Trazodone and Cannabis Interaction Profile: What Patients and Clinicians Need to Know

Does the label say anything about cannabis?

The current US label for trazodone hydrochloride tablets covers one indication, major depressive disorder in adults [1]. Sleep is not an approved use and the label gives no insomnia dose [1]. Its drug interaction table has an entry for CNS depressants: patients should be counseled that trazodone may enhance the response to alcohol, barbiturates and other CNS depressants [1]. Cannabis is not among the drugs named in that table, which also lists serotonergic drugs and QT-prolonging drugs [1].

Is there any human data on the pair?

One case series exists. It described three young adults with cannabis use disorder treated with prolonged-release trazodone 150 mg or 300 mg daily during COVID-19 lockdown [3]. Side effects were recorded as patients reported them, no significant side effects emerged, and the authors called for further study of trazodone in cannabis use disorder [3]. The series looked at craving and tolerability, not at an interaction, and with three people it cannot show whether the combination is safe [3].

Can CBD raise trazodone levels?

Trazodone is metabolized primarily by CYP3A4. In human liver microsome and expressed-enzyme experiments, only CYP3A4 produced its active metabolite mCPP [6], and the label describes trazodone as a CYP3A4 substrate [1]. CBD is metabolized in part by CYP2C19 and CYP3A4 [4]. A systematic review of the enzyme studies on THC, CBD and cannabinol concluded that inhibition and induction of major CYP isoforms generally reflect a low risk of clinically significant drug interactions with most use, but that specific human data are lacking [4].

What a strong CYP3A4 inhibitor does to trazodone has been measured. In a blinded four-way crossover study of 10 healthy volunteers, 50 mg of trazodone given with low-dose ritonavir cut oral clearance from 155 to 75 mL/min, extended half-life from 6.7 to 14.9 hours, and raised peak levels from 842 to 1,125 ng/mL [5]. Sedation, fatigue and performance impairment increased, though the difference was significant only for the digit-symbol substitution test; three volunteers had nausea, dizziness or hypotension and one of them fainted [5]. The label says to consider a lower trazodone dose based on tolerability with a strong CYP3A4 inhibitor [1].

Sedation and coordination

Trazodone is sedating on its own. In the label's controlled outpatient studies (157 on trazodone, 158 on placebo), drowsiness occurred in 41% vs 20%, dizziness or lightheadedness in 28% vs 15%, and blurred vision in 15% vs 4% [1]. The label says trazodone can impair judgment, thinking and motor skills and advises caution when operating machinery [1].

Cannabis affects similar functions. A review of acute and long-term cannabis effects found impairment of motor coordination and of executive functions such as planning, decision-making and memory, with severity varying by quantity, recency, age of onset and duration of use [2]. Neither source measured the two together, so the size of any combined impairment is unknown.

Serotonin syndrome

The label states that trazodone can precipitate serotonin syndrome, that the risk rises with other serotonergic drugs (triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's wort) and with MAOIs, and that it can also occur with trazodone alone [1].

In a cell-culture study, CBD acted as a modest-affinity agonist at the human 5-HT1A receptor, while THC did not displace the agonist at the same micromolar concentrations; the authors noted that more work was needed [7]. These data do not establish whether CBD acts meaningfully at that receptor at doses people actually take. The label lists the signs of serotonin syndrome: agitation, hallucinations, tachycardia, labile blood pressure, sweating, fever, tremor, rigidity, myoclonus, seizures, nausea, vomiting and diarrhea [1].

Heart rhythm and blood pressure

The label says trazodone prolongs the QT/QTc interval and that torsades de pointes and ventricular tachycardia have been reported after marketing at doses of 100 mg/day or less with the immediate-release tablet [1]. It advises avoiding trazodone in known QT prolongation, a history of arrhythmia, low potassium or magnesium, congenital long QT and the initial recovery phase after a heart attack, and avoiding combining it with other QT-prolonging drugs [1].

Orthostatic hypotension and fainting are also label effects. In the controlled outpatient studies, hypotension was reported in 4% on trazodone vs 0% on placebo and syncope in 5% vs 1% [1]; the label links the postural drop to trazodone's alpha-1 adrenergic blockade [1].

Alcohol is the interaction the label actually names

Alcohol sits in the label's CNS depressant entry, and the label notes that overdose deaths have occurred when trazodone was taken with alcohol, chloral hydrate/diazepam, amobarbital, chlordiazepoxide or meprobamate [1]. A double-blind crossover study of six healthy volunteers gave single doses of trazodone 100 mg with ethanol 0.5 mL/kg; trazodone alone had marked depressant effects on flicker fusion threshold, reaction time, manual dexterity and drowsiness ratings, and adding ethanol caused little further change except that manual dexterity was more impaired [8]. The authors wrote that the result does not suggest it is safe for patients on antidepressants to drink [8].

Older adults

The trazodone label says hyponatremia (SIADH) carries a higher risk in older adults, and it lists orthostatic hypotension and syncope among its warnings [1].