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. 2023 Dec 8;120(49):833–840. doi: 10.3238/arztebl.m2023.0223

Drug Interactions of Tetrahydrocannabinol and Cannabidiol in Cannabinoid Drugs

Recommendations for Clinical Practice

Thomas Herdegen 1,*, Ingolf Cascorbi 1
PMCID: PMC10824494  PMID: 37874128

Abstract

Background

Cannabinoid drugs containing tetrahydrocannabinol (THC), or its structural analogues, as monotherapeutic agents or as extracts or botanical preparations with or without cannabidiol (CBD) are often prescribed to multimorbid patients who are taking multiple drugs. This raises the question of the risk of drug interactions.

Methods

This review of the pharmacokinetics and pharmacodynamics of interactions with cannabinoid drugs and their potential effects is based on pertinent publications retrieved by a selective literature search.

Results

As THC and CBD are largely metabolized in the liver, their bioavailability after oral or oral-mucosal administration is low (6–8% and 11–13%, respectively). The plasma concentrations of THC and its active metabolite 11-OH-THC can be increased by strong CYP3A4 inhibitors (verapamil, clarithromycin) and decreased by strong CYP3A4 inductors (rifampicin, carbamazepine). The clinical significance of these effects is unclear because of the variable plasma level and therapeutic spectrum of THC. The metabolism of CBD is less dependent on cytochrome P450 enzymes than that of THC. THC and CBD inhibit CYP2C and CYP3A4; the corresponding clinically relevant drug interactions probably are likely to arise only with THC doses above 30 mg/day and CBD doses above 300 mg/day.

Conclusions

Potential drug interactions with THC and CBD are probably of little importance at low or moderate doses. Strong CYP inhibitors or inductors can intensify or weaken their effect. Slowly ramping up the dose of oral cannabinoid drugs can lessen their pharmacodynamic interactions, which can generally be well controlled. Administration by inhalation can worsen the interactions.

cme plus

This article has been certified by the North Rhine Academy for Continuing Medical Education. The CME questions on this article can be found at http://daebl.de/RY95. The deadline for submission is 7 December 2024.

Participation is possible at cme.aerztebatt.de

Tetrahydrocannabinol (THC, (-)-Δ9-trans-tetrahydrocannabinol) and cannabidiol (CBD) are the compounds in cannabis flower or cannabinoid drugs (CDs) of relevant therapeutic use. Under the German Medicines Act, only THC plus cannabidiol (nabiximols) and nabilone were approved in Germany, which is why data from controlled trials are exclusively refer to these substances. The remaining THC-containing cannabinoid drugs (THC-CDs) were made available on prescription in 2017 with a modification to the German Social Code (SGB, Sozialgesetzbuch). For this, an approval procedure of the German Federal Institute for Drugs and Medical Devices (BfArM, Bundesamt für Arzneimittel und Medizinprodukte) is no longer required. According to the German Drug Codex (DAC, DeutscherArzneimittel Codex) and the New German Formulary (NRF, Neue Rezeptur-Formularium), CBD in its pure form is not subject to the German Narcotic Drugs Act (BtMG, Betäubungsmittelgesetz), but can be prescribed (Epidyolex) and is to be distinguished from CBD in dietary supplements.

In addition to their approved indications (for example, spasticity in multiple sclerosis), THC-containing cannabinoid drugs that are subject to the German Narcotic Drugs Act are most frequently prescribed for the diagnoses pain, neoplasia, anorexia, and spasticity (1, e1), i.e. in clinical situations with polymedication. THC-containing cannabinoid drugs are being prescribed in increasing numbers: The German statutory health insurance funds (GKV, gesetzliche Krankenversicherungen) alone recorded 185 000 prescriptions in the first half of 2021 (e1). The effects and side effects of THC-CDs have been documented in observational studies and in the BfArM’s concomitant survey on the use of medical cannabis products (2017–2022) (1). From a pharmacological perspective, the oral use (monotherapeutic agents, extracts) with comparatively slow distribution into the central nervous system is considered the gold standard.

This selective literature search addresses drug interactions of THC and CBD from physician-prescribed, orally administered cannabinoid drugs with their defined dosages. Other cannabis ingredients, such as cannabigerol and cannabivarin (not detectable following oral administration) (2) or terpenes, are not included in our review. An overview of the pharmacology of THC and CBD as well as the endocannabinoid system can be found in a number of other publications (3–6, e2).

The use of cannabinoid drugs is based mainly on observational studies and reports from the field of empirical medicine (7–12, e3-e11), some of which are supported by meta-analyses (e12). By contrast, Cochrane reviews and the majority of meta-analyses which are based on randomized trials on, for example, chronic cancer and non-cancer pain, cancer-associated symptoms (e13, e14) and opioid sparing effects (13), have shown no or only small effect sizes. Positive effects have also been described for spasticity in multiple sclerosis (e15). For reasons of space, we can only refer here to other publications for a discussion of these discrepancies (e16–e20).

Nabilone has been approved for chemotherapy-induced vomiting and nabiximols for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis, each as third-line therapy after unsatisfactory response to other therapeutic agents (overview in e21).

This review focuses on the medically controlled prescription of oral doses of cannabinoid drugs. The potential toxicity and risk of drug interactions associated with recreational use as well as dose dependence are not discussed in this paper.

Methods and aims

This review is based on pertinent publications retrieved from a selective literature search in the PubMed database, on the BfArM’s concomitant survey on the use of medical cannabis products (1) and on product information. We used the search terms “THC“, “CBD“, “pharmacokinetic“, “pharmacodynamic“, “metabolism“, “interaction“, “CYP“, and “safety, adverse effect“ alone and in combination.

In our review, we discuss the drug interactions of THC- und CBD-containing cannabinoid drugs that are regulated by the German Cannabis Law and prescribed by physicians as well as those of prescription CBD. The primary focus is on cannabinoid drugs that are administered via the oral or oral-buccal route. To develop an understanding of these substances also helps to evaluate the interaction risks associated with inhaled cannabinoids.

Results

Tetrahydrocannabinol and its active metabolite

Oral THC-containing cannabinoid drugs are started in low doses which are gradually increased, with dose titration guided by the effects and side effects experienced by the patient (7). In the steady state, doses between 5 and 30 mg THC per day (on average about 15 mg/day, divided into three doses) are administered (1, 8–9). Plasma concentrations are 10 to 20 times lower than after inhalation (3).

Pharmacokinetics

After a single oral dose of 2.5–5 mg, lipophilic THC reaches fasting plasma concentrations of 1–3 ng/mL after 1–2 hours and its active metabolite 11-OH-THC reaches plasma levels of 2–5 ng/mL (10). Up to a THC dose of 20 mg, maximum plasma concentration (Cmax) and the area under the curve (AUC, a measure of the bioavailability of drugs) show a more or less linear increase with high intra-individual variability (± 200%) (14–16, e22).

Following almost complete intestinal absorption, THC is extensively metabolized in the liver so that systemic bioavailability is only 6–7%; after oral-mucosal administration, it is approximately 11–13% (15). THC accumulates in highly vascularized and fatty tissue; 95–99% of THC is bound to plasma proteins.

Only approximately 1% of the THC dose is detected in the brain (e2). The ATP-binding cassette (ABC) transporters P-glycoprotein and breast cancer resistance protein (BCRP) transport THC rapidly out of the brain (17); in vitro, THC itself is a weak inhibitor of the ABC and solute carrier (SLC) drug transporters (e23).

Drug metabolism: THC is metabolized by cytochrome P450 (CYP) 2C9 to the active CB1 agonist 11-hydroxy-THC (11-OH-THC). CYP3A4 inactivates both cannabinoids (Figure 1) (18). Subsequently, some of the 11-OH-THC and 11-COOH-THC is glucoronized by the UDP-glucuronosyl transferase UGT2B7 (19).

Figure 1.

Figure 1

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Drug metabolism of tetrahydrocannabinol and cannabidiol

CBD, cannabidiol; UGTs, UDP-glucuronosyltransferases; THC, tetrahydrocannabinol

Excretion: There is an initial phase of THC plasma elimination (half-life approx. 6 minutes), followed by a long terminal half-life of 22 hours (5). Two-thirds of THC und its metabolites is excreted by the intestine; conjugated glucuronides play a minor role (e24). Renal elimination amounts to 20%; in patients with severe renal failure, a dose adjustment may be indicated.

Conclusion: CYP3A4 plays a significant role in the inactivation of THC and 11-OH-THC, while CYP2C9 plays a significant role in the metabolism of THC to 11-OH-THC.

Pharmacokinetic interactions

THC as the “victim”: A dose of 400 mg of the CYP3A4 inhibitor ketoconazole increases the AUC of oral THC and 11-OH-THC by 45% and 74%, respectively, while Cmax increases by 27% and 204%, respectively (Table 1). Conversely, the CYP3A4 inducer rifampicin reduces the AUC by 28% and 90% and increases Cmax by 36% and 87%, respectively. CYP2C19 inhibition was of no significance (18).

Table 1. Pharmacokinetic interactions and their clinical effects with tetrahydrocannabinol and cannabidiol as the “victim“.

Metabolites Relevant cytochrome P450 Clinical effects of inhibition and measures to be taken Clinical effects of inhibition and measures to be taken
THC 11-OH-THC (active)
11-nor-9-COOH-THC, among others (inactive) 		CYP2C9
CYP3A4 		Little effect, because less 11-OH-THC but more THC
More 11-OH-THC, minor increase in effect due to strong CYP3A4 inhibitors*1
CBD can increase AUC of THC.
Measures: Monitor effect of THC; lower dose, if necessary
Less 11-OH-THC, moderate loss of effect due to strong CYP3A4 inducers
Measures: Monitor effect of THC; increase dose, if necessary
CBD 7-OH-CBD (active?)
7-COO-CBD (inactive) 		CYP2C19
CYP3A4 		Little effect, high therapeutic index of CBD, questionable significance of moderate accumulation of 7-OH-CBD
More 7-OH-CBD, minor increase in effect due to strong CYP3A4 inhibitors*1; questionable significance of accumulation of 7-OH-CBD
Measures: Monitor effect of CBD; lower dose, if necessary
Less 7-OH-CBD, minor decrease in effect due to known strong CYP3A4 inhibitors*2, questionable significance of reduction in 7-OH-CBD
Measures: Monitor effect of CBD; increase dose, if necessary
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*1 Strong CYP3A4 inhibitors include clarithromycin, voriconazole, grapefruit

*2 Strong CYP3A4 inductors include rifampicin, carbamazepine and St. John‘s wort

AUC, area under the curve; CBD, cannabidiol; THC, tetrahydrocannabinol

Genetically determined lower CYP2C9 activity prolongs the half-life of THC significantly from 7 h to 22 h and increases the AUC threefold, while for 11-OH-THC only a trend is noted (20). A 640 mg dose of CBD increases the AUC of THC by approximately 160% and the ratio of 11-OH-THC to THC by a factor of three (e25).

THC as the “perpetrator”: In vitro, THC is a moderate inhibitor of CYP1A2, 3A4, 2B6, 2C9, and 2D6, among others: dissociation constant (Ki) 1–3 µM; mean inhibitory concentration (IC50) approximately 20 to >50 µM (Table 2) (19–22, e26–e27). Significant perpetrator interactions have been reported for THC-containing cannabinoid drugs (23, e28–e29). The activity of CYP3A4 remained unchanged in patients with dementia who received an average oral dose of THC of 12.4 mg/day with 24.8 mg/day CBD over a period of 13 months (24). However, in individuals who smoked cannabis on a regular basis, one cannabis cigarette smoked in the evening increased the concentration of buprenorphine 2.7-fold and the concentration of norbuprenorphine, its metabolite activated by CYP3A4, by 40% (25). This is probably caused by comparatively high plasma concentrations of inhaled THC (with increased concentrations in the liver) and by CBD (see below).

Table 2. Pharmacokinetic interactions and their clinical effects with tetrahydrocannabinol und cannabidiol as the “perpetrator”.

Inhibited cytochrome P450 Example of substrates (“victim“) Clinical effects of inhibition and measures to be taken
THC CYP3A4

CYP2C9		 Phenprocoumon
Ciclosporin
Warfarin
Diclofenac 		No significant interactions if THC <30 mg/day po
Measures for higher doses or prolonged inhalation administration: Escalate dose slowly; monitor effects of the substrate; lower THC dose, if necessary
No significant interactions if THC <30 mg/day po
Measures: see above
CBD CYP3A4

CYP2C19
CYP3A4 und CYP2C9 		Phenprocoumon Ciclosporin
Clobazam
THC 		Moderate or strong increase in the AUC of the substrates at medium (300–500 mg/day) or high (>750 mg/day) CBD doses
Measures: Escalate dose slowly; monitor effects of the substrate; lower CBD dose, if necessary
See above
Increase in AUC of THC, reduce dose of THC, if necessary
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AUC, area under the curve; CBD, cannabidiol; PO, per os; THC, tetrahydrocannabinol

Nabilone: No CYP interactions are to be expected from the synthetic CB1 agonist nabilone, which is not metabolized presystemically (e30).

Conclusion: Under real-world conditions, it is difficult to assess the significance of AUC changes of oral THC and 11-OH-THC brought about by strong CYP2C 9 and CYP3A4 modulators, respectively (list provided in 26), due to the high intraindividual fluctuations in THC bioavailability. If THC/dronabinol is administered together with CYP3A4/2C9 inhibitors or inductors, it is possible to counteract these changes by titrating the CD dose. Strong CYP3A4 inhibitors, such as clarithromycin or grapefruit juice, can increase the plasma concentration especially of 11-OH-THC in patients with new prescriptions or dose changes. By contrast, strong inductors (rifampicin, St. John‘s wort) can reduce the effect. Other than data from the pivotal studies, there are hardly any reliable data on pharmacokinetic interactions available.

Pharmacodynamic interactions

The most common side effects and corresponding drug interactions of THC-containing cannabinoid drugs include dizziness, sleepiness, dry mouth, problems concentrating, and nausea (1, 8–9, e3, e31) (Figure 2). In most cases, these occur early in the course of treatment with subsequent habituation (7). Pharmacodynamic interactions are related to active substances causing sedation, dizziness (neuro-psychotropic drugs, alcohol) (27) or psychotic symptoms (28).

Figure 2.

Figure 2

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Side effects of various cannabinoid drugs, listed according to frequency of reporting (1)

CAM, cannabinoid drugs

THC (up to 15 mg orally) and nabiximols (high doses) do not change the heart rate or blood pressure, even in stroke patients (15, 29, e32).

The analysis of data from the German Pain e-Registry (PraxisRegister Schmerz) with particularly long and severe courses of pain (>10 years) and extensive use of multiple drugs showed that 5.9% and 14.1% of patients discontinued the treatment because of adverse drug reactions of nabiximols and dronabinol, respectively (each N = 337). The proportion of interactions remains undetermined (10). In the BfArM’s concomitant survey, only 0.4% of patients discontinued THC because of drug interactions (1). In patients with dementia (n = 19), treatment with oral doses of 12.4 mg/day THC (with 24.8 mg/day CBD) over a period of 13 months was safe and associated with substantial clinical improvement (24).

Conclusion: Symptom-focused titration of THC-containing cannabinoid drugs reduces the risk of side effects and also of pharmacodynamic interactions. The potential reduction in the use of opioids and other neuropsychotropic drug automatically reduces drug interactions, even if the savings potential remains controversial (13).

Cannabidiol

Only limited data is available on prescriptions, dosages and side effects of CBD administered alone or CBD in THC-containing cannabinoid drugs

Pharmacokinetics

Being highly lipophilic, one route by which CBD is absorbed is via the intestinal lymphatic system—food rich in fat increases its absorption (29). Furthermore, CBD undergoes extensive hepatic metabolism; the in the fasting patient low peroral bioavailability of 6–8% increases to up to 19% with food very rich in fat and to 30% with inhalation (30). CBD rapidly penetrates into the brain; it is not a substrate of ABC and SLC transporters (e33).

Drug metabolism: The hepatic metabolism of CBD exceeds 70% (a so-called high-clearance drug). CBD is metabolized via CYP2C19 (to a minor extent via CYP2C9) to 7-OH-CBD which is considered an active metabolite; however, valid confirmations are still entirely lacking (e34–e35). 7-OH-CBD is inactivated to 7-COOH-CBD via CYP3A4 (Figure 1). The contributions to metabolism/inactivation of CBD amounts in vitro to approximately 40% for CYP3A4, 20% for CYP2C19 and 30% for various UDP-glucuronosyltransferase enzymes (UGTs) (31).

Excretion: As with THC, two-thirds of CBD is excreted via the intestine and 20% via the kidneys. The terminal, i.e. relevant half-life of CBD is 68 hours (30, e35).

Pharmacokinetic interactions

CBD as the “victim”: The maximum plasma concentration of 10 mg oral-mucosal CBD was increased by the strong CYP3A4 inhibitor ketoconazole by 89% and reduced by 52% by the CYP3A4 inductor rifampicin (Table 1). The CYP2C19 inhibitor omeprazole produces a non-significant increase in plasma concentrations (18). These changes in concentration, classified as weak or moderate, are within the intraindividual fluctuations in CBD plasma concentrations and correspond to those seen with THC.

Clobazam, stiripentol and valproate change the AUC of twice 750 mg/day CBD insignificantly by 32%, 9% and –6% and Cmax by 31%, 9% and –26%, respectively (32). Fentanyl had no effect on the plasma concentrations of 800 mg CBD (e36).

CBD as the “perpetrator“ (Table 2): In vitro, CBD is an inhibitor of numerous cytochrome P450 enzymes, including CYP3A4, 2C9 and 2C19 (19, 21, e22, e26, e27). A dose of twice daily 750 mg of the CBD anticonvulsant Epidiolex increases the AUC of twice daily 5 mg clobazam by 60 ± 80% and the AUC of N-desmethylclobazam by 500 ± 300%. N-desmethylclobazam is the active metabolite of clobazam produced by CYP3A4 which is in turn inactivated by CYP2C19 to hydroxy-clobazam. These data indicate that CBD is a stronger inhibitor of CYP219 than of CYP3A4 (33, e37)..

In addition, CBD increases the plasma concentrations of CYP3A4 substrates such as warfarin or tacrolimus (23, e38). The administration of 2–3 g CBD per day increased the plasma concentration of tacrolimus to such an extent that the dose of the immunosuppressant had to be reduced by 90% (34). The increase of a CBD dose of 375 mg/day to 1500 mg/day doubled the plasma concentration of the CYP3A4 and 2C19 substrate methadone, resulting in severe clouding of consciousness (35).

By contrast, CBD had little or no effect on the plasma concentrations of the CYP3A4 and 2C19 substrate citalopram. Surprisingly, the plasma concentration of CBD remained unchanged, even when the dose was increased from 200 mg to 800 mg (36). The use of 200 mg CBD as a herbal tea did not alter the plasma concentrations of CYP3A4 substrates (e28). CBD oil with a content of <50 mg led to a minor reduction (12.6%) in the AUC of endoxifen, a metabolite of the prodrug tamoxifen, produced by CYP2D6 and CYP3A4 (e39). A dose of 640 mg CBD significantly increased the AUC of THC and the relative proportion of 11-OH-THC (e25).

In vitro, CBD also inhibits UDP-glucuronosyltransferases such as UGT1A9 and UGT2B7 which is involved in the excretion of buprenorphine and morphine. UGT2B7 inhibition may contribute to the above-mentioned buprenorphine accumulation after inhaled cannabis use (25). Furthermore, CBD moderately inhibits in vitro the ABC efflux transporter ABCC1 (multidrug resistance protein 1, MRP1), but not the important drug transporters ABCB1 (P-glycoprotein, P-gp) and ABCG2 (breast cancer resistance protein, BCRP) (e23).

Finally, it was observed that CBD inhibited the serine hydroxylase CES-1 in vitro, whereas a dose of 1500 mg/day did not change the plasma concentration of the CES-1 substrate methylphenidate (e40).

Conclusion: CBD was not significantly changed as a victim of CYP3A4 and 2C9 inhibitors or inductors. Starting at an estimated dose of 300 mg/day, clinically noticeable effects must be expected, primarily due to the inhibition of CYP2C19 substrates and to a lesser extent of CYP2C9 and CYP3A4 substrates (Table 2); there is no evidence of such effects at lower doses. CBD is not subject to efflux transport by ABC transporters; thus, interaction at the level of the blood-brain barrier is less likely than it is with THC.

Pharmacodynamic interactions

Frequent side effects of CBD include dizziness, fatigue, sleepiness, and dry mouth (37), in high doses irritability and aggression, as it is stated in the summary of product characteristics for Epidyolex. These effects can be amplified by sedative and stimulant neuropsychotropic drugs. Unlike THC, CBD causes a reduction in appetite as well as diarrhea. Furthermore, care must be taken with the additional use of anorectics and prokinetics. In very high doses and in animal experiments, CBD was found to be hepatotoxic and damaged the reproductive system (e35); attention must be paid here to possible additive effects with harmful comedication.

Interaction between THC and CBD

Based on the available data, the question of possible pharmacokinetic interactions between THC and CBD could not be answered without contradictions (38). In low doses, co-administered CBD improved at least the tolerability of THC (10).

Cannabis flower

Inhalation and vaporization showed the same pharmacokinetics and increased the concentrations of THC and CBD in plasma and brain. However, the proportion of 11-OH-THC in plasma is lower (2, 15). The rapid increase in concentrations after inhalation can increase the therapeutic effect of cannabinoid drugs, but also the risk of side effects, such as psychological symptoms (15, 39). CBD and 7-OH-CBD inhibit the inactivation of nicotine in vitro (e41), potentially leading to increased neurological symptoms after the inhalation of tobacco smoke

Interestingly, the BfArM’s concomitant survey on the use of medical cannabis products found optimum tolerability of cannabinoid drugs with inhalative administration (1) (Figure 2). However, the low rate of return of the questionnaires must be taken into account. The Canadian COMPASS study also demonstrated an acceptable safety profile of inhaled THC. A daily dose of 2.5 g cannabis flower with 12.5% THC was administered (e42). However, conversion into oral dose equivalents to enable dose comparisons is difficult.

Discussion

Depending on the dose and method of use of THC and CBD, pharmacokinetic and pharmacodynamic interactions are to be expected. In patients with chronic disease, oral cannabinoid drugs offer the highest level of safety. When THC is administered via the peroral route, it is rarely used in doses exceeding 30 mg/day (1, 8, 28). Inhibition of CYP3A4 and CYP2C9 is probably only of clinical relevance in doses higher than those currently used; given their narrow therapeutic index, CYP3A4 substrates (phenprocoumon, cyclosporine) would be more affected than CYP2C9 substrates (diclofenac). Conversely, inhibitors of the ABCB1 transporter (P-glycoprotein), for example verapamil, could prolong the presence of THC in the brain. Although it is unlikely that oral THC has an impact on the transport of, for example, cytostatic agents, this possibility should be investigated, if necessary (e43–e44). In patients receiving CBD, however, the inhibition of CYP3A4 and 2C19 requires attention, at least when CBD is administered in oral doses of 300 mg and higher. In older patients, the dose of cannabinoid drugs should be gradually increased with caution; however, the elderly in particular can benefit from CDs (1, 24, e45).

In addition to symptom aggravation or inhibition, interactions of cannabinoid drugs with receptors other than CB receptors should be discussed. There is a lack of clinical data in this regard. Preclinical observations indicate complex posttranslational effects on the dopamine and endorphin system in particular (e46). Desired drug interactions include dose reduction in neuropsychiatric comedication, including opioids (8, 12, e5, e47). A German cohort study (9) reports complete discontinuation of opioids, anticonvulsants and antidepressants in 64.7%, 57.9% and 60% of patients treated with cannabinoid drugs, respectively. Other observational studies have confirmed this finding (12; e10, e48–e50).

Side effects of oral treatment with CAM are rarely classified as severe (1, 9, 40); in a registry study, the discontinuation rates were considerably lower compared to those observed with opioids or COX inhibitors (11).

Attention must be paid to cannabis abuse, which is overestimated according to its official definition, but underestimated from the point of view of physicians (28). The risk of abuse is considerably increased if the CD is inhaled. This risk decreases when pain control is the main indication for the use of cannabis (39). Our findings show how important it is that the treatment with cannabinoid drugs is monitored by physicians, especially in view of the upcoming legalization of cannabis.

Questions regarding the article in issue 49/2023:

Drug Interactions of Tetrahydrocannabinol and Cannabidiol in Cannabinoid Drugs

The closing date for entries is 7 December 2024. You may select only one answer per question.

Please select the answer that is most appropriate.

Question no. 1

What is the average dose of cannabinoid-drug tetrahydrocannabinol (THC-CAM) consumed per day until the steady state is reached?

  1. Between 1 and 4 mg

  2. Between 5 and 30 mg

  3. Between 30 and 60 mg

  4. Between 90 and 130 mg

  5. Between 150 and 250 mg

Question no. 2

According to the article, what is the reason why the concentration of THC in the brain is only about 1% of the THC dose taken?

  1. THC is bound to the myelin of Schwann cells.

  2. The ABC transporters transport THC out of the brain

  3. THC is metabolized at the blood-brain barrier

  4. THC-degrading enzymes are present in the cerebrospinal fluid

  5. Glial cells take up THC and break it down

Question no. 3

What effect does a genetically determined low CYP2C9 activity have on THC metabolism?

  1. Reduced half-life of THC (from 22 h to 7 h)

  2. A threefold reduction in AUC

  3. Prolonged half-life of THC (from 7 h to 22 h)

  4. Reduced half-life of THC (from 7 h to 3 h)

  5. A tenfold reduction in AUC

Question no. 4

Which of the following substances or types of food can increase the effect of cannabinoids?

  1. St. John‘s wort

  2. Rifampicin

  3. Dexamethason

  4. Grapefruit juice

  5. Carbamazepine

Question no. 5

Which of the following substances is an inactive metabolite of THC?

  1. Tetrahydrocannabinol

  2. 11-OH-THC

  3. CBD

  4. 11-COOH-THC

  5. 7-OH-CBD

Question no. 6

What does the abbreviation CBD stand for in the text?

  1. Cannabidiol

  2. Cannabinol

  3. Cannabisol

  4. Cannabiol

  5. Cannabilol

Question no. 7

Which cytochrome P450 enzyme is significantly involved in the inactivation of both THC and CBD?

  1. CYP2C19

  2. CYP4C17

  3. CYP3B4

  4. CYP1A2

  5. CYP3A4

Question no. 8

Starting from what daily dose of CBD can clinically noticeable effects on the effect of other substances metabolized by the same cytochrome P450 enzymes be expected?

  1. approx. 50 mg

  2. approx. 100 mg

  3. approx. 300 mg

  4. approx. 500 mg

  5. approx. 1000 mg

Question no. 9

Which of the following combinations of side effects associated with the use of cannabinoid drugs are among the most common?

  1. Vomiting and delusions

  2. Fatigue and dizziness

  3. Hallucinations and palpitations

  4. Constipation and dysarthria

  5. Depression and tachycardia

Question no. 10

How can the intrinsically low bioavailability of CBD after oral administration be increased?

  1. By taking it with food rich in fat

  2. By taking it before going to bed

  3. By fasting for one hour before and after intake

  4. By taking it with acidic foods

  5. By taking it with food rich in carbohydrates

Acknowledgments

Translated from the original German by Ralf Thoene, MD.

Footnotes

Conflict of interest

TH has received lecture fees and reimbursement of travel expenses from the CD-producing or distributing companies Avextra, Demecan, Spectrum, Sanity-Group, and Stada as well as from the German Society of Pain Medicine (DGS, Deutsche Gesellschaft für Schmerzmedizin) and the German Association of Pharmaceutical Cannabinoid Companies (BPC, Bundesverbandes der pharmazeutischen Cannabinoidunternehmen) during the last three years. He is a member of the Advisory Boards of Avextra and Sanity-Group.

IC declares no conflict of interests.

References

  • 1.BfArM. Abschlussbericht der Begleiterhebung nach § 31 Absatz 6 des Fünften Buches Sozialgesetzbuch zur Verschreibung und Anwendung von Cannabisarzneimitteln 2022. www.bfarm.de/cannabis-begleiterhebung (last accessed on 8 October 2023) [Google Scholar]
  • 2.Newmeyer MN, Swortwood MJ, Barnes AJ, Abulseoud OA, Scheidweiler KB, Huestis MA. Free and glucuronide whole blood cannabinoids‘ pharmacokinetics after controlled smoked, vaporized, and oral cannabis administration in frequent and occasional cannabis users: identification of recent cannabis intake. Clin Chem. 2016;62:1579–1592. doi: 10.1373/clinchem.2016.263475. [DOI] [PubMed] [Google Scholar]
  • 3.Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42:327–360. doi: 10.2165/00003088-200342040-00003. [DOI] [PubMed] [Google Scholar]
  • 4.Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4:1770–1804. doi: 10.1002/cbdv.200790152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018;84:2477–2482. doi: 10.1111/bcp.13710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Herdegen T. Medizinische Cannabinoide. DasEndocannabinoidsystem und pharmakologische Grundlagen. Intern Praxis. 2022;64:701–713. [Google Scholar]
  • 7.Horlemann J, Schürmann N. DGS-Praxisleitlinie: Cannabis in der Schmerzmedizin. 2022 [Google Scholar]
  • 8.Ueberall MA, Horlemann J, Schuermann N, Kalaba M, Ware MA. Effectiveness and tolerability of dronabinol use in patients with chronic pain: a retrospective analysis of 12-week open-label real-world data provided by the German Pain e-Registry. Pain Med. 2022;23:1409–1422. doi: 10.1093/pm/pnac010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Böttge-Wolpers C, Bialas P, Gottschling S, et al. Benefits and harms of cannabis-based medicines from the viewpoint of patients with chronic pain and their physicians: a cohort study in three pain centers of the German federal state Saarland. Schmerz. 2023 doi: 10.1007/s00482-022-00688-0. German. doi: 10.1007/s00482-022-00688-0. Epub ahead of print. [DOI] [PubMed] [Google Scholar]
  • 10.Ueberall MA, Essner U, Vila Silván C, Mueller-Schwefe GHH. Comparison of the effectiveness and tolerability of nabiximols (THC:CBD) oromucosal spray versus oral dronabinol (THC) as add-on treatment for severe neuropathic pain in real-world clinical practice: retrospective analysis of the German Pain e-Registry. J Pain Res. 2022;15:267–286. doi: 10.2147/JPR.S340968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Ueberall MA, Vila Silván C, Essner U, Mueller-Schwefe GHH. Effectiveness, safety, and tolerability of nabiximols oromucosal spray vs typical oral long-acting opioid analgesics in patients with severe neuropathic back pain: analysis of 6-month real-world data from the German Pain e-Registry. Pain Med. 2022;23:745–760. doi: 10.1093/pm/pnab263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Bar-Lev Schleider L, Mechoulam R, Sikorin I, Naftali T, Novack V. Adherence, safety, and effectiveness of medical cannabis and epidemiological characteristics of the patient population: a prospective study. Front Med. 2022;9 doi: 10.3389/fmed.2022.827849. 827849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Nielsen S, Sabioni P, Trigo JM, et al. Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis. Neuropsychopharmacology. 2017;42:1752–1765. doi: 10.1038/npp.2017.51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Parikh N, Kramer WG, Khurana V, Cognata Smith C, Vetticaden S. Bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers. Clin Pharmacol. 2016;8:155–162. doi: 10.2147/CPAA.S115679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Karschner EL, Darwin WD, Goodwin RS, Wright S, Huestis MA. Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem. 2011;57:66–75. doi: 10.1373/clinchem.2010.152439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Badowski ME. A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics. Cancer Chemother Pharmacol. 2017;80:441–449. doi: 10.1007/s00280-017-3387-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Spiro AS, Wong A, Boucher AA, Arnold JC. Enhanced brain disposition and effects of Δ9-tetrahydrocannabinol in P-glycoprotein and breast cancer resistance protein knockout mice. PLoS One. 2012;7 doi: 10.1371/journal.pone.0035937. e35937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Stott C, White L, Wright S, Wilbraham D, Guy G. A phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. Springerplus. 2013;2 doi: 10.1186/2193-1801-2-236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86–95. doi: 10.3109/03602532.2013.849268. [DOI] [PubMed] [Google Scholar]
  • 20.Sachse-Seeboth C, Pfeil J, Sehrt D, et al. Interindividual variation in the pharmacokinetics of delta9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9. Clin Pharmacol Ther. 2009;85:273–276. doi: 10.1038/clpt.2008.213. [DOI] [PubMed] [Google Scholar]
  • 21.Patilea-Vrana GI, Anoshchenko O, Unadkat JD. Hepatic enzymes relevant to the disposition of (-)-Δ9-tetrahydrocannabinol (THC) and its psychoactive metabolite, 11-OH-THC. Drug Metab Dispos. 2019;47:249–256. doi: 10.1124/dmd.118.085548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Bansal S, Paine MF, Unadkat JD. Comprehensive predictions of cytochrome P450 (P450)-mediated in vivo cannabinoid-drug interactions based on reversible and time-dependent P450 inhibition in human liver microsomes. Drug Metab Dispos. 2022;50:351–360. doi: 10.1124/dmd.121.000734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Lopera V, Rodríguez A, Amariles P. Clinical relevance of drug interactions with cannabis: a systematic review. J Clin Med. 2022;11 doi: 10.3390/jcm11051154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Pautex S, Bianchi F, Daali Y, et al. Cannabinoids for behavioral symptoms in severe dementia: safety and feasibility in a long-term pilot observational study in nineteen patients. Front Aging Neurosci. 2022;14 doi: 10.3389/fnagi.2022.957665. 957665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Vierke C, Marxen B, Boettcher M, Hiemke C, Havemann-Reinecke U. Buprenorphine-cannabis interaction in patients undergoing opioid maintenance therapy. Eur Arch Psychiatry Clin Neurosci. 2021;271:847–856. doi: 10.1007/s00406-019-01091-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Cascorbi I. Drug interactions-principles, examples and clinical consequences. Dtsch Arztebl Int. 2012;109:546–555. doi: 10.3238/arztebl.2012.0546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Schubert EA, Alffenaar JC, Johnstone MT, Barlow JW, Wheate NJ. Medicinal cannabis for patients with chronic non-cancer pain: analysis of safety and concomitant medications. Int J Pharm Pract. 2023;31:70–79. doi: 10.1093/ijpp/riac073. [DOI] [PubMed] [Google Scholar]
  • 28.Bialas P, Böttge-Wolpers C, Fitzcharles MA, et al. Cannabis use disorder in patients with chronic pain: overestimation and underestimation in a cross-sectional observational study in 3 German pain management centres. Pain. 2023;164:1303–1311. doi: 10.1097/j.pain.0000000000002817. [DOI] [PubMed] [Google Scholar]
  • 29.Rosa GM, Puce L, Mori L, et al. Nabiximols effect on blood pressure and heart rate in post-stroke patients of a randomized controlled study. Front Cardiovasc Med. 2022;9 doi: 10.3389/fcvm.2022.990188. 990188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Perucca E, Bialer M. Critical aspects affecting cannabidiol oral bioavailability and metabolic elimination, and related clinical implications. CNS Drugs. 2020;34:795–800. doi: 10.1007/s40263-020-00741-5. [DOI] [PubMed] [Google Scholar]
  • 31.Yeung CHT, Beers JL, Jackson KD, Edginton AN. Verifying in vitro-determined enzyme contributions to cannabidiol clearance for exposure predictions in human through physiologically-based pharmacokinetic modeling. CPT Pharmacometrics Syst Pharmacol. 2023;12:320–332. doi: 10.1002/psp4.12908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Morrison G, Crockett J, Blakey G, Sommerville K. A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between Clobazam, Stiripentol, or Valproate and Cannabidiol in healthy subjects. Clin Pharmacol Drug Dev. 2019;8:1009–1031. doi: 10.1002/cpdd.665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP UAB CBD Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58:1586–1592. doi: 10.1111/epi.13852. [DOI] [PubMed] [Google Scholar]
  • 34.Leino AD, Emoto C, Fukuda T, Privitera M, Vinks AA, Alloway RR. Evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus. Am J Transplant. 2019;19:2944–2948. doi: 10.1111/ajt.15398. [DOI] [PubMed] [Google Scholar]
  • 35.Suzuki J, Prostko S, Szpak V, et al. Impact of cannabidiol on reward- and stress-related neurocognitive processes among individuals with opioid use disorder: a pilot, double-blind, placebo-controlled, randomized cross-over trial. Front Psychiatry. 2023;14 doi: 10.3389/fpsyt.2023.1155984. 1155984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Anderson LL, Doohan PT, Oldfield L, et al. Citalopram and Cannabidiol: in vitro and in vivo evidence of pharmacokinetic interactions relevant to the treatment of anxiety disorders in young people. J Clin Psychopharmacol. 2021;41:525–533. doi: 10.1097/JCP.0000000000001427. [DOI] [PubMed] [Google Scholar]
  • 37.Schmidt-Wolf G, Cremer-Schaeffer P. 3 Jahre Cannabis als Medizin—Zwischenergebnisse der Cannabisbegleiterhebung [Three years of cannabis as medicine—preliminary results of the survey accompanying the prescription of medical cannabis in Germany] Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2021;64:368–377. doi: 10.1007/s00103-021-03285-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Englund A, Oliver D, Chesney E, et al. Does cannabidiol make cannabis safer? A randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios. Neuropsychopharmacology. 2023;48:869–876. doi: 10.1038/s41386-022-01478-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Mills L, Lintzeris N, O‘Malley M, Arnold JC, McGregor IS. Prevalence and correlates of cannabis use disorder among Australians using cannabis products to treat a medical condition. Drug Alcohol Rev. 2022;41:1095–1108. doi: 10.1111/dar.13444. [DOI] [PubMed] [Google Scholar]
  • 40.Bajtel Á, Kiss T, Tóth B, et al. The safety of dronabinol and nabilone: a systematic review and meta-analysis of clinical trials. Pharmaceuticals. 2022;15 doi: 10.3390/ph15010100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E1.Cremer-Schaeffer P, Hennig B, Schmidt-Wolf G, Marschall U, Petzke F, Häuser W. Prescriptions of cannabioinod drugs 2019-2022. Dtsch Arztbl Int. 2023;120:186–187. doi: 10.3238/arztebl.m2022.0389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E2.Bouquié R, Deslandes G, Mazaré H, Cogné M, Mahé J, Grégoire M, Jolliet P. Cannabis and anticancer drugs: societal usage and expected pharmacological interactions—a review. Fundam Clin Pharmacol. 2018;32:462–484. doi: 10.1111/fcp.12373. [DOI] [PubMed] [Google Scholar]
  • E3.Bicket MC, Stone EM, McGinty EE. Use of cannabis and other pain treatments among adults with chronic pain in US states with medical cannabis programs. JAMA Netw Open. 2023;6 doi: 10.1001/jamanetworkopen.2022.49797. e2249797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E4.Hameed M, Prasad S, Jain E, et al. Medical cannabis for chronic nonmalignant pain management. Curr Pain Headache Rep. 2023;27:57–63. doi: 10.1007/s11916-023-01101-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E5.Bialas P, Fitzcharles MA, Klose P, Häuser W. Long-term observational studies with cannabis-based medicines for chronic non-cancer pain: a systematic review and meta-analysis of effectiveness and safety. Eur J Pain. 2022;26:1221–1233. doi: 10.1002/ejp.1957. [DOI] [PubMed] [Google Scholar]
  • E6.Fitzcharles MA, Rampakakis E, Sampalis JS, Shir Y, Cohen M, Starr M, Häuser W. Use of medical cannabis by patients with fibromyalgia in Canada after cannabis legalisation: a cross-sectional study. Clin Exp Rheumatol. 2021;130(39 Suppl):115–119. doi: 10.55563/clinexprheumatol/qcyet7. [DOI] [PubMed] [Google Scholar]
  • E7.Busse JW, Vankrunkelsven P, Zeng L, et al. Medical cannabis or cannabinoids for chronic pain: a clinical practice guideline. BMJ. 2021;374 doi: 10.1136/bmj.n2040. n2040. [DOI] [PubMed] [Google Scholar]
  • E8.Aprikian S, Kasvis P, Vigano M, Hachem Y, Canac-Marquis M, Vigano A. Medical cannabis is effective for cancer-related pain: Quebec Cannabis Registry results. BMJ Support Palliat Care. 2023: doi: 10.1136/spcare-2022-004003. spcare-2022-004003. [DOI] [PubMed] [Google Scholar]
  • E9.Stack SK, Wheate NJ, Moloney NC, Abelev SV, Barlow JW, Schubert EA. The effectiveness and adverse events of cannabidiol and tetrahydrocannabinol used in the treatment of anxiety disorders in a PTSD subpopulation: an interim analysis of an observational study. J Pharm Technol. 2023;39:172–182. doi: 10.1177/87551225231180796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E10.Wendelmuth C, Wirz S, Torontali M, Gastmeier A, Gastmeier K. Dronabinol bei geriatrischen Schmerz- und Palliativpatienten : Dronabinol in geriatric pain and palliative care patients : a retrospective evaluation of statutory-health-insurance-covered outpatient medical treatment. Schmerz. 2019;33:384–391. doi: 10.1007/s00482-019-00408-1. [DOI] [PubMed] [Google Scholar]
  • E11.Gastmeier K, Gastmeier A, Rottmann F, Herdegen T, Böhm R. Cannabinoids reduce opioid use in older patients with pain : retrospective three-year analysis of data from a general practice. Schmerz. 2023;37:29–37. doi: 10.1007/s00482-022-00642-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E12.Wong SSC, Chan WS, Cheung CW. Analgesic effects of cannabinoids for chronic non-cancer pain: a systematic review and meta-analysis with meta-regression. J Neuroimmune Pharmacol. 2020;15:801–829. doi: 10.1007/s11481-020-09905-y. [DOI] [PubMed] [Google Scholar]
  • E13.Häuser W, Welsch P, Radbruch L, Fisher E, Bell RF, Moore RA. Cannabis-based medicines and medical cannabis for adults with cancer pain. Cochrane Database Syst Rev. 2023;6 doi: 10.1002/14651858.CD014915.pub2. CD014915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E14.Adams D. Cannabis, cannabinoids and cannbis-based medicines in cancer care. Integr Cancer Ther. 2022;21:1–11. doi: 10.1177/15347354221081772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E15.Filippini G, Minozzi S, Borrelli F, Cinquini M, Dwan K. Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis. Cochrane Database Syst Rev. 2022;5 doi: 10.1002/14651858.CD013444.pub2. CD013444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E16.Eisenberg E, Morlion B, Brill S, Häuser W. Medicinal cannabis for chronic pain: the bermuda triangle of low-quality studies, countless meta-analyses and conflicting recommendations. Eur J Pain. 2022;26:1183–1185. doi: 10.1002/ejp.1946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E17.Petzke F, Tölle T, Fitzcharles MA, Häuser W. Cannabis-based medicines and medical cannabis for chronic neuropathic pain. CNS Drugs. 2022;36:31–44. doi: 10.1007/s40263-021-00879-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E18.Fitzcharles MA, Petzke F, Tölle TR, Häuser W. Cannabis-based medicines and medical cannabis in the treatment of nociplastic pain. Drugs. 2021;81:2103–2116. doi: 10.1007/s40265-021-01602-1. [DOI] [PubMed] [Google Scholar]
  • E19.To J, Davis M, Sbrana A, et al. MASCC guideline: cannabis for cancer-related pain and risk of harms and adverse events. Support Care Cancer. 2023;31 doi: 10.1007/s00520-023-07662-1. [DOI] [PubMed] [Google Scholar]
  • E20.De Feo G, Case AA, Crawford GB. Multinational Association of Supportive Care in Cancer (MASCC) guidelines: cannabis for psychological symptoms including insomnia, anxiety, and depression. Support Care Cancer. 2023;31 doi: 10.1007/s00520-023-07628-3. [DOI] [PubMed] [Google Scholar]
  • E21.Creanga-Murariu I, Filipiuc LE, Cuciureanu M, Tamba BI, Alexa-Stratulat T. Should oncologists trust cannabinoids? Front Pharmacol. 2023;14 doi: 10.3389/fphar.2023.1211506. 1211506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E22.Stott CG, White L, Wright S, Wilbraham D, Guy GW. A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray. Eur J Clin Pharmacol. 2013;69:1135–1147. doi: 10.1007/s00228-012-1441-0. [DOI] [PubMed] [Google Scholar]
  • E23.Anderson LL, Etchart MG, MacNair L, et al. In vitro screening of three commercial cannabis-based products on ATP-binding cassette and solute-carrier transporter function. Cannabis Cannabinoid Res. 2022;7:304–317. doi: 10.1089/can.2020.0053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E24.Wall ME, Perez-Reyes M. The metabolism of delta 9-tetrahydrocannabinol and related cannabinoids in man. J Clin Pharmacol. 1981;21:178S–189S. doi: 10.1002/j.1552-4604.1981.tb02594.x. [DOI] [PubMed] [Google Scholar]
  • E25.Bansal S, Zamarripa CA, Spindle TR, et al. Evaluation of cytochrome P450-mediated cannabinoid-drug interactions in healthy adult participants. Clin Pharmacol Ther. 2023;114:693–703. doi: 10.1002/cpt.2973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E26.Patilea-Vrana GI, Unadkat JD. Quantifying hepatic enzyme kinetics of (-)-Δ9-Tetrahydrocannabinol (THC) and its psychoactive metabolite, 11-OH-THC, through in vitro modeling. Drug Metab Dispos. 2019;47:743–752. doi: 10.1124/dmd.119.086470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E27.Nasrin S, Watson CJW, Perez-Paramo YX, Lazarus P. Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions. Drug Metab Dispos. 2021;49:1070–1080. doi: 10.1124/dmd.121.000442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E28.Engels FK, de Jong FA, Sparreboom A, et al. Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. Oncologist. 2007;12:291–300. doi: 10.1634/theoncologist.12-3-291. [DOI] [PubMed] [Google Scholar]
  • E29.Alsherbiny MA, Li CG. Medicinal cannabis-potential drug interactions. Medicines. 2018;6 doi: 10.3390/medicines6010003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E30.Tsang CC, Giudice MG. Nabilone for the management ofpain. Pharmacotherapy. 2016;36:273–286. doi: 10.1002/phar.1709. [DOI] [PubMed] [Google Scholar]
  • E31.Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. CMAJ. 2008;178:1669–1678. doi: 10.1503/cmaj.071178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E32.Pabon E, Rockwood F, Norman GJ, de Wit H. Acute effects of oral delta-9-tetrahydrocannabinol (THC) on autonomic cardiac activity and their relation to subjective and anxiogenic effects. Psychophysiology. 2022;59 doi: 10.1111/psyp.13955. e13955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E33.Brzozowska N, Li KM, Wang XS, et al. ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice. PeerJ. 2016;4 doi: 10.7717/peerj.2081. e2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E34.Beers JL, Fu D, Jackson KD. Cytochrome P450-catalyzed metabolism of cannabidiol to the active metabolite 7-hydroxy-cannabidiol. Drug Metab Dispos. 2021;49:882–891. doi: 10.1124/dmd.120.000350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E35.Gingrich J, Choudhuri S, Cournoyer P, Downey J, Muldoon Jacobs K. Review of the oral toxicity of cannabidiol (CBD) Food Chem Toxicol. 2023;176 doi: 10.1016/j.fct.2023.113799. 113799. [DOI] [PubMed] [Google Scholar]
  • E36.Manini AF, Yiannoulos G, Bergamaschi MM, et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med. 2015;9:204–210. doi: 10.1097/ADM.0000000000000118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E37.Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–1251. doi: 10.1111/epi.13060. [DOI] [PubMed] [Google Scholar]
  • E38.Thomas TF, Metaxas ES, Nguyen T, Bennett W, Skiendzielewski KV, Quinn DH, Scaletta AL. Case report: Medical cannabis-warfarin drug-drug interaction. J Cannabis Res. 2022;4 doi: 10.1186/s42238-021-00112-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E39.Buijs SM, Braal CL, Buck SAJ, et al. CBD-oil as a potential solution in case of severe tamoxifen-related side effects. NPJ Breast Cancer. 2023;9 doi: 10.1038/s41523-023-00570-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E40.Markowitz JS, De Faria L, Zhang Q, et al. The influence of cannabidiol on the pharmacokinetics of methylphenidate in healthy subjects. Med Cannabis Cannabinoids. 2022;5:199–206. doi: 10.1159/000527189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E41.Nasrin S, Coates S, Bardhi K, Watson C, Muscat JE, Lazarus P. Inhibition of nicotine metabolism by cannabidiol (CBD) and 7-hydroxycannabidiol (7-OH-CBD) Chem Res Toxicol. 2023;36:177–187. doi: 10.1021/acs.chemrestox.2c00259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E42.Ware MA, Wang T, Shapiro S, Collet JP COMPASS study team. Cannabis for the management of pain: assessment of safety study (COMPASS) J Pain. 2015;16:1233–1242. doi: 10.1016/j.jpain.2015.07.014. [DOI] [PubMed] [Google Scholar]
  • E43.Waissengrin B, Leshem Y, Taya M, Meiri D, Merimsky O, Shamai S, Wolf I, Rubinek T. The use of medical cannabis concomitantly with immune checkpoint inhibitors in non-small cell lung cancer: a sigh of relief? Eur J Cancer. 2023;180:52–61. doi: 10.1016/j.ejca.2022.11.022. [DOI] [PubMed] [Google Scholar]
  • E44.Woerdenbag HJ, Olinga P, Kok EA, et al. Vol. 15. Basel: Cancers; 2023. Potential, limitations and risks of cannabis-derived products in cancer treatment; 2119 pp. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E45.Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer‘s disease. Int J Geriatr Psychiatry. 1997;12:913–919. [PubMed] [Google Scholar]
  • E46.Hasbi A, Madras BK, George SR. Daily Δ9-tetrahydrocannabinol and withdrawal increase dopamine D1-D2 receptor heteromer to mediate anhedonia- and anxiogenic-like behavior through a dynorphin and kappa opioid receptor mechanism. Biol Psychiatry Glob Open Sci. 2022;3:550–566. doi: 10.1016/j.bpsgos.2022.07.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E47.Christensen C, Allesø M, Rose M, Cornett C. Clinical research evidence supporting administration and dosing recommendations of medicinal cannabis as analgesic in cancer patients. J Clin Med. 20221;2 doi: 10.3390/jcm12010307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E48.Solmi M, De Toffol M, Kim JY, et al. Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies. BMJ. 2023;382 doi: 10.1136/bmj-2022-072348. e072348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E49.Lucas P, Boyd S, Milloy MJ, Walsh Z. Cannabis significantly reduces the use of prescription opioids and improves quality of life in authorized patients: results of a large prospective study. Pain Med. 2021;22:727–739. doi: 10.1093/pm/pnaa396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • E50.Lee C, Lin M, Martins KJB, et al. Opioid use in medical cannabis authorization adult patients from 2013 to 2018: Alberta, Canada. BMC Public Health. 2021;21 doi: 10.1186/s12889-021-10867-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

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