehicle collisions (MVCs) from driving while impaired, cannabis use disorders (CUD), cannabis withdrawal, and psychiatric comorbidities.^10,41 Of note, there are no documented deaths from cannabis overdose.

Impairment

Cannabis is the most commonly detected illicit drug in persons involved in MVCs.⁴² THC impairs the cognitive and motor functions needed for safe driving.⁴³ A contributing factor may be the association between THC use and failure to use seat belts.⁴⁴ Unlike with ethanol consumption, there are no tests or devices that can be used in the field to measure serum concentration of THC.¹⁰ For now, behavioral testing has been used to detect impairment.⁴⁵ To date, two states with RMLs have set the legal THC blood limit for driving under the influence (DUI) at 5 ng/mL, as levels above 10 ng/mL have been shown to impair motor function.⁴⁶

Cannabis Use Disorders and Withdrawal

The etiology of CUD is complex, and not all cannabis users will develop CUD. Like many disorders associated with substance use, CUD involves genetic and societal/environmental factors.^47,48 In general, the incidence of CUD will increase proportionally to the incidence of heavy and frequent users of THC.¹⁰ (See Table 4.)

Approximately 19.5% of lifetime THC users meet DSM-V criteria for CUD.⁴⁹ About a quarter of those with CUD will have the severe form (six or more symptoms), and about half of those are not functioning in any major social roles, such as work.⁴⁹ Therefore, CUD is neither rare nor inconsequential.¹⁰

Cannabis withdrawal causes anxiety, myalgias, chills, and anorexia. It is most intense the first week and can persist for up to a month.^50,51 It can be severe enough to cause significant impairment.⁵² Up to one-third of regular cannabis users report withdrawal, and the number can be as high as 95% in heavy users.^53-55 Like CUD, withdrawal has both genetic and societal/environmental etiologies, so not every patient with CUD will develop withdrawal.⁵⁶ Cannabis withdrawal rarely presents to the ED. The treatment is mainly supportive.⁵⁷

Hyperemesis

Cannabis hyperemesis syndrome produces severe nausea, vomiting, and diffuse abdominal pain. Patients are typically healthy young males with chronic cannabis use. A unique observation about this syndrome is that patients find that hot showers help reduce symptoms, so those afflicted may compulsively shower. The symptoms usually last 24-48 hours, but have been described to last as long as 10 days. The symptoms can be refractory to the usual antiemetics and analgesics.⁵⁸ Although the pathophysiology is not well understood, the current thinking is that it is because of dysregulation of the endogenous cannabinoid system by desensitization or downregulation of its receptors.⁵⁹

Patients with cannabis hyperemesis frequently visit the ED and undergo extensive workups and procedures, which often are negative or show only signs of dehydration.⁶⁰ In the ED, it is important to try to identify the syndrome.

The San Diego Emergency Medicine Oversight Commission identified a series of evidence-based ED interventions. Fluids and electrolyte replacement are to be used as indicated for dehydration and electrolyte derangements. Capsaicin cream (0.075%) should be a first-line agent.^61-63 The effect of capsaicin is mediated by activation of the TRPV1 receptor, a capsaicin receptor that also interacts with the endogenous cannabinoid system. The cream is applied three times per day to the abdomen or the back of the arms. Gloves should be worn when applying the cream, and the hands should be washed thoroughly after application. Prioritize capsaicin application to areas of the body where hot showers produce symptom relief if the patient can identify those areas. Capsaicin should not be applied over areas of sensitive or broken skin, and the area should not be covered with occlusive dressings.⁶²

Haloperidol (5 mg intravenous [IV]/intramuscular [IM]) and olanzapine (5 mg IV/IM/orally disintegrating tablet [ODT]) are the best antiemetics.⁶² Ondansetron, metoclopramide, diphenhydramine, and promethazine also have been used, with mixed results.^62,64 Opioids to treat abdominal pain should be avoided and actually may exacerbate the symptoms.^58,65 These patients often undergo repeat imaging, endoscopies, and even surgery, all with the potential to result in complications. Cannabis cessation is the only intervention that will result in complete resolution of the symptoms.^58,62 Therefore, education, reassurance, and referral are important ED interventions. It is helpful to document clearly in the medical record to assist colleagues, as these patients are likely to present multiple times for care.⁶²

Psychiatric Comorbidities

There are strong associations between CUD and other substance abuse disorders (in particular ethanol and nicotine use dependence) and with other psychiatric conditions, such as mood disorders, anxiety disorders, personality disorders, and post-traumatic stress disorder (PTSD).^49,66,67

Some studies have shown a causal relationship between the use of THC and the development of psychosis (termed cannabis-induced psychotic disorder) and schizophrenia.^46,68-71 Up to half of the patients with cannabis-induced psychotic disorder are diagnosed later with primary schizophrenia.⁷² Cannabis use also changes the trajectory of the disease by advancing the time of a first psychotic episode by two to six years and by precipitating exacerbations in stable patients.¹³ Most studies support that heavier cannabis use leads to increased disease risk.⁷³

In the ED, patients with symptoms of psychosis can be treated with antipsychotics, preferably oral atypical agents such as olanzapine and risperidone. Symptoms of anxiety and agitation can be treated with benzodiazepines. The patients must be kept in a safe environment until the symptoms resolve and psychiatric care is delivered.^46,74,75

Pulmonary Complications

Unlike tobacco, cannabis has not been associated with the development of lung cancer.^76,77 However, many THC users also use nicotine and tobacco, which makes an association very difficult to establish.

Cannabis smoking causes upper airway inflammation, increases upper airway resistance, and causes lung hyperinflation.⁷⁷ The effect is more pronounced when cannabis is smoked “wet,” that is, with the addition of phencyclidine (PCP), sometimes known as “embalming fluid.”⁷⁸ Cannabis smokers also report bronchitis and pneumonia more often than nonsmokers.⁷⁹

Cardiovascular Events

THC increases sympathetic tone and decreases parasympathetic activity.^80.,81 It also results in premature atherosclerosis. Cannabis has been shown to have a pro-coagulant effect and to cause platelet activation.⁸¹

Various atrial and ventricular arrhythmias have been associated with the use of cannabis and cannabinoids in both adult and pediatric patients.^81-83 Hypokalemia has been demonstrated, which can further increase the risk of these arrhythmias.⁸⁴ Acute coronary events, myocardial infarction (MI), and sudden cardiac death have been reported after the use of cannabis, although their incidence seems to be higher with the use of synthetic cannabinoids.⁸¹

Stroke

There are case reports and epidemiologic studies showing an association between cerebrovascular disease and stroke with the use of cannabis.^85-87 In a case series of 17 patients, 53% of the strokes were in the posterior circulation territory.⁸⁸ Most reported cases in a recent review article were in men (80%), and the mean age was 32 years.⁸⁶ Half of the patients in this review had concomitant risk factors.⁸⁶ The principal mechanism seems to be multifocal reversible cerebrovascular spasm (RCVS), although other mechanisms also are implicated.^81,89-91

Arteritis

Rare cases of cannabis vasculopathy have been described.⁹² The arteritis, similar to thromboangiitis obliterans, can lead to limb ischemia and gangrene.

Adverse Effects of Synthetic Cannabinoids

As discussed earlier, SCs are high-affinity, full agonists at both CB receptors.²⁸ Some SCs also have been shown to interact with other receptors, such as potassium, nicotinic, and serotonin receptors.⁹³ These unpredictable interactions provide a basis for the various clinical responses observed after the use of SCs.

Minor adverse effects include nausea, vomiting, tachycardia, and mild agitation. Severe symptoms include extreme agitation, delirium, psychosis, arrhythmias, MI, hyperthermia, rhabdomyolysis, seizures, coma, and death.^28,94 Although tachycardia and agitation are more common findings at presentation, cases of bradycardia and central nervous system (CNS) depression also have been observed.⁹⁵

This highlights the difficulty in identifying SC use in patients presenting to the ED. The adverse effects of SCs have been shown to be much more frequent and severe than those of cannabis, specifically in regard to neurotoxicity and cardiotoxicity.⁹⁶

Adverse Neurologic Effects

Agitation is the most common adverse neurologic effect associated with the use of SCs.^97,98 The most extreme form of agitation is excited delirium syndrome, which has been associated more with the use of cocaine, the synthetic cathinones (bath salts), and other sympathomimetics. However, there are reports implicating the use of SCs as a trigger for excited delirium syndrome.⁹⁹ Seizures are common, and there have been several reports of ischemic stroke as well.¹⁰⁰ The spectrum of CNS effects also includes CNS depression, loss of consciousness, and coma.¹⁰⁰

Agitation. Agitation associated with the use of SCs is unpredictable and depends on which SC was consumed, its potency, and the dose involved. Coingestants and contaminants are common and further complicate the clinical presentations. It is possible that some SCs are associated more closely with agitation and delirium than others.

In addition to the acute delirium and agitation that are seen commonly with the use of SCs, there are reports of new-onset psychosis after use. In the literature, some authors have coined the term “spiceophrenia” to describe the syndrome.¹⁰¹ Psychosis seems to be associated more with heavy and prolonged use of SCs and with certain SCs, such as the JWH series.¹⁰¹ In vulnerable individuals, SC use can exacerbate psychosis in stable patients with schizophrenia.¹⁰² The symptoms of SC-induced psychosis and schizophrenia are very similar. However, it has been observed that patients with psychosis secondary to SC use have higher rates of suicidal ideation compared to those with psychosis of other etiologies.¹⁰³ As mentioned in the cannabis section, anxiety and agitation can be managed with benzodiazepines, while atypical antipsychotics are preferred when psychosis predominates.⁴⁶

Seizures. Seizures are another relatively common neurologic complication associated with SC use. Reports range between an incidence of 3.8% (using poison center data) and 14% (Centers for Disease Control [CDC] case series).^104,105 In a pediatric case series, the reported incidence was 15%.¹⁰⁶ Seizures may be immediate or delayed, and patients can present with new-onset refractory status epilepticus.¹⁰⁷ The biochemical link between the use of SCs and seizures remains unknown. Although marijuana is thought to increase the seizure threshold, SCs are thought to lower the threshold.⁹⁵ Seizures and status epilepticus are treated with benzodiazepines as first-line agents.

Stroke. Although less commonly reported, there are case reports involving patients experiencing cerebral infarction after the consumption of SCs.¹⁰⁸ Most reported cases involve younger patients with no identifiable risk factors. As with cannabis, the mechanism for cerebral infarction is multifactorial but most relevantly involves RCVS.^81,109,110

Adverse Cardiovascular Effects

Numerous adverse cardiovascular effects are associated with the use of SCs, including tachycardia and bradycardia, hypertension and hypotension, chest pain, arrhythmias, and even MI and stress cardiomyopathy.^{81,83,111,112} Although tachycardia and hypertension are among the most prominent adverse effects, there also have been cases of patients presenting with marked bradycardia and profound hypotension requiring fluid resuscitation and even vasopressors.^113,114 Some SC samples have been tainted with clenbuterol, a beta-2 adrenergic agent that can contribute to the tachycardia.¹¹⁵

Arrhythmias. Numerous electrocardiographic abnormalities and arrhythmias have been reported in association with the use of SCs, including atrial fibrillation, supraventricular tachycardia, QT interval prolongation, atrioventricular block, and even ventricular fibrillation.^81,116-118 The mechanism behind the pro-arrhythmic effects of SCs is unknown but may involve interaction with sodium, potassium, and calcium channels.

Acute Myocardial Infarction. There are reports of patients presenting with MI, including ST-elevation MI, after consumption of SCs. It is thought that SCs can cause coronary artery vasospasm, which could lead to plaque rupture from irritation at a plaque site. Both cannabis and SCs contribute to an increased risk of early coronary artery disease.^119,120 Therefore, it is difficult to attribute MI to use of SCs in patients who regularly use both substances. Patients with prior atherosclerotic disease are additionally at risk due to the increased oxygen demand and cardiac workload associated with the sympathetic activation exhibited by SCs.^81,121 However, there have been reports of MIs in patients with no known cardiac risk factors and with unremarkable coronary angiograms.^122-124

Sudden Cardiac Death. Sudden cardiac death also has been associated with the use of SCs and may be the complication of acute MI or arrhythmias. Autopsies are available from several patients who died suddenly after SC use. In some cases, coronary artery atherosclerosis with acute superimposed thrombosis was described.¹²⁵ However, the cause of death in other cases remains elusive.¹²⁶

Adverse Renal Effects

In 2012, the CDC released a report regarding the association between SC use and acute kidney injury (AKI). The initial episode started in Wyoming, where three patients presented with nausea, vomiting, and flank or abdominal pain shortly after SC use. Public health officials were able to identify additional cases throughout the nation, for a total of 16 cases to review. Twelve of these patients had abdominal, flank, or back pain; all but one had nausea and vomiting. Peak creatinine among these patients ranged from 3.3-21 mg/dL. Many patients recovered, but five required hemodialysis. It could not be determined whether the renal toxicity was due to an SC, an SC metabolite, or a contaminant. In some samples available, XLR-11 was identified.¹²⁷

Other causes of AKI in the setting of SC use include cannabinoid hyperemesis syndrome. Vomiting may lead to volume depletion and ultimately an AKI.¹²⁸ AKI associated with SC use also may be secondary to rhabdomyolysis.¹²⁹ The psychomotor agitation that often accompanies SC use likely is responsible for the elevated creatine kinase and rhabdomyolysis seen in some patients.^130,131

Coagulopathy and Bleeding

Bleeding is the most recent adverse effect identified with SC use. In March 2018, the Illinois Department of Public Health reported several cases of unexplained bleeding in patients who had used SCs. Since that time, just more than 200 total cases have been reported, with five deaths. Testing of available drug and biological samples revealed the presence of brodifacoum, a long-acting vitamin K-dependent antagonist, or “superwarfarin,” used as a rodenticide. It is hypothesized that the brodifacoum is a contaminant mixed with the SC used by these patients. The signs and symptoms seen in these patients are those seen with any coagulopathy: easy bruising, epistaxis, menorrhagia, hematemesis, hemoptysis, hematuria, bleeding gums, etc.¹³² Some patients have been asymptomatic with a numerical coagulopathy incidentally discovered on laboratory testing. Given these new findings, it is important to suspect coagulopathy in patients with SC use, especially if they are symptomatic. International normalized ratio (INR) is the most valuable test in this scenario, with confirmatory brodifacoum testing if available.¹³²

Conclusions

Cannabis use is on the rise, along with the percentage of THC content and the ratios of THC:CBD in the available products. As a result, there is an increase in the number of adverse events and complications from what is otherwise a relatively safe Schedule I drug. The advent of RMLs and MMLs has begun to change the landscape of patients’ perceptions regarding cannabis use, as access to cannabis and cannabis-containing products increases.

As Americans adjust to increased access to marijuana, the U.S. government continues to fight against the spread of SCs. Given that SC use emerged very recently and that SCs are a diverse group of drugs, preventing their manufacture, distribution, and use has proven to be difficult. The result is an increased toxicity and, therefore, more ED visits. This presents emergency physicians with the challenge of identifying potential SC use as a contributing factor to their patients’ presentations.

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