Cannabis is one of the most commonly used drugs in the United States. More than 48.2 million people in the US aged 12 years and older (17.5%) have used cannabis in the last year.1 Although evidence suggest that some medical conditions may benefit from cannabis use, there is a lack of high-quality randomized controlled trials examining the potential therapeutic uses of cannabis and a lack of prospective studies looking at associated adverse effects.
The risks and benefits of any cannabinoid-containing compound need to be carefully weighed for each patient. This includes consideration of potential effects on comorbidities and drug-drug interactions. The increasingly widespread use of cannabis makes screening and counseling patients about the potential risks vs benefits a priority.
Cannabis sativa and Cannabis indica are the 2 most commonly used strains of cannabis, a plant containing approximately 540 chemical compounds, of which more than 100 are classified as cannabinoids.2 The compound generally responsible for producing intoxication (high) is delta-9-tetrahydrocannabinol (THC); cannabidiol (CBD) does not produce this effect but may have therapeutic effects.3
Cannabis can be found in natural and synthetic formulations that contain psychoactive and inactive compounds. Cannabis concentrates can be inhaled or vaporized. Products for oral ingestion include pills, teas, edibles, tinctures, and gummies. Lozenges, lollipops, and dissolvable strips can be taken sublingually. Topical products include oils, lotions, and bath salts.4
The potency of THC content in samples of recreational cannabis has increased dramatically, from less than 4% in the early 1990s to more than 15% in 2018; some current variants and cannabis concentrates can have much higher THC levels.4 In the last 2 decades, the percentage of nonpsychoactive components has steadily decreased, resulting in an increase in the psychoactive to nonpsychoactive component ratio from 14 times in 2001 to 80 times in 2017.5 The result is that some currently available products may have a greater ability to produce a high.
Psychoactive Drug Components
The absorption and distribution of THC is highly variable depending on the route of administration and individual patient characteristics. When consumed via inhalation (smoking or vaping), the onset of action is typically within 10 minutes; systemic bioavailability is 11% to 45%.6 When THC is consumed orally there is a greater variability in onset and effects due to first-pass metabolism through the liver and significant degradation by gastric acid. Peak THC levels have been reported at 1 to 6 hours after oral ingestion; systemic bioavailability is 4% to 20%.6
The metabolism of cannabis occurs via 2 hepatic cytochrome oxidases, CYP2C9 and CYP3A4. Its plasma half-life ranges from 1 to 3 days in occasional users to up to 13 days in chronic users, and it is eliminated through feces (65%) and urine (20%).6 The elimination half-life can be substantially longer in regular cannabis users because cannabis is highly lipophilic. With regular use, cannabis accumulates in adipose tissues over time, resulting in a slow release when blood levels are low and accounting for a positive urine drug screening for up to 6 weeks after last consumption vs 4 weeks in occasional users.7
Receptors and Reward Pathways
Endogenous cannabinoid receptors are found in the brain, spine, and peripheral nervous system, with components of cannabis acting as a partial agonist at both cannabinoid receptor type 1 (CB1) and type 2 (CB2) sites.8 Within the central nervous system, THC strongly binds to CB1 receptors accounting for its psychoactive properties; CBD does not.8 Cannabis impacts the release of several neurotransmitters such as acetylcholine, norepinephrine, γ-aminobutyric acid, and serotonin within multiple regions of the brain. Areas impacted include the frontal cortex, basal ganglia, cerebellum, hippocampus, and cerebral cortex, accounting for some of the drug’s clinical effects.6,8,9
Binding within the peripheral tissues occurs at CB2 receptors, primarily located within cells in the immune system (B lymphocytes and splenic macrophages), peripheral nerve terminals, and the vas deferens.8 The mechanism of action in the periphery is less clear, but cannabinoids may play a role in the regulation of immune and/or inflammatory reactions.8 Both CB1 and CB2 cells are found in the cardiovascular system.6
Like alcohol and other psychoactive substances, cannabis is processed through the mesolimbic dopamine pathway, the same circuitry involved in the regulation of reinforcement and reward.9 This pathway is associated with reinforcement of adaptive behaviors and the natural high associated with joy or accomplishment. Cannabis binding bypasses the brain’s neurotransmitters and directly stimulates the release of dopamine within the reward pathway, triggering an artificial high. Long-term cannabis use eventually causes changes in this reward circuit. Over time, this results in an increase in impulsiveness to use the substance, which provides a reward, and a decrease in the pleasure or gratification associated with it, accounting for clinical symptoms related to tolerance.9
Physiologic Effects of Cannabis Use
Physiologic effects of acute intoxication may include euphoria, tachycardia, hypertension, conjunctival injection, dry mouth, increased appetite, impaired judgment, and paranoid delusions.10 Acute neuropsychiatric effects can be highly variable in presentation and appear to be dose dependent. At low doses, mood is described as euphoric, with decreased depression, anxiety, and tension; conversely, at higher doses there is increased anxiety, dysphoria, and panic.10 Other neurologic or psychiatric effects may include10-12:
- Slowed reaction times and impaired motor coordination
- Impaired attention, concentration, short-term memory, and risk assessment
- Distortions in time and spatial perception
- Increased intensity of visual/auditory perception
- Depersonalization, hallucination, grandiosity, paranoia, and/or other signs of psychosis
These effects are additive when combined with other central nervous system (CNS) depressants. Mood-altering effects typically resolve within hours, but residual effects of a dose of cannabis might last for 24 hours. In laboratory studies of cognitive and behavioral effects, evidence suggests that the effects of cannabis increase as the dose consumed or level of THC in blood increases. Evidence also suggests that effects of cannabis on driving simulator performance and collision risk increase as dose consumed and levels in the body increase.13
The heart and vascular smooth muscle contain CB1 and CB2 receptors; thus, dose-dependent increases in heart rate and blood pressure can occur with acute intoxication.11,12 Orthostatic hypotension is a common side effect in older adults.14 Other potential physiologic changes can include increased platelet aggregation, arterial vasospasm, and increased cerebral vascular tone, which can result in decreased cerebrovascular blood flow.12 In the hours after ingestion, cannabis increases the risk for major cardiovascular events, such as hypertensive emergency, myocardial infarction, transient ischemic attack, and cerebrovascular accident.11 Chronic use in individuals with a history of angina may lower the angina threshold and, thus, precipitate chest pain.12 There also is evidence to suggest a link to new cardiac arrhythmia secondary to ischemia.12 Atrial fibrillation, ventricular fibrillation, and Brugada pattern (ventricular arrhythmia) are the most commonly associated arrhythmias; when such arrhythmias occur, the mortality rate is estimated at 11%.12,15
Inhalation of cannabis and associated respiratory irritants can cause acute or chronic cough, increased mucous production, and shortness of breath.16 Pneumomediastinum can be an acute complication associated with holding ones breath in during inhalation.17 Evidence suggests that long-term cannabis use may lead to large airway inflammation, increased airway resistance, and lung hyperinflation.11 In individuals with underlying pulmonary disease, such as asthma or chronic obstructive pulmonary disease (COPD), this may increase the risk for respiratory infection and acute exacerbations of chronic disease.
Although cannabis is known to contain potential carcinogens, the connection between lung carcinoma and cannabis use remains less clear.14 By comparison, cannabis contains 50% more benzopyrene and 75% more benzanthracene than tobacco.11 Evidence also suggests cannabis is associated with 4 times more deposition of tar than tobacco products, suggesting that an underlying link to carcinoma is possible, although there is no definitive evidence linking cannabis to increased head, neck, or lung cancer.4,11,14
Prolonged Neuropsychiatric Effects
Cannabis use in children has the potential to alter brain development and can be linked to poor educational outcomes, such as increased drop-out rates.11 Use in adolescents is correlated with cognitive impairment and lower IQ scores.11 In adults, use causes memory impairment and difficulty learning new information.18 In some individuals, cannabis increases the risk of developing or worsening of depression, anxiety, and post-traumatic stress disorder.11 Cannabis use is linked with the development of psychosis, particularly among youth who have preexisting genetic vulnerability, and may advance onset of first psychotic episode by 2 to 6 years in such individuals.11,18 Long-term use has been linked with the development of amotivational syndrome and reports of decreased life satisfaction.18
Cannabis Hyperemesis Syndrome
There are no clinically established diagnostic or treatment guidelines for cannabis hyperemesis syndrome (see Case Presentation), but there are definitive patterns in clinical presentation. Patients typically present with intense and unremitting abdominal pain with persistent nausea and vomiting, often with reports of multiple episodes over months to years.19 Clinical history reveals a heavy use of cannabis daily over a prolonged period of time. Often patients report the only effective alleviating factor for associated abdominal pain is the use of hot baths or showers. Generally, symptom presentation occurs in 3 phases: prodromal, acute nausea and diffuse abdominal pain, the intensity of which often causes fear of vomiting; hyperemetic, multiple episodes of vomiting, driving the patient to seek medical care; and recovery, during which normal eating patterns resume.19
|A 32-year-old mother of 3 presents to the emergency department with a 10-day history of persistent nausea with intermittent nonbiliary, nonbloody emesis, and diffuse abdominal pain. She denies alcohol or “illicit” drug use but does admit to smoking cannabis 2 to 3 times a day for the last several years. Her vital signs are within normal limits, her electrocardiogram is normal, and her laboratory tests (complete blood cell count, comprehensive metabolic panel, lipase, and serial troponins) are normal. Computed tomography of the abdomen shows no acute pathology. She has received 2 liters of normal saline, as well as multiple doses of intravenous ondansetron and metoclopramide, without improvement in nausea and continued active emesis.|
Cannabis has dose-dependent biphasic effects. At a low dose, it acts as an antiemetic; at higher doses, it becomes proemetic.19 Clinical priorities lay in achieving cessation of hyperemesis, addressing any secondary issues, such as dehydration, electrolyte disturbance, acute kidney injury, or rhabdomyolysis, and advising the patient about long-term cessation of cannabis use.19
It is unclear why traditional antiemetics are ineffective in addressing nausea and emesis associated with cannabis use. However, it is known that cannabis is active within the dopaminergic pathways of the brain; clinically, dopamine-blocking agents such as intravenous haloperidol (5 mg) often are more effective in treating nausea in these patients.19 Other treatments, including topical capsaicin (applied to the stomach), corticosteroids, benzodiazepines, and tricyclic antidepressants have been studied but none have demonstrated consistently effective symptom relief.19
Potential Drug Interactions, Toxicity, and Overdose
The large volume of chemical compounds within cannabis makes examining potential drug-drug interactions challenging, and knowledge in this area is largely theoretical. Cannabinoids bind at a wide variety of sites to impact gene expression.20 It is presumed that specific chemical components and formulations affect actions and that the duration of exposure may dictate potential drug interactions. The primary metabolism of cannabinoid compounds is via cytochrome P450 (CYP450): THC (CYP2C9/CYP3A4), CBD (CYP2C19/CYP3A4), and cannabinol (CYP2C9/CYP3A4).20
Any prescription drug processed through one or more of these CYP450 pathways, including commonly used medications (eg, NSAIDs, opioids, statins, anticonvulsants, selective serotonin reuptake inhibitors, and antibiotics) has the potential to cause a drug-drug interaction. Generally, data demonstrate that even low doses of alcohol increase plasma levels of THC.20 When cannabis is used in combination with opioid pain medications, there may be increased opioid analgesic effects without correspondingly increased plasma levels.20 Cannabinoids also may work synergistically with gabapentin to improve therapeutic window and effects.20
Adverse effects are more common when cannabis is orally ingested, and symptoms can last up to 12 hours. Naturally occurring cannabinoids act as partial agonists at CB1/CB2 receptors, limiting fatal overdoses.21 However, children have an increased risk for overdose, most commonly through unintentional oral ingestion, and they are significantly more likely than adults to experience severe or life-threatening symptoms including hyperkinesis, respiratory depression, lethargy, coma, and death.22 Duration of symptoms in children can vary from 4 to 48 hours postingestion, with treatment involving supportive care.22
Synthetic cannabinoids act as pure agonists with very high affinity at the CB1 receptor and, thus, their effects are more intense and longer lasting.23 Synthetic formulations are not detectable on routine laboratory screening tests. If potential ingestion is suspected, cannabis toxicity should be included within a differential diagnosis, regardless of a negative toxicology screening. Synthetic compounds have a greater potential for serious neuropsychiatric toxicity, producing hallucinations, delirium, and/or psychosis in up to 66% of individuals.23 Life-threatening toxicity, most characteristically manifesting as severe agitation or seizures, is possible at any age.23
Considerations in Recommending Medical Cannabis
The US Food and Drug Administration (FDA) has approved medical cannabis for 3 clinical syndromes.24 Naturally derived cannabis, labeled as cannabidiol (Epidiolex), is approved for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older. The agent is approved in the United Kingdom for treatment of seizures associated with tuberous sclerosis complex.25 The synthetic cannabinoid dronabinol (Marinol and Syndros) is approved for the management of anorexia with associated weight loss in patients with AIDS and nausea associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.24 Nabilone (Cesamet) is also a synthetic cannabinoid approved for the treatment of nausea associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.24
Potential Off-Label Therapeutic Uses
The use of cannabinoids in the treatment of chronic pain (fibromyalgia, rheumatoid arthritis, central pain in multiple sclerosis, and neuropathic pain) is supported by study evidence, with no serious adverse events related to its use.2,26 There has been clear efficacy established in the improvement of chemotherapy-induced nausea and vomiting with medical cannabis products that are not FDA-approved, particularly with ingestible products vs inhaled products.11,26
The treatment of seizures beyond those associated with Lennox-Gastaut syndrome and Dravet syndrome is perhaps the most discussed applications for cannabis, but data are highly variable, ranging from no improvement to an estimated 50% reduction in symptoms.26 In the treatment of mental health disorders, studies have shown improvement in generalized and social anxiety disorders but no clear benefits in major depression and variability in the efficacy for psychotic disorders.26 No clear benefit has been found in the treatment of acute postoperative or dental pain, and use improves intraocular pressure in those with glaucoma only transiently. 264 The application in Alzheimer disease is purely theoretical, minimal data is available in Parkinson’s disease, and no efficacy has been established in the treatment of Huntington disease (Table).26 No cannabis formulation has yet proven to have greater efficacy than other FDA-approved medications options for these conditions.26
Use in Pregnancy and Breastfeeding
Minimal data exist on the safety and effects of cannabis use in pregnancy. Both the American College of Obstetrics and Gynecology and the American Academy of Pediatrics advise against cannabis use during pregnancy and breastfeeding, citing concern for adverse neurodevelopmental effects.27,28
Some psychoactive components of cannabis likely cross the placental barrier, with fetal plasma concentrations estimated to be 10% to 30% of maternal serum concentrations.29 With the highly lipophilic nature of THC, it is important to counsel patients that fetal exposure may occur for 4 to 6 weeks after maternal cessation.29
Based on the available evidence, complications of use during pregnancy may include higher rates of maternal anemia, up to twice the rate of preterm births, reduced birth weight, increased likelihood of neonatal intensive care unit stays, and learning/attention deficits into childhood.30
Studies suggest that THC accumulates in breast milk. Peak levels occur approximately 4 hours after maternal inhalation and detectable levels persist for at least 6 days after last maternal use.31 Lack of federal regulation in cannabis supply and distribution also raises concern for the potential secondary exposure to pesticides, heavy metals, bacteria, and fungi through cannabis use.32
Research on use of cannabis in the treatment of medical conditions is emerging at a rapid pace. The expanding number of states that have legalized recreational marijuana use is likely to increase the number of patients who present in the primary care setting seeking information on cannabis use for medical conditions. Clinicians will need to remain updated on evolving evidence to provide tailored patient education on the benefits and risks associated with cannabis use.
|Click here for an accompanying article by Dr Kalensky on cannabis use disorder, intoxication,
withdrawal, and other cannabis-related disorders.
Melissa Kalensky, DNP, APRN, FNP-BC, PMHNP-BC, CNE, is an assistant professor at Rush University College of Nursing in Chicago.
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25. Jazz Pharmaceuticals. GW Pharmaceuticals receives approval for EPIDYOLEX® (cannabidiol) from the MHRA for the treatment of seizures associated with tuberous sclerosis complex. Press release. Accessed October 20, 2021. https://investor.jazzpharma.com/news-releases/news-release-details/gw-pharmaceuticals-receives-approval-epidyolexr-cannabidiol-mhra
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This article originally appeared on Clinical Advisor
From the November/December 2021 Issue of Neurology Advisor