Herb-Drug Interactions: Cannabis

2011

Contents

Cannabis sativa L. (Cannabaceae)

Synonym(s) and related species

Bhang, Dagga, Ganja, Hashish, Indian hemp, Marihuana, Marijuana.

Cannabis indica Lam.

Constituents

Cannabis herb contains a wide range of cannabinoids, which are the major active compounds. The main psychoactive constituent is delta9-tetrahydrocannabinol (THC; dronabinol), and it is the cause of many of the pharmacological effects elicited by the consumption of cannabis. However, other cannabinoids, which do not possess psychoactive properties, such as cannabidiol, cannabinol (a decomposition product of delta9-tetrahydrocannabinol), cannabigerol and cannabichromene, are increasingly being investigated for their pharmacological and therapeutic properties. Cannabinoids are often found in the plant as their acid metabolites, e.g. ll-nor-9-carboxy-delta9-tetrahydrocannabinol, cannabidiol acid and others, especially if the plant has been grown in a cooler climate. These decarboxylate to the parent cannabinoid at high temperatures, such as during smoking. Most medicinal cannabis products have been heat treated to ensure that the cannabinoids are present only in the non-acid form.

Use and indications

Cannabis has no current established use in herbal medicine because of its legal position in most parts of the world. However, medicinal cannabis is increasingly being used to treat chronic conditions, as an adjunct, or where other treatments may be inadequate. For example, a buccal spray preparation of cannabis, containing mainly dronabinol (the medicinal name for delta9-tetrahydrocannabinol) with cannabidiol, is available as an adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis in adults. It is also being investigated for use as an analgesic in other disease states such as diabetic neuropathy and rheumatoid arthritis, and to relieve spasticity in multiple sclerosis and spinal cord injury. Dronabinol and nabilone (a synthetic cannabinol) are used as antiemetics in patients receiving cancer chemotherapy, and dronabinol has been used as an appetite stimulant in AIDS. Cannabis is a widely used illicit drug because of its psychoactive properties, and has a long history of such use, including by those with chronic illnesses.

Varieties of Cannabis sativa that contain very little cannabinoids (often referred to as hemp) have been cultivated for their fibre and seeds, and these, and the oil derived from the seeds, may be found in some herbal products.

Pharmacokinetics

The most important pharmacokinetic effects of cannabis depend on whether the herb (or its extracts) are smoked or taken orally. When smoked, cannabinoid acids are decarboxylated by the high temperature, and reach the lung as active free cannabinoids. Psychotropic effects start from within seconds to a few minutes, reach a maximum after 20 to 30 minutes, and taper off within 3 to 4 hours. If the same preparation were to be taken orally, however, cannabinoid acid absorption would be lower and much less predictable,with psychotropic effects starting after a delay of 30 to 90 minutes, reaching their maximum after 2 to 4 hours and lasting for about 6 hours.

The metabolism of cannabis is complex, resulting in both active and inactive compounds. The cannabinoids are extensively metabolised by cytochrome P450, in particular, by the isoenzymes CYP2C9 and CYP3A4.2 Smoking cannabis may induce CYP1A2, see theophylline, and also clozapine. Dronabinol has also been shown to inhibit CYP1A1, despite increasing its expression.Cannabis also induces the expression of CYP2E1 and CYP2D6 in mice.

Research suggests that some constituents of cannabis can affect others. Cannabidiol, an active but non-psychotropic cannabinoid, has been shown to partially inhibit the hydroxylation of dronabinol, probably by CYP2C. There is limited evidence that some cannabinoids might inhibit P-glycoprotein or reduce P-glycoprotein expression.

Interactions overview

Most of the drug interaction data relate to smoking cannabis. Smoking cannabis has been shown to decrease levels of theophylline, chlorpromazine and probably clozapine. Use of transdermal nicotine with cannabis enhances tachycardia, and increases the stimulant effect of cannabis. Tachycardia has also been seen with combined use of tricyclic antidepressants and cannabis. Cannabis might increase the effects of opioids such as morphine. Isolated cases of hypomania have been seen when cannabis was used with disulfiram and with fluoxetine, and a man taking cannabis and sildenafil had a myocardial infarction. Another case report describes a fatal stroke in a young man who received cisplatin and smoked cannabis. Indometacin might antagonise some of the effects of smoking cannabis. Smoking cannabis does not appear to affect the pharmacokinetics or antiviral efficacy of indinavir or nelfmavir, and oral cannabis does not appear to affect the pharmacokinetics of docetaxel or irinotecan.

Cannabis + Alcohol

The detrimental effects of drinking alcohol and smoking cannabis may be additive on some aspects of driving performance. However, there is some evidence that regular cannabis use in itself does not potentiate the effects of alcohol. Smoking cannabis may alter the bioavailability of alcohol.

Evidence and mechanism

(a) CNS effects

Simultaneous use of alcohol and oral delta9-tetrahydrocannabinol (THC, the major active ingredient of cannabis) reduced the performance of psychomotor tests, suggesting that those who use both drugs together should expect the deleterious effects to be additive. In a further placebo-controlled study, subjects smoked cannabis containing 100 or 200 micrograms/kg of delta9-tetrahydrocannabinol and drank alcohol (to achieve an initial blood level of 70mg%, with further drinks taken to maintain levels at 40mg%) 30 minutes before driving. They found that cannabis, even in low-to-moderate doses, negatively affected driving performance in real traffic situations. Further, the effect of combining moderate doses of both alcohol and cannabis resulted in dramatic performance impairment as great as that observed with blood-alcohol levels of 140 mg% alone. Similar results (including a suggestion of a synergistic impairment of performance) have been found in a number of other studies, including different doses of cannabis and regular cannabis users.

A study in 22 healthy subjects, who occasionally used cannabis cigarettes and drank moderate amounts of alcohol, found that the number of euphoric events in response to a cannabis cigarette was greater after alcohol ingestion, and the duration of euphoric events was longer. The speed of onset of the effects of cannabis was also faster when it was smoked after the ingestion of alcohol.

One study in 14 regular cannabis users (long-term daily use) and 14 infrequent cannabis users found that regular use reduced the disruptive effects of alcohol on some psychomotor skills relevant to driving, whereas infrequent use did not have this effect. In this study, neither group had smoked any cannabis in the 12 hours before the alcohol test. Another study found that moderate doses of alcohol and cannabis, consumed either alone or in combination, did not produce significant behavioural or subjective impairment the following day.

A study in 12 healthy subjects who regularly used both cannabis and alcohol found that alcohol 0.5 g/kg significantly increased break latency without affecting body sway, whereas cannabis given as a cigarette containing tetrahydrocannabinol 3.33%, increased body sway but did not affect brake latency. There were no significant additive effects on brake latency, body sway or mood when the two drugs were used together. A population-based study of 2,777 drivers involved in fatal road crashes, who drank alcohol and/or used cannabis, found that, although both cannabis and alcohol increased the risk of being responsible for a fatal crash, no statistically significant interaction was observed between the two drugs.

(b) Pharmacokinetic studies

Fifteen healthy subjects given alcohol 0.7 g/kg developed peak plasma alcohol levels of about 78 mg% at 50 minutes, but, if they smoked a cannabis cigarette 30 minutes after the drink, their peak plasma alcohol levels were only 55mg% and they occurred 55 minutes later. In addition, their subjective experience of the drugs decreased when used together. However, another study found that smoking cannabis 10 minutes before alcohol consumption did not affect blood-alcohol levels. A further study found that blood-alcohol levels were not affected by delta9-tetrahydrocannabinol given orally one hour before alcohol. A study in 22 healthy subjects, who occasionally used cannabis cigarettes and drank moderate amounts of alcohol, found that plasma delta9-tetrahydrocannabinol levels were higher when alcohol was consumed before smoking a cannabis cigarette.

Importance and management

Several studies have found that cannabis and alcohol produce additive detrimental effects on driving performance, but other studies have not found any potentiation. This is probably due to the variety of simulated driving tests used and possibly the time lag between the administration of alcohol and cannabis; behavioural impairment after cannabis has been reported to peak within 30 minutes of smoking. Nevertheless, both drugs have been shown to affect some aspects of driving performance and increase the risk of fatal car accidents. Concurrent use of cannabis and alcohol before driving should therefore be avoided.

Cannabis + Chlorpromazine

Smokers of cannabis may possibly need larger doses of chlorpromazine than non-smokers.

Clinical evidence

A study in 31 patients found that the clearance of chlorpromazine was increased by 38% by tobacco smoking, by 50% by cannabis smoking, and by 107% when both tobacco and cannabis were smoked.

Experimental evidence

No relevant data found.

Mechanism

Not established. The probable reason is that some of the components of tobacco smoke act as enzyme inducers, which increase the rate at which the liver metabolises chlorpromazine, thereby reducing its serum levels and clinical effects.

Importance and management

Established interactions but of uncertain clinical importance. Be alert for the need to increase the dosages of chlorpromazine and related antipsychotics in patients who smoke, and reduce the dosages if smoking is stopped.

Cannabis + Ciclosporin

Cannabidiol, an important constituent of cannabis, may increase ciclosporin levels. This interaction is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

An in vitro study found that the incubation of human and mouse liver microsomes with cannabidiol, an active but non-psychoactive constituent of cannabis, resulted in inhibition of ciclosporin metabolism. The production of ciclosporin metabolites was reduced by 73 to 83%. Similar results were found in studies in mice)

Mechanism

Cannabidiol may inhibit the cytochrome P450 subfamily CYP3A, and so increase ciclosporin levels. However, cannabis does not affect the metabolism of other CYP3A4 substrates, see Cannabis + Irinotecan.

Importance and management

These preclinical data suggest that one constituent of cannabis might possibly raise ciclosporin levels. These data require confirmation in humans. Until such data are available, bear in mind the possibility that irregular use of cannabis might be a factor in unstable ciclosporin levels. It might be unwise for patients taking ciclosporin to use cannabis.

Cannabis + Cisplatin

A case report describes a fatal stroke when a young man receiving cisplatin smoked cannabis.

Evidence, mechanism, importance and management

A 27-year-old man who smoked cannabis and tobacco daily developed tinnitus and paraesthesias after receiving the first course of chemotherapy consisting of cisplatin, etoposide and bleomycin for testicular cancer. Following the second course of chemotherapy, the patient reported distal paresis of the right arm and, 2 days later, about 30 minutes after cannabis inhalation, he developed headache, paresis of his right leg and aphasia. A large thrombus was found in the carotid artery. The patient died the next day. He had no cardiovascular risk factors apart from the smoking (about 4 cigarettes per day).

Cisplatin is known to carry a small risk of stroke, and cases have also been reported for cannabis smoking alone. In this case it was suggested that the use of cannabis may have also contributed to the adverse outcome in this patient. It might be prudent for patients receiving cisplatin to avoid smoking cannabis.

Cannabis + Clozapine

Patients who give up smoking cannabis may develop higher blood levels of clozapine and be at risk of adverse reactions, since plasma levels of clozapine are lower in smokers than in non-smokers.

Clinical evidence

A 37-year-old man who smoked both tobacco and cannabis daily, and took clozapine 700 mg daily, experienced elevated clozapine plasma levels and signs of clozapine toxicity, one month after he stopped smoking both tobacco and cannabis. One week after reducing the dose of clozapine to 500 mg daily, his psychotic symptoms disappeared and plasma levels returned to normal.

Experimental evidence

No relevant data found.

Mechanism

Tobacco smoke contains aromatic hydrocarbons that are potent inducers of the cytochrome P450 isoenzyme CYP1A2, by which clozapine is metabolised. The contribution of cannabis smoking to this case is unknown, but cannabis smoking alone is also known to induce CYP1A2, independent of tobacco. See Cannabis + Theophylline.

Importance and management

It is known that patients who smoke tobacco may experience lower serum clozapine levels and, although there is no direct evidence, this may equally apply to cannabis smoking. Irregular smoking of cannabis might cause fluctuations in clozapine levels.

Cannabis + Disulfiram

Two isolated case reports describe hypomanic-like reactions when patients taking disulfiram used cannabis, whereas no unusual interaction with the combination was seen in other subjects.

Evidence, mechanism, importance and management

A man with a 10-year history of drug abuse (alcohol, amfetamines, cocaine, cannabis) taking disulfiram 250 mg daily, experienced a hypomanic-like reaction (euphoria, hyperactivity, insomnia, irritability) on two occasions, associated with the concurrent use of cannabis. The patient said that he felt as though he had been taking amfetamine. One other similar case has been reported. The reason for this reaction is not understood. In a randomised study in alcohol-dependent subjects who had previously used cannabis, no unusual interaction effects were found in a group of 11 subjects receiving disulfiram and smoking cannabis twice weekly for 4 weeks.Therefore the interaction described in the two case reports would not appear to be of general significance.

Cannabis + Docetaxel

The pharmacokinetics of docetaxel are not altered by a herbal tea containing cannabis.

Clinical evidence

In a study investigating the effects of cannabis on docetaxel pharmacokinetics, 12 patients were given 200 mL of a herbal tea containing cannabis 1 g/L each day for 15 days. The tea was prepared from medicinal-grade cannabis (Cannabis sativa L. Flos, Bedrocan®) containing the cannabinoids delta9-tetrahydrocannabinol 18% and cannabidiol 0.8%. The clearance and the AUC of docetaxel given on day 12 of the cannabis tea were not significantly altered, when compared with docetaxel given before the cannabis tea. The dose of docetaxel used was 180 mg, reduced to 13 5 mg in 3 patients who experienced dose-related docetaxel toxicity.

Experimental evidence

No relevant data found.

Mechanism

Docetaxel is metabolised by the cytochrome P450 isoenzyme CYP3A4, and this does not appear to be affected by oral cannabis.

Importance and management

This study suggests that cannabis taken orally will not affect the pharmacokinetics of docetaxel. No dosage adjustments are likely to be needed if docetaxel is given with cannabis tea. It is not known if this applies to other drugs metabolised by CYP3A4, or to other preparations and routes of administration of cannabis, but see also Cannabis + Ciclosporin, and Cannabis + Irinotecan, below.

Cannabis + Ecstasy

The information regarding the use of cannabis with ecstasy is based on experimental evidence only.

Evidence, mechanism, importance and management

An animal study found that pretreatment with cannabidiol, a major constituent of cannabis, did not affect the levels of ecstasy (MDMA, methylenedioxymethamfetamine) in the brain of mice.

Cannabis + Fluoxetine

An isolated report describes mania when a patient taking fluoxetine smoked cannabis.

Evidence, mechanism, importance and management

A 21-year-old woman with a 9-year history of bulimia and depression was taking fluoxetine 20 mg daily. A month later, about 2 days after smoking two ‘joints’ of cannabis (marijuana), she experienced a persistent sense of well-being, increased energy, hypersexuality and pressured speech. These symptoms progressed into grandiose delusions, for which she was hospitalised. Her mania and excitement were controlled with lorazepam and perphenazine, and she largely recovered after about 8 days. The reasons for this reaction are not understood but the authors of the report point out that one of the active components of cannabis, dronabinol (delta9-tetrahydrocannabinol), is, like fluoxetine, a potent inhibitor of serotonin uptake. Thus a synergistic effect on central serotonergic neurones might have occurred. This seems to be the first and only report of an apparent adverse interaction between cannabis and fluoxetine, but it emphasises the risks of concurrent use.

Cannabis + Food

No interactions found.

Cannabis + Herbal medicines

No interactions found.

Cannabis + Irinotecan

The pharmacokinetics of irinotecan are not altered by a herbal tea containing cannabis.

Clinical evidence

In a crossover study, 24 patients were given intravenous irinotecan 600 mg before and 12 days after starting a 15-day course of 200 mL daily of a herbal tea containing cannabis 1 g/L. This was prepared from medicinal-grade cannabis (Cannabis sativa L. Flos, Bedrocan®) containing the cannabinoids delta9-tetrahydrocannabinol 18% and cannabidiol 0.8%. The clearance and the AUC of irinotecan and its metabolites, SN-38 and SN-38G, were not significantly altered by the presence of cannabis.

Experimental evidence

No relevant data found.

Mechanism

Irinotecan is metabolised by cytochrome P450 isoenzyme CYP3A4, and this does not appear to be affected by oral cannabis.

Importance and management

This study suggests that cannabis taken orally will not affect the pharmacokinetics of irinotecan. No dosage adjustments are likely to be needed if irinotecan is given with cannabis tea. It is not known if this applies to other drugs metabolised by CYP3A4, or to other preparations and routes of administration of cannabis, but see also Cannabis + Ciclosporin, and Cannabis + Docetaxel.

Cannabis + Nicotine

The effects of transdermal nicotine and cannabis smoking on increasing the heart rate are additive, and nicotine increased the stimulant effect of cannabis. Combined use might increase the addictive potential of both drugs.

Clinical evidence

In a study in 20 healthy subjects who smoked either a low-dose or a high-dose cannabis cigarette 4 hours after the application of a placebo or a 21 mg nicotine patch, nicotine enhanced the maximum increase in heart rate seen with cannabis. The increase in heart rate for nicotine alone was between 10 and 15 bpm, for cannabis alone 32 and 42 bpm, for women and men, respectively, and, for the combination, 45 and 58bpm, respectively. In addition, the duration of tachycardia after smoking the low-dose cannabis was prolonged by 30 minutes by nicotine, but was not changed after the high-dose cannabis. Nicotine increased the subjective stimulant effects of cannabis, but the reported duration of effects of cannabis were shortened by nicotine. Plasma levels of nicotine and delta9-tetrahydrocannabinol (THC) did not differ on concurrent use. The cannabis cigarettes were standardised to 1.99% THC (low dose) and 3.51% THC (high dose).

Experimental evidence

Studies in mice found that nicotine enhanced the effects of delta9-tetrahydrocannabinol in terms of hypolocomotion, hypothermia and antinociceptive responses. Somatic signs of withdrawal from delta9-tetrahydrocannabinol were more severe in mice that had received nicotine.

Mechanism

Unknown. The additive effect on heart rate may be due to sympathetic activity of both drugs, and might also involve cannabinoid receptors.

Importance and management

Cannabis is often smoked with tobacco. The findings of the clinical study show that transdermal nicotine has additive effects with cannabis on heart rate, and increased the stimulant effect of cannabis. The clinical significance of these findings is uncertain.

Cannabis + NSAIDs

Indometacin appears to antagonise some of the effects of cannabis, and cannabis might antagonise the analgesic efficacy of NSAIDs.

Clinical evidence

Four healthy subjects were given placebo or indometacin 25 mg three times daily for one day, and then a single-dose 2 hours before smoking cannabis 400 micrograms/kg on the following day. Indometacin did not alter the pharmacokinetics of delta9-tetrahydrocannabinol. Subjective measures of heart rate acceleration and intoxication were modestly attenuated by indometacin. Subjects also reported that the effects of marihuana on time perception were antagonised by indometacin.

Experimental evidence

In a study rabbits received placebo or 2% indometacin applied topically to both eyes one hour prior to an intravenous injection of delta9-tetrahydrocannabinol. The fall in intraocular pressure caused by delta9-tetrahydrocannabinol was inhibited by topical indometacin.

In an animal model of analgesia, chronic treatment with delta9-tetrahydrocannabinol markedly reduced the efficacy of aspirin, celecoxib, indometacin, ketorolac and naproxen, and reduced the potency of diclofenac and paracetamol (acetaminophen).

Mechanism

It is suggested that prostaglandins have some part to play in some of the effects of cannabis, and that these are antagonised by indometacin, which is a prostaglandin inhibitor. Similarly, cannabis antagonises the effects of NSAIDs.

Importance and management

The effects of indometacin on the subjective measures and intraocular pressure-lowering effects of delta9-tetrahydrocannabinol are probably not of clinical significance. However, the relevance of the finding that chronic use of delta9-tetrahydrocannabinol might result in reduced efficacy and potency of NSAIDs requires further study.

Cannabis + Opioids

Low doses of cannabis enhanced the effect of morphine in three patients. Animal studies have shown that cannabinoids may enhance the potency of opioids.

Evidence, mechanism, importance and management

A report of 3 patients with chronic pain (due to multiple sclerosis, HIV-related peripheral neuropathy and lumbar spinal damage) found that small doses of smoked cannabis potentiated the antinociceptive effects of morphine. The patients were able to decrease the dose of opioid by 60 to 100%.! Studies in animals have shown that delta9-tetrahydrocannabinol, the major psychoactive constituent of cannabis, enhances the potency of opioids such as morphine, codeine, hydromorphone, methadone, oxymorphone and pethidine (meperidine). It has been suggested that low doses of delta9-tetrahydrocannabinol given with low doses of morphine may increase opioid potency without increasing adverse effects. Cannabis use in methadone-maintained patients did not appear to affect treatment progress, although some psychological difficulties were slightly more prevalent. However, other workers have suggested that heavy cannabis use is associated with poorer progress when methadone is given in the treatment of opioid addiction.

Cannabis + Phencyclidine

The interaction between cannabis and phencyclidine is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

An animal study found that pretreatment with cannabidiol significantly increased the levels of phencyclidine in the brain and blood of mice. Behavioural tests indicated that the increase in brain levels led to an increase in intoxication caused by phencyclidine. When the study was repeated using delta9-tetrahydrocannabinol in doses of 120 mg/kg, the brain levels of phencyclidine were increased twofold. Lower doses of delta9-tetrahydrocannabinol did not result in such an effect.

Mechanism

Unknown.

Importance and management

This preclinical study provides some evidence that cannabis might increase the abuse potential of phencyclidine.

Cannabis + Phenytoin

There is one in vitro study suggesting that delta9-tetrahydrocannabinol, a major constituent of cannabis, might induce phenytoin metabolism. Note that, in clinical use dronabinol has induced seizures.

Clinical evidence

No interactions found.

Experimental evidence

In an in vitro study in which human liver microsomes were incubated with phenytoin alone, or phenytoin and delta-tetrahydrocannabinol, a major constituent of cannabis, the rate of metabolism of phenytoin was slightly increased in a dose-dependent manner. The rate of metabolism of delta9-tetrahydrocannabinol to its 11-hydroxy metabolite was not altered by phenytoin.

Various cannabinoids have shown antiepileptic effects in animal studies. In one study, the antiepileptic effect of phenytoin was increased when combined with cannabidiol.

Mechanism

The in vitro data suggest that delta9-tetrahydrocannabinol induces the cytochrome P450 isoenzyme CYP2C9.

Importance and management

This appears to be the only evidence that cannabis might affect phenytoin levels, and is only in vitro data. As such, it requires confirmation before any recommendations can be made. Note also that there are no reports in the literature of cannabis use affecting phenytoin levels. Note that oral dronabinol (delta9-tetrahydrocannabinol) has caused seizures in clinical use, and the manufacturer recommends caution in those with a seizure disorder.

Cannabis + Protease inhibitors

The short-term use of cannabis cigarettes or dronabinol (delta9-tetrahydrocannabinol) did not appear to adversely affect indinavir or nelfinavir levels or viral loads in HIV-positive patients.

Clinical evidence

In 9 HIV-positive patients on a stable regimen containing indinavir (mostly 800 mg every 8 hours), smoking a cannabis cigarette (3.95% tetrahydrocannabinol) three times daily before meals for 14 days resulted in a median 14% decrease in AUC and maximum level and a 34% decrease in minimum indinavir level. However, only the change in maximum level was statistically significant. Similarly, dronabinol (delta9-tetrahydrocannabinol) 2.5 mg three times daily for 14 days had no significant effect on indinavir pharmacokinetics.

In another 11 patients on a stable regimen containing nelfinavir 750 mg three times daily, there was a non-significant 10% decrease in AUC, 17% decrease in maximum level and 12% decrease in minimum nelfinavir level after 14 days of cannabis cigarettes. Similarly, dronabinol 2.5 mg three times daily for 14 days had no significant effect on nelfinavir pharmacokinetics.

There was no adverse effect on viral load or CD4 count in the patients receiving cannabis cigarettes or dronabinol.

Experimental evidence

No relevant data found.

Mechanism

No mechanism expected.

Importance and management

Short-term use of cannabis cigarettes or dronabinol does not appear to have any important effect on levels of indinavir or nelfinavir, nor on markers of HIV infection.

Cannabis + Sildenafil

Myocardial infarction occurred in a man who had smoked cannabis and taken a tablet of sildenafil.

Clinical evidence

A 41-year old man with no history of cardiac disease experienced a myocardial infarction after smoking cannabis and recreationally taking a tablet of sildenafil (strength not specified). Later tests showed that he had no evidence of inducible ischaemia.

Experimental evidence

No relevant data found.

Mechanism

Myocardial infarction is a rare adverse effect of sildenafil alone. It was suggested that the metabolism of sildenafil by cytochrome P450 isoenzyme CYP3A4 might be inhibited by constituents of cannabis such as cannabidiol, thereby increasing the risk of adverse events. However, in clinical studies, oral cannabis did not alter levels of other CYP3A4 substrates. These included Cannabis + Irinotecan, and Cannabis + Docetaxel.

Importance and management

The vasodilatory effects of sildenafil necessitate caution in its use in patients with cardiovascular disease; myocardial infarction has rarely been associated with its use. The contribution of an interaction to this case is unclear, but bear the possibility in mind in the event of adverse effects on concurrent use.

Cannabis + Theophylline

Cannabis smokers may need more theophylline than non-smokers to achieve the same therapeutic benefits, because the theophylline is cleared from the body more quickly.

Evidence, mechanism, importance and management

One study found that tobacco or cannabis smoking similarly caused higher total clearances of theophylline (given as oral aminophylline) than in non-smokers (about 74mL/kg per hour compared with 52 mL/kg per hour), and that clearance was even higher (93 mL/kg per hour) in those who smoked both. A later analysis by the same authors, of factors affecting theophylline clearance, found that smoking two or more joints of cannabis weekly was associated with a higher total clearance of theophylline than non-use (82.9 mL/kg per hour versus 56.1 mL/kg per hour).

Tobacco and cannabis smoke contain polycyclic hydrocarbons, which act as inducers of the cytochrome P450 isoenzyme CYP1A2, and this results in a more rapid clearance of theophylline from the body.

Little is known about the effects of smoking cannabis on theophylline levels, but be alert for the need to increase the theophylline dosage in regular users. Note that irregular cannabis use might cause fluctuations in theophylline levels.

Cannabis + Tricyclic antidepressants

Tachycardia has been described when patients taking tricyclic antidepressants smoked cannabis.

Evidence, mechanism, importance and management

A 21-year-old woman taking nortriptyline 30 mg daily experienced marked tachycardia (an increase from 90 to 160 bpm) after smoking a cannabis cigarette. It was controlled with propranolol. A 26 year old complained of restlessness, dizziness and tachycardia (120 bpm) after smoking cannabis while taking imipramine 50 mg daily. Four adolescents aged 15 to 18 taking tricyclic antidepressants for attention-deficit hyperactivity disorder had transient cognitive changes, delirium and tachycardia after smoking cannabis.

Increased heart rates are well-documented adverse effects of both the tricyclic antidepressants and cannabis, and what occurred was probably due to the additive beta-adrenergic and antimuscarinic effects of the tricyclics, with the beta-adrenergic effect of the cannabis. Direct information is limited but it has been suggested that concurrent use should be avoided.