Mechanism of action
Tetrahydrocannabinol acts as a partial agonist at cannabinoid receptors CB1 and CB2, which are G-protein coupled receptors distributed throughout the body.
CB1 receptors are highly concentrated in the central nervous system, particularly in the basal ganglia, hippocampus, cerebellum, and cerebral cortex. Activation of CB1 receptors inhibits adenylyl cyclase, reduces calcium influx, and increases potassium conductance, leading to decreased neurotransmitter release (including dopamine, GABA, and glutamate). This mechanism underlies THC's psychoactive effects, antiemetic properties, appetite stimulation, analgesia, and effects on memory and cognition.
CB2 receptors are primarily found in peripheral tissues and immune cells. CB2 activation modulates immune function and may contribute to anti-inflammatory and analgesic effects, though these are less clinically significant than CB1-mediated actions.
The antiemetic effect results from CB1 activation in the dorsal vagal complex and other brainstem nuclei involved in emesis control. Appetite stimulation occurs through hypothalamic CB1 receptor activation and modulation of hunger-related neuropeptides including leptin and ghrelin.
- THC is a partial agonist at CB1 receptors in the CNS and CB2 receptors peripherally
- Approved for chemotherapy-induced nausea refractory to other antiemetics and AIDS-related anorexia
- Major adverse effects: euphoria, impaired short-term memory, tachycardia, orthostatic hypotension
- Cannabinoid hyperemesis syndrome presents as paradoxical cyclic vomiting with compulsive hot bathing in chronic users
- Contraindicated in patients with schizophrenia or psychotic disorders due to risk of exacerbation
- THC is highly lipophilic with prolonged detection in urine (days to weeks) due to adipose accumulation
- Metabolized by CYP2C9, CYP2C19, and CYP3A4 to active 11-hydroxy-THC and inactive THC-COOH
- Adolescent use is associated with increased risk of schizophrenia and impaired neurodevelopment
Indications
Approved indications
- Chemotherapy-induced nausea and vomiting (CINV) refractory to conventional antiemetics
- AIDS-related anorexia and cachexia to stimulate appetite and prevent weight loss
Off-label uses
Various jurisdictions permit medical cannabis containing THC for conditions including chronic pain, spasticity in multiple sclerosis, glaucoma, and epilepsy, though evidence quality varies. Synthetic THC formulations have different schedules: nabilone is Schedule II, while dronabinol capsules are Schedule III controlled substances in the United States. Plant-derived cannabis remains Schedule I federally despite state-level legalization programs.
THC is considered a second-line or adjunctive therapy for CINV, typically reserved for patients who fail to respond adequately to serotonin (5-HT3) antagonists, NK1 antagonists, and corticosteroids.
Pharmacokinetics
Absorption: Oral bioavailability of THC is 10-20% due to extensive first-pass hepatic metabolism. Smoked or vaporized THC has higher bioavailability (18-50%) with rapid onset. Peak plasma concentrations occur 2-4 hours after oral administration and within minutes when inhaled.
Distribution: THC is highly lipophilic with a large volume of distribution (approximately 10 L/kg). It readily crosses the blood-brain barrier and accumulates in adipose tissue. Protein binding is approximately 95-99%.
Metabolism: Hepatic metabolism via CYP2C9, CYP2C19, and CYP3A4 produces 11-hydroxy-THC, an active metabolite with similar or greater potency, which is further metabolized to inactive 11-nor-9-carboxy-THC (THC-COOH). The carboxy metabolite has a long half-life and is used in drug screening.
Elimination: The elimination half-life of THC is 20-30 hours for occasional users but may extend to several days in chronic users due to tissue accumulation. Excretion occurs primarily in feces (65%) and urine (25%) as metabolites. THC-COOH can be detected in urine for days to weeks after last use, depending on frequency and chronicity of use.
Adverse effects
Central nervous system
- Psychoactive effects: Euphoria, dysphoria, anxiety, paranoia, panic attacks
- Cognitive impairment: Impaired short-term memory, decreased concentration, altered time perception
- Sedation and drowsiness
- Dizziness and ataxia
- Hallucinations (rare, dose-dependent)
Cardiovascular
- Tachycardia (dose-dependent increase in heart rate)
- Orthostatic hypotension
- Hypertension (less common)
- Increased myocardial oxygen demand; risk in patients with coronary artery disease
Psychiatric
- Acute psychosis in susceptible individuals
- Exacerbation of schizophrenia and other psychotic disorders
- Dependence and withdrawal with chronic use (irritability, insomnia, decreased appetite, restlessness)
- Amotivational syndrome with chronic heavy use
Other effects
- Dry mouth (xerostomia)
- Conjunctival injection (red eyes)
- Increased appetite (therapeutic in some contexts, adverse in others)
- Impaired motor coordination
- Respiratory effects: Bronchitis, cough with smoked forms
- Cannabinoid hyperemesis syndrome: Paradoxical cyclic vomiting with chronic heavy use, characteristically relieved by hot baths
Serious adverse effects
- Seizures (rare, but documented)
- Psychiatric hospitalization
- Motor vehicle accidents due to impaired driving ability
Contraindications and warnings
Absolute contraindications
- Hypersensitivity to THC, cannabinoids, sesame oil (vehicle in some formulations), or related compounds
- History of schizophrenia or other psychotic disorders (may precipitate or exacerbate psychosis)
Relative contraindications and precautions
- Cardiovascular disease: Use with caution due to tachycardia and potential myocardial oxygen demand increase
- Substance abuse history: Risk of dependence and abuse
- Bipolar disorder, depression, anxiety disorders: May worsen symptoms
- Seizure disorders: Conflicting evidence; may lower seizure threshold in some patients
- Hepatic impairment: Reduced metabolism and clearance
- Elderly patients: Increased sensitivity to CNS effects
Pregnancy and lactation
Pregnancy: Category C (US, where applicable). THC crosses the placenta. Associated with potential neurodevelopmental effects, low birth weight, and preterm birth. Avoid use during pregnancy unless potential benefit justifies risk.
Lactation: THC is excreted in breast milk and may affect infant neurodevelopment. Breastfeeding is not recommended during THC use.
Special populations
Pediatric use is not recommended except in specific circumstances with careful monitoring. Adolescent exposure may impact brain development, particularly in areas governing memory, learning, and impulse control.
Drug interactions
Pharmacodynamic interactions
- CNS depressants (benzodiazepines, opioids, alcohol, sedative-hypnotics): Additive sedation, respiratory depression, and cognitive impairment
- Sympathomimetics and anticholinergic agents: Additive tachycardia and hypertension
- Antihypertensives: Additive hypotension, particularly orthostatic effects
Pharmacokinetic interactions
CYP450 interactions: THC is metabolized by CYP2C9, CYP2C19, and CYP3A4.
- CYP2C9 inhibitors (fluconazole, amiodarone): May increase THC levels
- CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin): Potential increase in THC exposure
- CYP inducers (rifampin, carbamazepine, phenytoin): May decrease THC levels
Smoking cannabis (like tobacco smoking) induces CYP1A2 due to polycyclic aromatic hydrocarbons, leading to decreased levels of CYP1A2 substrates including theophylline. THC may inhibit CYP2C9, potentially increasing levels of substrates including warfarin. Monitor INR closely in patients on warfarin.
Other interactions
- Disulfiram and metronidazole: Some THC formulations contain alcohol; avoid combination
- Immunosuppressants: Theoretical concern due to CB2-mediated immune modulation, though clinical significance is unclear
Clinical pearls
- Biphasic dose response: Low doses may reduce anxiety and have antiemetic effects, while high doses can cause anxiety, paranoia, and paradoxically worsen nausea in susceptible individuals (cannabinoid hyperemesis syndrome).
- Cannabinoid hyperemesis syndrome is a paradoxical condition seen in chronic heavy cannabis users presenting with cyclic vomiting, abdominal pain, and compulsive hot bathing behavior. Treatment is cessation of cannabis use.
- Tolerance develops rapidly to many effects including tachycardia and subjective high, but less so to cognitive impairment. Cross-tolerance occurs between THC and other cannabinoids.
- Drug testing: Standard urine drug screens detect THC-COOH, not active THC. Positive tests can occur weeks after last use in chronic users due to slow release from adipose tissue.
- Psychosis risk: THC use, especially high-potency products and use during adolescence, is associated with increased risk of developing schizophrenia in vulnerable individuals. The risk is dose-dependent and higher with earlier age of initiation.
- Driving impairment: THC significantly impairs reaction time, motor coordination, and divided attention. Effects on driving ability can persist 3-4 hours after inhalation and longer after oral ingestion.
- Synthetic cannabinoids (K2, Spice) are structurally distinct from THC, often act as full CB1 agonists, and carry higher risk of severe toxicity including seizures, psychosis, and death.
- For CINV, cannabinoids are generally less effective than modern antiemetic regimens (5-HT3 + NK1 antagonists + dexamethasone) but may help in refractory cases.
- Legal status varies widely: THC remains a federally controlled substance (Schedule I for plant-derived, Schedule III for synthetic dronabinol) in the US despite state-level medical and recreational legalization.
Practice questions
1. A 28-year-old man with AIDS-related wasting syndrome is started on dronabinol to stimulate appetite. Three days later, he presents to the emergency department reporting intense anxiety, paranoia, and feeling that time is moving very slowly. His heart rate is 118 bpm and blood pressure is 108/65 mmHg. Physical examination shows conjunctival injection. Which receptor is primarily responsible for this patient's symptoms?
2. A 35-year-old chronic cannabis user presents with severe cyclic vomiting, abdominal pain, and admits to taking multiple hot showers daily for relief. He has had three similar episodes over the past year, each lasting 2-3 days. Laboratory studies and abdominal imaging are unremarkable. Which of the following is the most appropriate long-term management?
3. A 42-year-old woman receiving chemotherapy for breast cancer has refractory nausea despite treatment with ondansetron, aprepitant, and dexamethasone. Her oncologist considers adding dronabinol. Which condition in her past medical history represents an absolute contraindication to this medication?
Frequently asked questions
How does tetrahydrocannabinol (THC) work?
THC works as a partial agonist at CB1 and CB2 cannabinoid receptors, which are G-protein coupled receptors. CB1 receptors in the brain mediate psychoactive effects, appetite stimulation, and antiemetic actions by inhibiting neurotransmitter release. CB2 receptors in peripheral tissues and immune cells contribute to anti-inflammatory effects. The antiemetic action specifically results from CB1 activation in brainstem emesis centers, while appetite stimulation occurs through hypothalamic receptor activation.
What are the side effects of THC?
Common side effects include euphoria, impaired short-term memory, altered time perception, anxiety, tachycardia, and orthostatic hypotension. CNS effects include drowsiness, dizziness, and impaired motor coordination. Dry mouth and red eyes are frequent. Serious adverse effects include acute psychosis in susceptible individuals, exacerbation of schizophrenia, and cannabinoid hyperemesis syndrome with chronic heavy use. Cardiovascular effects like tachycardia can increase myocardial oxygen demand, posing risk in patients with heart disease.
Is THC a controlled substance?
Yes, THC is a controlled substance in the United States. Plant-derived cannabis containing THC is classified as Schedule I federally, indicating high abuse potential and no accepted medical use according to federal law. However, synthetic THC formulations like dronabinol are Schedule III, recognizing accepted medical use with moderate dependence potential. State laws vary widely, with many states permitting medical or recreational cannabis despite federal prohibition. Legal status differs internationally.
What is cannabinoid hyperemesis syndrome?
Cannabinoid hyperemesis syndrome is a paradoxical condition occurring in chronic heavy cannabis users characterized by cyclic episodes of severe nausea and vomiting, abdominal pain, and compulsive hot bathing or showering for symptom relief. Despite THC's antiemetic properties, chronic use can lead to this syndrome. The pathophysiology is not fully understood but may involve CB1 receptor desensitization or effects on hypothalamic thermoregulation. Treatment requires complete cessation of cannabis use, with symptoms typically resolving within days to weeks.
THC vs CBD — what is the difference?
THC (tetrahydrocannabinol) is the primary psychoactive cannabinoid that produces euphoria, altered perception, and cognitive impairment through CB1 receptor agonism. CBD (cannabidiol) is non-psychoactive and does not produce a high. While THC is a CB1/CB2 agonist, CBD has weak affinity for these receptors and may actually antagonize some THC effects. THC is approved for nausea and appetite stimulation, while CBD is approved for certain epilepsy syndromes. CBD lacks the abuse potential and psychiatric risks associated with THC.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: A04AD10
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.