Cannabis (Marijuana) Overview

Mechanism of Action

Marijuana comprises over 400 compounds, such as flavonoids, terpenoids, and cannabinoids. Among these, cannabinoids are the active ingredients that exhibit clinical effects. Cannabinoids are a class of biological compounds that bind to cannabinoid receptors. These compounds are most frequently sourced from plants in the genus Cannabis, including Cannabis sativa, Cannabis indica, and Cannabis ruderalis. The earliest known use of cannabinoids was 5000 years ago in modern Romania, whereas the documentation of the earliest medical use dates back to around 400 AD.[13][14] However, the formal extraction, isolation, and structural elucidation of cannabinoids occurred relatively recently, in the late 19th and early 20th centuries.[13] Since then, numerous advancements have been made in further isolating naturally occurring cannabinoids, synthesizing artificial equivalents, and discovering the endogenous endocannabinoid system in mammals, reptiles, fish, and birds.[15][16] Cannabinoids have 3 forms, including:

• Phytocannabinoids: Derived naturally from flora
• Endocannabinoids: Produced endogenously
• Synthetic cannabinoids: Created artificially

Of all known cannabinoids that have been isolated and identified, the most notable are the phytocannabinoids THC and CBD, the former being responsible for psychoactive effects sought by recreational users and the therapeutic effects of the drug. Throughout their storied history, cannabinoids have been renowned for their psychotropic and physiological effects. Cannabinoids are frequently the targets of pharmaceutical innovation, with most being either structurally related to or mimicking the ligand-receptor activity of THC and CBD. 

Cytochrome P450 enzymes metabolize cannabinoids in the liver. Although ongoing research continues to elucidate the mechanism of action, it is established that the brain and peripheral tissues harbor widespread cannabinoid receptors forming the endocannabinoid system. This system regulates various bodily functions, including metabolism, appetite, blood pressure, glycemic control, immune response, and sense of reward. Although cannabinoid receptors are located throughout the body, the most prominent effects arise from the interactions in the central nervous system (CNS). Due to their high lipid solubility, cannabinoid receptors are widely distributed throughout the body, producing diverse effects depending on receptor activation and dose.[17]

The primary action of cannabinoids occurs through G-protein–coupled receptors, specifically CB1 and CB2. CB1 receptors located in the CNS modulate the release of several neurotransmitters, including norepinephrine, dopamine, serotonin, and gamma-aminobutyric acid. Conversely, CB2 receptors are located in the immune system and modulate immune and inflammatory responses. Notably, CB2 expression becomes highly inducible in the microglia in the CNS following inflammation.[18][19]

Pharmacokinetics

Absorption: Inhaling marijuana rapidly elevates THC concentration in the bloodstream, reaching its peak within 3 to 10 minutes. Conversely, oral ingestion leads to peak levels within 1 to 2 hours. 

Distribution: The lipophilic THC disseminates to adipose tissue, liver, lungs, and spleen. Metabolism results in the generation of psychoactive 11-hydroxy-9-tetrahydrocannabinol and the formation of inactive tetrahydrocannabinol (THC-COOH). After absorption into the bloodstream, THC rapidly penetrates fatty and highly vascularized tissues, including the brain and muscles. This initial distribution is followed by a slower redistribution of the compound from deep fat deposits back into the bloodstream.[20][21]

Metabolism: The cytochrome P450 enzymes, found in liver cells, facilitate microsomal hydroxylation and oxidation, which metabolize THC. Plasma clearance rates vary depending on factors such as gender and usage history. Liver metabolism significantly reduces the oral bioavailability of THC.[22]

Elimination: Most of the metabolized cannabis is excreted through feces (65%) and urine (20%). Glucuronic acid conjugation enhances the solubility of metabolites. THC-COOH is commonly found in urine, whereas 11-hydroxy-9-tetrahydrocannabinol is usually dominant in feces. The detection times of THC vary among users.[23]

Administration

Federally, marijuana (cannabis) remains Schedule I under the Controlled Substances Act. Although many states allow medical or adult-use sales, many consumer CBD products are not FDA-approved, and the FDA has taken the position that CBD and THC are generally not lawful as dietary supplements. However, enforcement and state rules vary. Marijuana is being administered in various ways, including orally, sublingually, or topically. Consumer cannabis products are sold in state-regulated dispensaries (where legal) and via unregulated markets. Formulations include flower for smoking or vaping, edibles, tinctures, and beverages.

Typically, cannabis is smoked, offering the advantage of rapid onset and easy titration as it swiftly reaches the brain and circulatory system. However, the approval of smoked cannabis for medical use has faced challenges for various reasons, with a significant concern being the variable mixture of THC, other cannabinoids, carcinogens, and other toxic substances introduced into the lungs. Topical cannabinoid preparations, particularly creams and ointments, have been evaluated for localized pain conditions such as arthritis, but current evidence is limited and mixed, precluding definitive conclusions regarding efficacy. Variability in product composition and study methodology further complicates the interpretation of available data.

Nonoral delivery methods, including suppositories, lozenges, sublingual tablets, and transdermal formulations, have been explored in clinical and experimental settings. However, their use has been limited by significant variability in cannabinoid content, insufficient pharmacokinetic and pharmacodynamic data, and the absence of standardized dosing, leading to unpredictable clinical effects.[24] When ingested orally, the pharmacokinetics of marijuana vary greatly. The onset is delayed (approximately 30 to 90 minutes), with peak effects commonly occurring around 2 to 3 hours (sometimes longer, depending on the product or food), and elimination is prolonged and highly variable due to redistribution into fat stores.[25]

Retail CBD products often provide 10 to 50 mg per serving, but dosing is not standardized, and the labeled content and quality may vary. Clinically studied prescription CBD uses weight-based dosing. In jurisdictions where cannabis products are regulated, oral THC formulations are typically standardized in unit doses of 5 to 10 mg per serving. Lower initial doses (2.5-5 mg) are commonly advised for individuals without prior THC exposure to minimize adverse psychoactive effects. Doses exceeding 10 to 15 mg per serving are generally reserved for individuals with established tolerance and are associated with a higher likelihood of dose-dependent adverse effects.[26]

Available FDA-Approved Dosage Forms

Depending on the cannabinoid, the route of administration varies. Medical cannabinoids are generally administered orally as a capsule or liquid suspension:

• CBD (Epidiolex): Available as an oral solution at 100 mg/mL, taken twice daily, starting at 2.5 mg/kg/d and titrated based on clinical response and tolerability.
• Dronabinol (Marinol, Syndros): Available as a capsule in 2.5, 5, and 10 mg strengths, as well as an oral solution in a 5 mg/mL formulation. The medication is generally taken twice daily, 1 hour before meals, with titration from the initial dose performed gradually based on tolerability and response.
• Nabilone (Cesamet): Available as a 1 mg capsule and may be taken 2 to 3 times daily, depending on the clinician and patient preference.

Adult Dose

The recommended doses for FDA-approved marijuana analogs (CBD, dronabinol, and nabilone) are as follows:

Cannabidiol: 

• Lennox-Gastaut syndrome or Dravet syndrome
  • Starting dose: 2.5 mg/kg orally twice daily (5 mg/kg/d)
  • Maintenance dose: 5 mg/kg twice daily (10 mg/kg/d)
  • Maximum dose: 10 mg/kg twice daily (20 mg/kg/d)

• Tuberous sclerosis complex
  • Starting dose: 2.5 mg/kg orally twice daily (5 mg/kg/d)
  • Maintenance dose: 12.5 mg/kg twice daily (25 mg/kg/d)

Dronabinol: 

• Anorexia is associated with weight loss in patients diagnosed with AIDS
  • Starting dose: 2.5 mg dronabinol capsules orally twice daily, 1 hour before lunch and dinner
  • Maintenance dose: Increased gradually to 2.5 mg before lunch and 5 mg before dinner, as tolerated
  • Maximum dose: 10 mg twice daily

• Nausea and vomiting associated with cancer chemotherapy
  • Starting dose: 5 mg/m² dronabinol orally, 1 to 3 hours before chemotherapy, continued every 2 to 4 hours after chemotherapy daily for 4 to 6 doses
  • Maintenance dose: Modified according to the response, increasing or decreasing in 2.5 mg/m² increments
  • Maximum dose: Up to 15 mg/m² per dose, 4 to 6 times daily

Nabilone: 

• Refractory chemotherapy-induced nausea and vomiting
  • Starting dose: 1 mg or 2 mg,  twice daily, or 1 to 3 hours before chemotherapy. Doses should be low initially and adjusted as required to minimize adverse effects.
  • Maintenance dose: Administered 2 or 3 times daily throughout each chemotherapy cycle.
  • Maximum daily dose: 6 mg, which should be divided into 3 equal doses taken throughout the day

Specific Patient Populations

Hepatic impairment: No dose adjustments are necessary for CBD in patients with mild hepatic impairment. However, reduction is required for individuals with moderate-to-severe hepatic impairment.[27] CBD should be discontinued if symptoms of jaundice occur alongside alanine aminotransferase elevations or if alanine aminotransferase levels are 5 times the upper limit of normal.[28] Nabilone product labeling does not specify any dosage adjustments; this medication should be administered cautiously to patients with hepatic impairment. Similarly, the manufacturer's labeling does not indicate that any dosage adjustments are necessary for dronabinol.

Renal impairment: The manufacturer's labeling for nabilone, CBD, or dronabinol does not specify any dosage adjustments for patients with renal impairment.

Pregnancy considerations: The use of CBD and dronabinol is not recommended during pregnancy as they can cause fetal harm. Cannabinoid use during pregnancy is unsafe and associated with adverse effects on the fetus, including small-for-gestational-age infants, preterm birth, and possible neurodevelopmental consequences.[29] The American College of Obstetricians and Gynecologists states that cannabinoids primarily affect the CNS through CB1. These receptors are formed in the fetal brain by 14 weeks of gestation and increase with age, indicating a neurodevelopmental role. Animal studies have demonstrated that exposure to external cannabinoids during pregnancy can disrupt fetal brain development, leading to potential cognitive impairment. Human studies have linked prenatal marijuana exposure to attention, behavior, and visual-motor coordination deficits and a higher likelihood of adolescent marijuana use. 

Although structural congenital disabilities are not consistently associated with marijuana exposure, some studies have reported a possible increased risk of anencephaly with first-trimester use, potentially confounded by folic acid deficiency. Evidence regarding perinatal mortality is mixed; some studies show no significant differences, whereas others indicate a slight stillbirth risk, often complicated by tobacco use. Frequent marijuana use in the first and second trimesters has been associated with lower birth weight, shorter crown-heel length, and smaller head circumference. Additionally, weekly or more frequent use may also increase the risk of preterm birth, especially with tobacco. Due to potential fetal neurodevelopment and perinatal outcome risks, the American College of Obstetricians and Gynecologists advises against marijuana use during pregnancy and recommends routine, nonjudgmental screening and cessation counseling.[30] Pregnant women should be advised to avoid the use of CBD, dronabinol, and nabilone. 

Breastfeeding considerations: CBD, a component of cannabis, has been detected in breastmilk. However, data on its use as an antiepileptic during lactation are lacking. Due to the absence of safety data, an alternate drug is preferred, particularly for newborns or preterm infants. Dronabinol, a synthetic form of Δ9-THC, has also been found in breastmilk. Although its presence does not necessitate stopping breastfeeding, an alternate antiemetic is recommended due to limited safety data during lactation. The Lactation and Cannabis Study showed that Δ-9-THC peaks in milk a few hours after use and accumulates with repeated exposure. Cannabinoid concentrations in milk vary among individuals and correlate with the frequency of use. These findings highlight the need for cautious counseling about cannabis use during breastfeeding.[31][32]

The psychoactive element of cannabis, THC, is present in breast milk in insignificant amounts. Research indicates that THC can be detected in milk for periods ranging from 6 days to over 6 weeks. Concerns arise regarding potential impacts on neurological development, neurotransmitters, and endocannabinoid-related functions. The research observed reduced levels of secretory immunoglobulin A in the breast milk of mothers who use cannabis. A study suggested that regular cannabis use may affect infants' motor development but not their intellectual progress. Guidelines suggest avoiding cannabis while nursing due to potential developmental effects from breast milk exposure. Paternal cannabis use might raise the risk of sudden infant death syndrome.[33]

Pediatric patients: The use of nabilone and dronabinol should be avoided.[34] The American Academy of Pediatrics opposes the use of medical marijuana outside the regulatory framework of the FDA. However, the American Academy of Pediatrics recognizes that cannabinoid-based therapies may be considered for children with severe or life-limiting conditions when standard treatments have failed.[35] Notably, the prevalence of cannabis use disorder was 10.7% among adolescents and 6.4% among young adults within 1 year. Moreover, this discrepancy persisted, with rates of 20.1% for adolescents and 10.9% for young adults when considering a period extending beyond 36 months. This phenomenon aligns harmoniously with the established trajectory, indicating a swifter transition to substance use disorders (SUDs) when drug initiation occurs at an earlier age. Although the American Academy of Pediatrics advocates SUD screening for adolescents, the US Preventive Services Task Force emphasizes screening for SUDs exclusively in adults.[36]

Older patients: Research findings indicate a significant increase in the frequency of emergency department visits associated with cannabis use among individuals aged 65 or older. The comprehensive rate surged from 20.7 per 100,000 emergency department visits in 2005 to 395.0 per 100,000 in 2019. Incorporating discussions about cannabis use and providing valuable advice on its safe use should become a standard component of health care for older adults.[37] Older adults may be more sensitive to adverse effects such as postural hypotension and neuropsychiatric symptoms. These patients should initially take a lower dose of nabilone, dronabinol, and CBD.

Adverse Effects

The most commonly reported adverse effects of cannabis, particularly THC-containing products, include dizziness, dry mouth, impaired attention and coordination, euphoria or dysphoria, anxiety, confusion, disorientation, sedation, and tachycardia. Respiratory symptoms, such as cough or wheeze, are more strongly associated with inhalational exposure.[38][39][40][41] Acute anxiety reactions, including panic symptoms, are a common reason for emergency evaluation after cannabis exposure, particularly with high-THC products.[42] Marijuana use has been associated with cases of acute reversible psychotic reactions in adolescents. Furthermore, cannabis elevates the risk of psychotic disorders and worsens or causes relapses of symptoms in individuals with preexisting psychotic disorders.[43] Results from certain studies suggest an elevated risk of lung cancer is associated with the inhalation of marijuana, along with a connection between inhalational marijuana use and spontaneous pneumothorax. In addition, inhaled marijuana is linked to bullous emphysema and complications related to chronic obstructive pulmonary disease, including increased wheezing, cough, and phlegm production.[44]

Prenatal cannabis use has been associated with increased odds of adverse neonatal outcomes, including preterm birth and small-for-gestational-age infants. Marijuana use is also associated with impaired spermatogenesis.[45] Long-term marijuana use has also been associated with periodontal disease and more frequent pain crises in sickle cell patients, but data remain limited and heterogeneous.[46] Epidemiologic studies estimate that approximately 22% to 30% of individuals who use cannabis meet criteria for cannabis use disorder, with a higher risk among those who initiate use in adolescence and those who use frequently.[47] Furthermore, adolescents who used marijuana were significantly less likely than their peers to complete high school or attain a degree. However, these associations are subject to confounding factors, including socioeconomic status, co-occurring substance use, and mental health conditions. Marijuana may also worsen verbal memory, depression, and anxiety disorders.[48] Chronic use has been well-documented as a cause of cannabinoid hyperemesis syndrome, initially described in Australia by Allen et al in 2004. This syndrome is characterized by recurrent episodes of nausea and vomiting that are alleviated by hot showers.[49]

Withdrawal

Complications have been associated with the abrupt cessation of marijuana following chronic use. Cannabis withdrawal typically necessitates supportive care, and symptoms may include irritability, poor sleep, poor appetite, and restlessness.[50][51] As a combination of CBD with alcohol increases the potential for sedation, lethargy, and CNS depression, the combination should be avoided.[52]

Drug-Drug Interactions

Potent inducers of CYP3A4 and CYP2C19 enzymes, such as rifampin, can reduce CBD and its metabolite 7-OH-CBD levels by approximately 32% and 63%, respectively, potentially affecting CBD's effectiveness.[53] CBD inhibits CYP1A2, affecting the metabolism of substances such as caffeine, theophylline, and tizanidine.[54] CBD shows potential interactions with substrates of CYP2B6, such as bupropion and efavirenz; UGT1A9, such as diflunisal, propofol, and fenofibrate; UGT2B7, such as gemfibrozil, lamotrigine, morphine, and lorazepam; CYP2C8; and CYP2C9. Plasma concentrations of CYP2C19 substrates, such as diazepam, can increase when coadministered with CBD, necessitating a dosage reduction. The concurrent administration of CBD and valproate increases the risk of hepatocellular enzyme elevation, which may require treatment discontinuation. Clobazam's active metabolite levels elevate 3-fold in the presence of CBD, impacting dosing considerations. Because CBD increases stiripentol levels, careful monitoring for associated adverse effects is recommended.[55][56] CBD increases the concentration of P-glycoprotein substrates, such as everolimus, necessitating careful dose adjustments.[57]

When dronabinol is taken concomitantly with drugs that have comparable cardiovascular effects, such as hypotension, hypertension, and tachycardia, the potential for additive cardiac effects exists, including syncope. Dronabinol's metabolism is primarily mediated by CYP2C9 and CYP3A4. Inhibitors of these enzymes can increase dronabinol levels, whereas inducers may decrease them. These interactions can lead to increased adverse reactions or reduced dronabinol efficacy. Monitoring is advised when combining dronabinol with CYP2C9 inhibitors, such as amiodarone and fluconazole, and CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin, or grapefruit juice, to detect potential adverse reactions related to dronabinol. Dronabinol strongly binds to plasma proteins, potentially impacting the free fraction of coadministered protein-bound drugs. Although not confirmed in vivo, cautious monitoring is recommended when initiating or increasing the dose of dronabinol or when using highly protein-bound drugs such as cyclosporine and amphotericin B.

Concurrent use of amphetamines, cocaine, and other sympathomimetic drugs may lead to additive hypertension, tachycardia, and potential cardiotoxicity. The concurrent usage of amitriptyline, amoxapine, desipramine, and other tricyclic antidepressants with cannabis may induce additive tachycardia, hypertension, and drowsiness. Concurrent use of barbiturates, benzodiazepines, lithium, buspirone, antihistamines, muscle relaxants, and other CNS depressants may result in significant CNS depression. Marijuana use in combination with disulfiram has been associated with a reversible hypomanic reaction. In addition, hypomania has been reported following the simultaneous use of marijuana with fluoxetine.[58] As the simultaneous use of opioids and marijuana can lead to potentiation, clinicians should be cautious when prescribing opioids to individuals who are using medical cannabis.[59]

Contraindications

Contraindications

Limited standardized information exists regarding contraindications for non–FDA-approved medical cannabis products because composition and dosing vary widely. In contrast, contraindications for FDA-approved cannabinoid pharmaceuticals are clearly defined in product labeling. Dronabinol is contraindicated in patients with a prior hypersensitivity reaction to the active ingredient. Dronabinol capsules (Marinol) are contraindicated in individuals with hypersensitivity to sesame oil, whereas dronabinol oral solution (Syndros) is contraindicated in those with hypersensitivity to alcohol, which is present as an excipient. CBD (Epidiolex) and nabilone (Cesamet) are contraindicated in patients with prior hypersensitivity to the drug or, in the case of nabilone, to cannabinoids.[60]

Warnings and Precautions

Cardiovascular and psychiatric risk: Cannabis and cannabinoid products should be used cautiously in patients with clinically significant cardiovascular disease, such as coronary disease, arrhythmias, or unstable hemodynamics, and in those with a history of psychotic disorders or severe psychiatric illness, as THC-containing products may exacerbate psychiatric symptoms and can alter heart rate and blood pressure. Acute marijuana smoking has been associated with a transient increase in the risk of myocardial infarction during the first hour after use, based on findings from observational trigger studies.[61][62]

Allergy and contamination: Cannabis allergy has been documented, including cross-reactivity with certain plant foods in sensitized individuals; both direct and passive exposure have been reported as triggers in findings from case reports.[63] Patients who are immunocompromised may be at risk from contaminated inhaled cannabis. Invasive fungal infections, including aspergillosis, have been reported in association with cannabis use, and contamination has been documented.[64][65] 

Hepatic effects (cannabidiol): Prescription CBD can cause dose-related elevations in transaminases. Concomitant use of valproate along with elevated baseline liver enzymes increases this risk, necessitating monitoring and possible dose adjustment or discontinuation as per the labeling.

Seizure risk (dronabinol): Seizures and seizure-like activity have been reported with dronabinol. Patients should discontinue the medication and seek medical attention if a seizure occurs, and caution is advised in those with a prior seizure history. Individuals with a history of substance use disorder may be at increased risk of misuse.[66]

Cannabidiol

• Hepatic injury: CBD can increase liver transaminases, especially at higher doses or when used with valproate. Regular monitoring of liver enzymes and bilirubin is advised.
• Sedation: Patients should be monitored for signs of drowsiness. Caution is advised when engaging in activities that require alertness, such as driving or operating machinery.
• Suicidal behavior and ideation: Patients should be evaluated for new or worsening suicidal thoughts or behaviors.
• Withdrawal of antiepileptic drugs: CBD dosage should be reduced gradually to lower the risk of increased seizure activity and status epilepticus.

Dronabinol 

• Neuropsychiatric adverse reactions: Dronabinol may cause psychiatric and cognitive effects, impairing mental or physical abilities. Therefore, its use should be avoided in patients with a history of psychiatric disorders.
• Hemodynamic instability: Patients with cardiac conditions may experience hypotension, hypertension, syncope, or tachycardia. Clinicians should avoid using drugs with similar effects and monitor patients for changes in blood pressure and heart rate after initiating dronabinol or increasing the dosage.
• Strong CYP3A4 and CYP2C9 inhibitors: Certain azole antifungals and protease inhibitors, such as ritonavir, may increase dronabinol levels. Caution and monitoring are recommended for these interactions.[53]
• Paradoxical nausea, vomiting, or abdominal pain: If these symptoms worsen during treatment, dose reduction or discontinuation of dronabinol should be considered.

Nabilone 

• Psychiatric adverse effects: The effects of nabilone are unpredictable after oral administration, with psychiatric reactions potentially lasting 48 to 72 hours after treatment is discontinued.
• Central nervous system effects: Nabilone may affect the CNS, causing dizziness, drowsiness, euphoria, ataxia, anxiety, disorientation, depression, hallucinations, and psychosis.
• Cardiovascular effects: Nabilone can cause tachycardia and orthostatic hypotension.
• Precautions for hazardous activities: Patients taking nabilone should be cautioned against driving, operating machinery, or engaging in other hazardous activities.

Monitoring

Monitoring of patients receiving cannabinoids should be guided by clinical presentation. Clinical monitoring should include assessment for tachycardia, orthostatic hypotension, and behavioral changes.[67] Patients with a history of cannabis use disorder warrant close observation due to the high risk of relapse.[68] Coadministration with CYP inhibitors may lead to toxicity, and concurrent administration with CYP inducers may reduce efficacy, as discussed above. Clinicians should use the prescription drug monitoring program when substance use disorder is suspected.[69] Evaluating alanine transaminase, aspartate transaminase, and total bilirubin levels before initiating treatment, during dose changes, or when changing hepatotoxic medications is crucial.[28] 

Clinicians can typically detect marijuana use for approximately 1 to 3 days after exposure in infrequent users, though detection may extend up to 5 days in some cases. In chronic or heavy users, detection may persist for 10 to 30 days or longer, reflecting accumulation of THC in adipose tissue and slow redistribution. Detection times vary based on multiple factors, including frequency and route of use, dose, individual metabolism, body fat composition, and volume of distribution. Detection also depends on the specific analyte measured, as most routine tests identify the inactive metabolite 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) rather than parent THC. Although immunoassay screening tests may yield presumptive positives, confirmatory testing with more specific methods, such as gas or liquid chromatography-mass spectrometry, can distinguish true positives from rare false positives.

Toxicity

Clinical Features

Data on cannabinoid toxicities remain limited in the literature. The lethal dose has not been established, and studies on dog and monkey models have shown that doses up to 3000 mg/kg do not lead to fatality.[70] Findings from a recent study suggest that electroencephalography can detect acute cannabis consumption. Electroencephalography displays alterations in θ-band oscillatory activity (4-7 Hz); it is not a validated clinical tool for diagnosing cannabis intoxication.[71] Cannabinoid overdose has no known antidote; only supportive therapy is available to help manage the symptoms. Chronic, prolonged, high-volume use of cannabinoids can lead to neuropsychiatric effects, with intelligence quotient and cognition being most impacted.[72] The estimated toxic dose for dronabinol is 30 mg/kg. Illicit synthetic cannabinoids are known to lead to toxicity at much lower doses.

Overdose with dronabinol or nabilone can lead to a range of symptoms affecting the CNS, cardiovascular system, gastrointestinal tract, and autonomic functions. These symptoms may include drowsiness, euphoria, heightened sensory perception, altered time awareness, memory impairment, mood alteration, depersonalization, lethargy, slurred speech, and impaired motor coordination. Autonomic features include dry mouth, reddened conjunctiva, urinary retention, and reduced bowel motility. Tachycardia and postural hypotension are also observed. Individuals with a history of anxiety or nervousness may experience panic reactions, and seizures can occur in patients with known seizure disorders. Psychotic features such as hallucinations, delusions, or paranoia are observed at very high doses. Marijuana toxicity may manifest with clinical features such as tachycardia, postural hypotension, tachypnea, nystagmus, ataxia, euphoria or dysphoria, conjunctival injection, hypotonia, seizures associated with the coingestion of cocaine, impaired cognition, respiratory depression, and coma.[73]

Diagnosis

Following guidance from the Substance Abuse and Mental Health Services Administration, the recommended detection threshold is 50 ng/mL.[23][74]

Management

An anecdote for overdose is not available; only supportive therapy to help manage the symptoms. Discontinuation of the drug is essential. The management of conditions related to marijuana toxicity involves the following actions:

• Maintain airway, breathing, and circulation. In patients with respiratory depression or significantly altered mental status, airway protection and ventilatory support are essential. Hypotension should be managed with intravenous fluids and, if necessary, vasopressors or inotropes. Activated charcoal is preferred for gastrointestinal tract decontamination and may be administered in repeated doses to enhance elimination. Gastric emptying should only be considered if the airway is protected. 
• Administer benzodiazepines, such as lorazepam or midazolam, for seizures.
• Treat cannabis hyperemesis syndrome with intravenous fluids and antiemetics, such as ondansetron, and consider haloperidol in refractory cases.[75]
• Consult a psychiatrist following stabilization for patients with cannabis use disorder. Reassurance and verbal support may be sufficient for managing mild-to-moderate psychiatric symptoms. In more severe cases, antipsychotic medications may be used with caution.[76]

Enhancing Healthcare Team Outcomes

A substantial body of literature exists on marijuana and its potential health benefits. However, this evidence consists of observational studies, small trials, or anecdotal reports, depending on the indication. Due to the absence of clinical trials and a lack of a universal formula for marijuana, significant controversies persist regarding the clinical benefits of marijuana. All clinicians, including nurse practitioners and pharmacists, should educate patients that marijuana may not be a panacea for all medical disorders. Marijuana has demonstrated appetite-stimulating and antiemetic effects in specific clinical settings. Until data from randomized clinical trials are available, the recommendation of marijuana use should be approached cautiously, as more evidence seems to indicate that this product may not be entirely safe for long-term consumption.[77][78][79] 

Opinions and values regarding the use of cannabinoids in medicine vary widely. Some individuals see cannabinoids as having significant potential to reduce pain, whereas others believe cannabis-derived compounds have no place in modern clinical practice. Regardless of personal values, clinicians should recognize the existence and use of cannabinoids among their patient population when deciding treatment options. Patients should feel comfortable discussing their cannabinoid use, including the type, dose, and CBD-to-THC ratio.[80] 

Dronabinol and nabilone are both legal and are available by prescription throughout all 50 states of the United States.[81] The legal status of formulas containing only CBD is more variable. Laws concerning the restriction of products containing THC vary widely across states.[82] If a patient informs the medical staff about using a cannabinoid, this information should be communicated to the primary clinician overseeing their care.

The effective use of cannabinoids for emetic control is best achieved through an interprofessional healthcare team approach. Dronabinol and nabilone are most commonly prescribed by oncologists, palliative care specialists, and infectious disease specialists. Oncologists frequently prescribe cannabinoids alongside chemotherapy regimens.[83] Palliative care and infectious disease specialists often prescribe cannabinoids to provide comfort in the setting of nausea or to benefit from their orexigenic components. In states where medical marijuana is legal, a team of healthcare professionals, including clinicians, nurse practitioners, and physician assistants, can authorize the use of CBD- and THC-containing formulations for patients with various conditions, including nausea and vomiting. Pharmacists play a crucial role in verifying dosing, checking for potential drug interactions, and providing additional counseling to patients as needed.[84]

Findings from a 2019 survey of 178 community-based pharmacists and medical marijuana dispensing pharmacists revealed that both pharmacist groups highly valued opioid use information within the Connecticut Prescription Monitoring and Reporting System. Although approximately 90% of healthcare professionals in both groups checked opioid use, 81.2% of medical marijuana dispensing pharmacists and 38.4% of community-based pharmacists monitored medical marijuana use. Medical marijuana dispensing pharmacists highlighted the need for marijuana-related data for effective counseling. The study underscores the potential benefits of integrating marijuana data into prescription drug monitoring programs, enhancing pharmacist recommendations by addressing drug interactions and workflow issues.[85] The entire clinical picture must be considered when deciding whether to initiate cannabinoid therapy. Triage nurses and clinicians in the emergency department should assess and maintain airway, breathing, and circulation in acute intoxication. Psychiatrists should evaluate for signs of psychosis and administer proper treatment. Critical care clinicians should care for the patient in the intensive care unit. Additionally, clinicians should refer patients with cannabis dependency to social workers. Clinicians, pharmacists, specialists, nurses, and other healthcare professionals are involved in patient care, and an interprofessional approach helps minimize the risk associated with the use of marijuana and its analogs.