1. Introduction
During the last years, an increased number of countries (states) have legalized the medical use of cannabis and/or its recreational use. Because the legalization and social acceptance of cannabis continue to expand, it is crucial to understand how these substances can impact public health and clinical practice. One relevant issue is the possibility of interaction with other medicines and its consequences.
1.1. Cannabis
Cannabis sativa L., an herbaceous plant belonging to the Cannabaceae family, is globally recognized as “marijuana” and “hemp”. It consists of a single species, “sativa”, which encompasses several subspecies or varieties, such as Cannabis sativa ssp. sativa, Cannabis sativa ssp. indica, Cannabis sativa ssp. ruderalis, and Cannabis sativa ssp. afghanica [1].
The cannabis plant harbors over 100 cannabinoids and a plethora of other compounds, such as terpenoids, flavonoids, and omega-3 and 6 fatty acids. Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most important cannabinoids, widely studied and sought after by consumers, along with their acidic forms. A crucial biochemical process in cannabis involves the conversion of cannabigerolic acid (CBGA) into tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), which are inactive acidic forms of the cannabinoids THC and CBD, naturally occurring in the cannabis plant. Under high temperatures (as in smoking or vaporizing) or through decarboxylation, THCA can convert into ∆-9-THC or its isomer ∆-8-THC. Additionally, THCA can oxidize to form cannabinolic acid (CBNA), which converts to cannabinol (CBN). On the other hand, CBDA can convert into CBD [2].
THC, the main psychoactive compound in cannabis, is recognized for its reinforcing and addictive properties, which result from its interaction with the endocannabinoid system. This system is primarily composed of cannabinoid type 1 receptors (CB1R) and cannabinoid type 2 receptors (CB2R). CB1R is mainly found in the central nervous system (CNS), and CB2R predominantly in the immune system, hematopoietic cells, and certain brain regions [3,4]. THC primarily targets CB1R, as a partial agonist, eliciting the characteristic “high” associated with marijuana use. In contrast, CBD acts chiefly as an antagonist of CB1R and as a non-competitive negative allosteric modulator of CB2R, and also interacts with various other receptors, thereby not eliciting the characteristic effects of THC, including its abuse potential [5,6]. Consequently, CBD has shown analgesic, anti-inflammatory, and neuromodulatory properties, suggesting its therapeutic potential [7,8,9].
1.2. Cannabis Products
Cannabis products are used for both “medical” and “non-medical” purposes, and the latter include recreational and industrial applications. To differentiate them, various terms are employed: “medical cannabis”, “recreational cannabis”, and “industrial hemp” [10].
While most cannabis use is recreational, the concept of legal medical cannabis use has gained increasing attention over the past few decades and has been legislated in various countries [11,12]. Since the mid-1990s, several states in the United States of America (USA) have legalized medical cannabis for various symptoms and illnesses, including multiple sclerosis, chronic pain, and terminal cancer. In 1999, Canada introduced a medical cannabis program. Since the early 2000s, many countries have progressively legislated the medical use of cannabis under specified conditions [13]. Over the last two decades, there has been a resurgence in the use of cannabis and cannabinoids to treat a variety of health conditions, such as chemotherapy-induced nausea/vomiting, chronic pain, and spasticity associated with multiple sclerosis and refractory epilepsy, with potential efficacy in treating post-traumatic stress disorder (PTSD) [14].
Currently, the term “medical use of cannabis” refers to the practice of permitting cannabis use for medical purposes or the utilization of cannabis-based products (Table 1), cannabis-derived compounds, or cannabis-related compounds (Table 2). “Medical cannabis products” encompass a wide array of preparations and pharmaceutical forms, offering various routes of administration, each containing different active cannabinoid compounds with distinct regulatory and medical implications [15]. Presently, nabilone (Cesamet®, a synthetic cannabinoid), CBD (Epidiolex®, a natural extract), nabiximols (Sativex®, a natural blend of THC/CBD), and dronabinol (Marinol®, Syndros®, synthetic THC) are the only pharmaceutical cannabinoid drugs approved for prescription use [12,16]. These are authorized for treating secondary muscle spasticity in multiple sclerosis, refractory epilepsy associated with Dravet syndrome and Lennox–Gastaut syndrome, antiemetic therapy in oncological patients, chronic pain, glaucoma, and anorexia with weight loss in patients with human immunodeficiency virus (HIV) [17,18,19].
1.3. Epidemiology
Cannabis remains the most widely used illicit recreational drug worldwide [20]. The cannabis industry has expanded significantly due to increasing legal access. In 2022, the global population of drug users reached 292 million, making a 20% rise over the past decade. Cannabis continues to be the most commonly used drug worldwide, with 228 million individuals reported as users [21].
The potency of cannabis products in the market has increased in recent years. From 2011 to 2021, the average potency of herbal cannabis in the European Union increased by 57%, and the potency of cannabis resin increased by nearly 200% [22]. The FDA reports that the rapidly expanding cannabinoid market raises safety concerns, particularly due to the increased consumption of formulations with high concentrations of emerging semi-synthetic cannabinoids, such as delta-8-tetrahydrocannabinol (Δ-8-THC), delta-10-tetrahydrocannabinol (Δ-10-THC), or hexahydrocannabinol (HHC). This trend may pose potential risks to public health, including increased co-use with other cannabis derivatives, other substances of abuse like nicotine, and concurrent medications [23].
Epidemiological data on medical cannabis usage are limited, with prevalence estimates varying widely, based on the context and population of interest [13,22]. Most prevalence studies do not specify the type of cannabis preparation or administration route. A cross-sectional study in Washington State (USA), examining the prevalence and clinical characteristics of documented medical cannabis use in electronic primary care health records (n = 185,565), revealed that approximately 2% of patients had documented medical cannabis use and 20% had other cannabis use. Those using medical cannabis had a higher prevalence of conditions for which cannabis use might confer potential benefits (chronic pain, multiple sclerosis, muscle spasticity, severe nausea, sleep disorders) at 49.8%, compared to 39.9% for patients with other types of use. Notably, chronic pain was the most common condition among medical cannabis users at 35.4% [24]. Another prevalence study with 27,169 participants from Canada and the USA found a medical cannabis usage rate of 27%, highest among young adults. States with legal recreational cannabis use showed a prevalence of 34% versus 23% in states where it was illegal. The most common therapeutic purposes were chronic pain (53%), sleep difficulties (46%), headaches/migraines (35%), appetite disturbances (22%), and nausea/vomiting (21%). For mental health, the most common uses were for anxiety (52%), depression (40%), and PTSD (17%). Additionally, 11% used cannabis to manage alcohol or other substance consumption [25]. A retrospective study across 33 clinics in the United States, with 61,379 patients, found that 44.2% used prescribed cannabis. The most common medical conditions treated were chronic pain (38.8%), anxiety (13.5%), and PTSD (8.4%). Other conditions included back and neck problems (6.5%), arthritis (3.9%), insomnia (3.4%), and cancer-related pain (2.7%). Migraines, depression, attention-deficit, muscle spasms, fibromyalgia, chronic nausea, epilepsy, and headaches have been reported as the primary conditions in 2% or fewer cases [26]. There is a high prevalence of CBD use among individuals with physical and mental health issues, justifying the need for public health warnings about potential adverse effects and drug interactions [27].
In reference to the scope of this review, two studies have been published, based on case reports and data from the FDA Adverse Event Reporting System Database (FAERS), that explore the interactions between cannabis-derived products and medications in pediatric and adult populations. In individuals under 18 years of age, an increased risk of severe adverse reactions was observed when cannabinoids were combined with medications such as methadone, everolimus, fluoxetine, and paroxetine [28]. In adults, the medications most involved in potential interactions were anticonvulsants, antidepressants, warfarin, and tacrolimus. A higher proportion of severe events, including deaths, were found when cannabis was used in combination with controlled substances (medications with strict regulation, such as opioids, benzodiazepines, and certain stimulants) compared to non-controlled substances [29].
1.4. Pharmacokinetics
Understanding the pharmacokinetic profile of cannabis is crucial to determine its potential interactions with other approved prescription drugs. The pharmacokinetics of cannabis vary depending on the formulation, the method, and route of administration [30,31,32].
1.4.1. Absorption
The primary routes of cannabis administration are smoking and vaporization. THC and CBD can be detected in plasma within seconds following initial inhalation, with peak concentrations (Cmax) observed between 1.2 and 30 min. The bioavailability of THC post-inhalation varies from 10% to 35%, whereas the bioavailability of CBD ranges from 11% to 45%. The quantity absorbed is contingent upon the number of inhalations, duration of each puff, and depth of inhalation [30,31,33].
Inhalation and oromucosal administration of cannabis circumvent or diminish first-pass metabolism, which is typically seen with the oral administration of cannabis [33]. Oromucosal preparations, such as buccal aerosols like nabiximols, are quickly absorbed, leading to higher plasma concentrations of THC than those achieved orally, although lower than those from inhalation. Such preparations are beneficial for symptoms that require swift alleviation [31,34].
THC (dronabinol) and CBD are lipophilic and have low oral bioavailability [22]. Oral bioavailability is estimated to be approximately 5–20% due to erratic absorption. They undergo gastric destruction and first-pass hepatic metabolism, reaching a maximum plasma concentration (Tmax) at 1–5 h after oral administration. Effects begin within 30 min of ingestion and can last for up to 6 h post-ingestion [32,34]. Given this profile, oral formulations are beneficial for patients who require extended symptom relief [31].
Transdermal administration of cannabis circumvents first-pass metabolism. Cannabis has a highly hydrophobic nature that impedes diffusion through the aqueous layer of the skin. Studies have shown that CBD has greater skin permeability than THC [31,32,35]. Research has documented that, following the application of a dermal patch (Δ-8-THC 16 mg/mL in propylene glycol–water–ethanol, in a 1:1:1 ratio), the mean steady-state plasma concentration of Δ-8-THC reached approximately 4.4 ng/mL at 1.4 h and was sustained for at least 48 h. Additionally, the permeabilities of CBD and cannabinol (CBN) were 10 times higher than those of Δ-8-THC [36]. Although transdermal administration is not currently employed clinically, it has potential for future use [35].
1.4.2. Distribution
Cannabinoids generally exhibit high liposolubility, enabling them to easily cross the blood–brain, placental, and breast tissue barriers. They bind to plasma proteins at approximately 95%, primarily to lipoproteins and albumin, and accumulate in the liver, lungs, and fatty tissues, leading to multicompartmental pharmacokinetics [30,31,32]. The volume of distribution (Vd) of THC and CBD in adults varies from 2.5 to 10 L/kg, assuming a body weight of 70 kg [30,37].
1.4.3. Metabolism
The two primary cannabinoids, CBD and THC, undergo extensive metabolism in the liver, primarily by cytochrome P450 isozymes CYP2C9, CYP2C19, and CYP3A4. In humans, these processes involve hydroxylation or oxidation, followed by glucuronidation catalyzed by UDP-glucuronosyltransferase (UGT) enzymes [30,37,38].
THC (dronabinol) undergoes first-pass metabolism in the liver, transforming into 11-hydroxy-THC (11-OH-THC), primarily through CYP2C9. This metabolite is active and slightly more potent than ∆-9-THC. Additionally, 11-OH-THC crosses the blood–brain barrier more readily. After a second hepatic metabolism, 11-OH-THC is converted into various inactive metabolites (CYP2C9), including 11-nor-carboxy-∆9-THC (THC-COOH), which subsequently binds to glucuronic acid to produce THC-COO-Glucuronide; these inactive metabolites are primarily excreted through urine. Other metabolic pathways involve CYP3A4 and UGT enzymes, with more than 80 distinct THC metabolites being identified [5,30,37,38]. Figure 1 shows the metabolism of THC in a simplified way.
CBD is primarily metabolized by the isoenzymes CYP2C19 and CYP3A4, with additional metabolism by CYP1A1, CYP1A2, CYP2C9, and CYP2D6. The UGT isoforms responsible for the phase 2 conjugation of CBD are UGT1A7, UGT1A9, and UGT2B7. Following hydroxylation by CYP2C9 to form 7-hydroxy CBD (7-OH-CBD), other hepatic metabolism occurs to form 7-carboxy-cannabidiol (7-COOH-CBD), the primary inactive metabolite of CBD, as well as other metabolites such as 6-hydroxycannabidiol (6-OH-CBD). These metabolites are then excreted primarily via feces, with a lesser amount excreted in urine [5,31,39]. Figure 2 shows the metabolism of CBC in a simplified way.
1.4.4. Elimination
THC is primarily excreted through feces (approximately 65–80%) and urine (about 20–35%). Following THC consumption, urine predominantly contains acidic metabolites, such as THC-COOH, mainly in its glucuronidated form, whereas feces contain both neutral and acidic metabolites, with THC-COOH (28%) and 11-OH-THC (20%) being the most prevalent. In contrast, the majority of CBD is excreted unchanged in feces (33%), with both unchanged CBD and CBD glucuronide excreted in the urine [28,31,33,40].
The elimination half-life of THC is highly variable, and is characterized by a rapid initial phase and a relatively short intermediate half-life (approximately 4 h), followed by a significantly prolonged terminal elimination phase, with half-lives ranging from 24 to 36 h or more. This extended duration is attributed to the slow redistribution of THC from deep compartments, such as fatty tissues. As a result, THC concentrations exceeding 1 μg/L can be detected in the blood of heavy users for more than 24 h after the last cannabis use. Similarly, CBD has been reported to exhibit a long terminal elimination half-life, with values of 24 ± 6 h after intravenous dosing, 31 ± 4 h post-inhalation, and 2–5 days following repeated daily oral administration [31,41]. For occasional cannabis users, traces of metabolites can be found in urine for up to a week after consumption, whereas for those who use it daily, these metabolites may remain detectable for as long as a month [32].
1.5. Pharmacogenetics/Pharmacogenomics
Polymorphisms in genes encoding receptors, enzymes, and transporters can influence the pharmacokinetics, efficacy, and resistance to cannabinoid therapy.
Multiple genetic polymorphisms have been identified in phase 1 metabolic enzymes (CYP2C9, CYP3A4, and CYP2C19) and phase 2 metabolic enzymes (UGT1A3, UGT1A9, UGT1A10, and UGT2B7) that affect the metabolism of cannabinoids. These polymorphisms can result in either rapid (ultrarapid metabolizers) or slow (poor metabolizers) enzymatic metabolisms. Interactions between cannabinoids and other drugs are complex. For instance, individuals with CYP2C9*2 or CYP2C9*3 variants, especially those homozygous for CYP2C9*2 or heterozygous/homozygous for CYP2C9*3, may experience significantly reduced THC and CBD metabolism. Poor metabolizer phenotypes indicate a decreased rate of THC conversion into its active metabolite 11-OH-THC, resulting in a higher concentration ratio of THC/11-OH-THC. However, since both 11-OH-THC and THC possess psychoactive properties, altering their ratio is expected to have a minimal impact on the onset of psychotic symptoms, but the decreased formation of inactive metabolites (THC-COOH) enhances the risks associated with cannabis use [42]. In a retrospective study of 71 patients, it was suggested that atypical genetic variants (in CYP2C9, CYP2C19, CYP3A4, and CYP3A5) and concomitant medications may alter the metabolism of THC and CBD. However, the lack of clinical data makes it difficult to estimate their impact [43].
Considering the genetic variations, certain individuals or populations may be at a heightened risk of toxicity and adverse events. The label information for dronabinol indicates that individuals with genetic variants associated with diminished CYP2C9 function could experience a two-to-three-fold increase in dronabinol exposure. Moreover, individuals with genetic glucuronidation disorders, such as Gilbert’s syndrome, may exhibit increased serum bilirubin levels and should be treated cautiously when administered nabiximols according to label [39,44,45,46].
1.6. Acute, Chronic Effects and Intoxication
The impact of cannabis preparations varies with their THC and CBD content. This variation underpins the differing effects of medicinal cannabis products, which typically contain higher levels of CBD and lower levels of THC than recreational cannabis [16].
THC primarily induces psychoactive effects, such as pleasure, relaxation, and euphoria, along with cognitive alterations, including impaired memory and attention, diminished psychomotor and cognitive performance, and altered perception of time passage [16,17,18,19]. Sensory perception is often enhanced; however, feelings of increased well-being may lead to anxiety, dysphoria, or panic [16,17,19,47] Common physiological effects of cannabinoids include tiredness, tachycardia, dizziness, dry mouth, orthostatic hypotension, conjunctival injection, decreased lacrimation, increased appetite, and muscle relaxation [48]. Acute impairments in psychomotor performance, such as anxiety and attention deficits, have been associated with driving impairment, heightening the risk of traffic accidents and hindering the operation of heavy machinery, particularly when combined with alcohol [4,17,18].
Regular cannabis inhalation can lead to chronic respiratory symptoms, including a cough and chronic obstructive pulmonary disease. It has also been associated with an elevated risk of cardiovascular disorders, such as acute myocardial infarction, stroke, and transient ischemic attack. Furthermore, chronic consumption may increase the likelihood of mental health disorders, including depression, schizophrenia, and other psychoses. Cannabis use is a critical factor in acute psychosis and is associated with a high incidence of schizophrenia. The risk of mental illness escalates with increased frequency and duration of use, and early initiation of cannabis consumption is a significant risk factor [18,47]. Other nonspecific cannabis-related disorders include flashbacks, memory impairment, and amotivational syndrome [17,49]. THC can modify the secretion of sex hormones [18]. Cannabinoid hyperemesis syndrome (CHS) is associated with chronic cannabis use [50].
Long-term cannabis consumption can lead to substance use disorder (addiction). Tolerance to the undesired effects of cannabinoids, such as dizziness, tiredness, cardiovascular, and psychoactive effects, may develop over days or weeks. Withdrawal symptoms occur only in heavy cannabis users after the abrupt cessation of use [44,51]. Abstinence can present with symptoms including irritability, nervousness, anxiety, insomnia, vivid dreams, decreased appetite, weight loss, depressive disorder, craving for cannabis, headache, restlessness, tremors, chills, and sweating [51]. However, withdrawal symptoms are rarely problematic in the controlled medical administration of cannabinoids [47,52].
According to the DSM-5 manual, a diagnosis of cannabis intoxication requires a recent history of cannabis use and clinically significant behavioral or psychological changes following consumption, such as euphoria, impaired judgment, and compromised motor skills. Additionally, at least two of the following symptoms should be present within approximately two hours after cannabis use: red eyes, dry mouth, increased appetite, and elevated heart rate. These symptoms must not be attributable to any other medical or psychiatric condition [4,49].
THC is primarily sought by recreational users in social settings and is often referred to as a “gateway drug”. This designation suggests that individuals who use it may be at an increased risk for other substance use disorders, such as those involving cocaine or opioids [17,49].
Medications with similar effects to those of cannabis can potentiate these effects. For instance, sedatives such as benzodiazepines, when used concomitantly with cannabis, may augment sedative effects. Likewise, cannabis use can exacerbate the adverse effects of medications with similar side effects, such as additive tachycardia, when cannabinoids and atropine are taken together. In some cases, additive effects are beneficial, and medicinal cannabis may be administered concurrently with antispasmodics, bronchodilators, antiemetics, and analgesics [16,47].
2. Data Search and Selection Methods
We utilized the PubMed database, using the search strategy: (Cannabis OR medical cannabis OR THC OR tetrahydrocannabinol OR CBD OR cannabidiol OR synthetic cannabinoids OR dronabinol OR Marinol OR Syndros OR nabilone OR Cesamet OR Canemes OR Epidyolex OR Bedrocan OR nabiximols OR Bedrobinol OR Bediol OR Bedica OR Bedrolite OR Sativex) AND (interaction OR drug interaction). We only selected human data written in English. The filters applied included Clinical Trial, Humans, and English. The search, performed on 12 January 2024, yielded 275 articles.
Additionally, data from the interactions section of the Summary of Product Characteristics/Prescriber Information for cannabis products were reviewed and included in the Stockley’s Drug Interactions book. For interaction risk rating, we relied on the UpToDate search platform (UpToDate,
We classified the evidence as follows:
Strong: the interaction is supported by evidence from at least one meta-analysis, systematic review, or a clinical trial (randomized or non-randomized);
Moderate: the interaction is supported by evidence from at least one observational study (cohort or case-control) or a minimum of three case reports;
Weak: the interaction is supported by evidence from fewer than three case reports.
And we classified clinical relevance as follows:
Major: the interaction poses a risk of harm or injury. The parameter variation is 400% or more [Internationalized Normalized Ratio (INR), transaminases, Area Under the Curve (AUC)] or at least 80% (clearance);
Significant: the interaction requires closer monitoring. The parameter variation is between 100 and 400% (INR, transaminases, AUC) or between 50% and 80% (clearance);
Minor: the interaction causes little to no harm. The parameter variation ranges between 25% and 100% (INR, transaminases, AUC) or between 20% and 50% (clearance);
Lack of relevance and/or not applicable (not classified in previous definitions).
3. Cannabis Products’ Drug Interactions
Pharmacokinetic interactions occur when a cannabis product is combined with another substance, such as a medicine or drug of abuse, leading to altered concentrations that may result in changes in the effects. Conversely, pharmacodynamic interactions arise when the effects of pharmacological targets are altered. In both scenarios, it is crucial to consider the implications of efficacy and safety.
Cannabinoids can act as either precipitant drugs, which induce changes in the concentrations or effects of another drug, or as an object drug, whose concentrations or effects are altered by other substance. Cannabinoids, when mainly acting as precipitant drugs, can enhance the bioavailability or decrease the clearance of other medications via enzymatic inhibition. This may lead to heightened systemic exposure, and consequently, an elevated risk of adverse effects.
Research on the risks of interactions between drugs and cannabis products has mainly focused on THC and CBD, and, therefore, the potential risk of other cannabinoids is still unknown.
As previously noted, THC and CBD act as substrates, primarily for CYP2C19, CYP2C9, and CYP3A4, and as modulators, functioning as inhibitors or inducers of various CYP450 isoenzymes. These isoenzymes are crucial for the metabolism of various medications. While primary pharmacokinetic interactions can be attributed to inhibition, induction, or shared CYP metabolism between cannabinoids and other drugs, interactions involving UGT enzymes or P-gp have also been reported. In vitro studies have revealed that cannabinoids and the major metabolites of THC strongly inhibit several P450 enzymes, including CYP2B6, CYP2D6, CYP1A2, and CYP2C9. CBD exhibits inhibitory competition with CYP3A4, CYP2C9, CYP2D6, CYP2B6, and CYP2E1, whereas CBN also inhibits CYP2C9, CYP2B6, and CYP2E1 [5,11]. Additionally, CBD is a weak inhibitor of CYP1A2 (label) and P-glycoprotein (P-gp) [55].
When considering combined in vitro studies examining the induction and inhibition of the major isoforms of human CYP450 by THC, CBD, and CBN, a low risk of clinically significant interactions with the majority of medications is suggested [48]. However, those involving drugs with a narrow therapeutic index (NTI) as object drugs or strong inhibitors/inducers as precipitant drugs are more likely to be clinically significant. Additionally, cannabinoids are highly protein-bound, which may lead to displacement interactions with other protein-bound drugs, potentially increasing the free fraction of NTI medications and altering their pharmacokinetics. Kocis and Vrana describe a list of at least 60 medications with a NTI [53,56]. Table 3 shows how cannabinoid medications affect the metabolism of substrate medication (object) with NTI, based on the medication label. In Table 4 we present medications with NTI and cannabinoid medications with high protein binding.
Nabiximols (Sativex®, THC: CBD; 1:1, equal quantities) can produce metabolic interactions, mainly mediated by its CBD component. Nabiximols was observed to be a reversible inhibitor of CYP3A4, CYP2C9, CYP2C19, CYP1A2, and CYP2B6 at concentrations significantly higher than those likely to be clinically achieved. In vitro research also demonstrated the potential of nabiximols for the time-dependent inhibition of CYP3A4 at clinically relevant concentrations. The inactivation rate of CYP3A4 is expected to be rapid. In an in vitro study, nabiximols inhibited the UGT enzymes, UGT1A9 and UGT2B7, at concentrations achievable in clinical settings [39]. Plasma concentrations of CBD and THC from clinical doses of nabiximols may be sufficient to induce CYP3A4, CYP2B6, and CYP1A2 at the mRNA level, potentially inducing drug-metabolizing enzymes and transporters in vitro; however, the clinical relevance of this induction remains unknown [56].
Dronabinol, a synthetic form of THC (see THC sections), has an inhibitory potential on enzymes that is not fully understood; however, it is suspected that there may be potential drug–drug interactions (DDI) with CYP2C9 and CYP3A4 substrates. CYP3A4 inhibitors may increase the systemic exposure of dronabinol and/or its active metabolite [56]. The liquid formulation of dronabinol (Syndros®) contains 50% dehydrated alcohol, which can cause a disulfiram-like reaction with medications such as disulfiram or metronidazole, leading to symptoms like abdominal cramps, nausea, and flushing [45].
Evidence indicates that nabilone (Cesamet®, synthetic cannabinoid) is extensively metabolized by multiple P450 enzyme isoforms. Nabilone exhibits a weak inhibitory effect on CYP3A4 and CYP2E1, and a moderate inhibitory effect on CYP2C9 and CYP2C8 [44,56].
CBD (Epidiolex®) may induce or inhibit the metabolism of other medications that are substrates of CYP1A2 and CYP2B6, resulting in either a decrease or an increase in the effect of the other medication. Additionally, CBD can inhibit the metabolism of other medications by the enzymes CYP2C9, CYP2C19, CYP2C8, and by the UGT2B7 and UGT1A9 enzymes. Figure 3 summarizes the influence of CBD, dronabinol, nabiximols, and nabilone on the activity of different enzymes.
CBD is purported to mitigate the adverse effects of THC; however, studies in humans and dogs present conflicting evidence suggesting that CBD may inhibit the metabolism of Δ9-THC and 11-OH- THC, increasing the adverse events of THC. These may be influenced by the ratio of the compounds, administered dose, and individual responses [51,57,58]. In a randomized, crossover, double-blind clinical trial, 18 healthy adults underwent experimental sessions involving the oral administration of brownies with varying cannabinoid contents: a placebo with no cannabis extract, a Δ9-THC-dominant extract (20 mg Δ9-THC without CBD), and a CBD-dominant extract (20 mg Δ9-THC + 640 mg CBD). The CBD-dominant extract led to a higher Cmax and a larger area under the plasma concentration-time curve for Δ9-THC-COOH, Δ9-THC, and 11-OH-Δ9-THC compared to the Δ9-THC-dominant extract at an equivalent Δ9-THC dose, resulting in more pronounced adverse effects, such as anxiety, sedation, and memory difficulties [57]. Conversely, other studies have indicated that CBD minimally affects THC concentrations in saliva when both compounds are vaporized at a 1:1 ratio [59]. Studies using functional magnetic resonance imaging in adolescent and young adult cannabis users have found no evidence that CBD attenuates the effects of THC [60]
Given the escalating use of cannabis products and their enzymatic metabolism, it is pertinent to examine the potential pharmacokinetic interactions between these products and medications [5,11,61]. Considering that cannabis is often used concurrently with other drugs of abuse, this review incorporates a section on interactions with such substances.
3.1. Interactions with Medicines
Here we describe some of the main interactions classified by pharmacological groups. For further information about interactions classified by pharmacological groups, please refer to Table 5, which summarizes the interactions found between cannabis and other medications, with a description of the observed pharmacokinetic effects, clinical effects, the risk rating (based on the UpToDate classification: A, B, C, D, or X) and if it is documented in the prescribing information, evidence (strong, moderate, weak), and clinical relevance (major, significant, minor, lack of relevance, and/or not applicable).
3.1.1. Anticoagulants
In general, there is no evidence to support an interaction between cannabinoids and anticoagulants, except for warfarin. Warfarin is primarily metabolized by CYP2C9 and CYP3A4. CBD inhibits the CYP2C9 and CYP3A4 enzymes, and, therefore, co-administration can lead to the accumulation of warfarin, increasing INR levels and the risk of bleeding. Close monitoring of INR is recommended during the initiation and adjustment of CBD dosage. Regarding THC, there is an in vitro study that shows THC inhibits the CYP2C9-mediated metabolism of warfarin [62,63,64].
3.1.2. Antiepileptics
Antiepileptic drugs represent one of the primary classes of medications involved in pharmacological interactions with cannabis. Generally, the combination of antiepileptic drugs and CBD leads to an increase in the plasma levels of these medications, especially in the case of eslicarbazepine due to the inhibition of CYP2C19. Although no severe adverse effects have been reported, monitoring plasma levels is recommended when coadministered with CBD.
Stiripentol through CYP2C19 inhibition and valproate via an unknown mechanism (possible UGT1A9 and UGT2B7 inhibition) may interact with CBD. CBD may increase stiripentol levels by 28% for Cmax and 55% for AUC, resulting in variable adverse effects, including rashes and elevated liver enzymes (AST/ALT). Elevated liver enzyme levels have also been observed with the coadministration of CBD and valproic acid, even with normal valproic acid levels, possibly due to a hepatotoxic interaction [39,65]. Therefore, active monitoring of side effects, including liver function tests, is recommended, considering a dose reduction of valproate/stiripentol and CBD [66,67,68]
For some CNS depressants used as anticonvulsants and barbiturates, it has been documented that THC decreased clearance of these agents, presumably through competitive inhibition of metabolism [44,45,46].
There is significant evidence of interaction between CBD and clobazam (see benzodiazepine section).
3.1.3. Analgesics
THC has been shown to reduce the clearance of antipyrine (phenazone), likely through the competitive inhibition of metabolism [44,45,46,69]. Globally, the use of this analgesic has significantly decreased due to the increased prevalence of acetaminophen and ibuprofen as preferred alternatives used in some countries.
3.1.4. Opioids
Buprenorphine is primarily metabolized by the enzyme CYP3A4. Recreational cannabis use has been found to inhibit CYP3A4, leading to increased concentrations of buprenorphine, thereby increasing the risk of intoxication [70].
The use of cannabis with oxycodone or morphine may enhance analgesic effects, but no significant changes in the area under the curve of concentrations have been revealed to explain this occurrence. It has been suggested that the improved analgesia might be due to cannabis-induced slowing of gastrointestinal motility, resulting in a sustained release effect of morphine. However, there is no conclusive evidence of this interaction [71]. No evidence of interaction between CBD and fentanyl IV has been found [72]. In patients with cannabis use disorder undergoing opioid substitution therapy, a higher risk of drug interactions has been identified, predominantly with levomethadone, buprenorphine, and morphine. Therefore, clinical and therapeutic monitoring is recommended to enhance treatment safety [73].
3.1.5. Benzodiazepines
There is evidence of a significant interaction between clobazam and CBD. CBD inhibits the enzyme CYP2C19 involved in the metabolism of the active metabolite of clobazam, n-desmethylclobazam [66,74,75,76,77,78]. It has been found that levels of N-desmethylclobazam can increase three- to four-fold when combined with clobazam. Additionally, clobazam may increase exposure to 7-OH-CBD, with plasma AUC potentially increasing by 47% [39,74]. This interaction leads to an increase in n-desmethylclobazam levels, the prolongation of elimination half-life, and an elevated risk of adverse effects such as sedation and somnolence [53].
3.1.6. Immunosuppressants and Proliferation Inhibitors
Interactions have been identified between cannabinoids and mTOR inhibitors (sirolimus and everolimus), as well as with calcineurin inhibitors (tacrolimus), involving the inhibition of CYP3A4 and P-glycoprotein/ABCB1. Significant increases in everolimus and sirolimus levels have been found following CBD treatment [79]. CBD may increase everolimus exposure of approximately 2.5-fold for both Cmax and AUC [39,80].
CBD use has been associated with elevated tacrolimus levels, leading to adverse events including nausea, dry mouth, dizziness, heat episodes, and severe toxicity with encephalopathy [81,82,83,84]. However, there are inconsistent outcomes in some patients, which may be explained by interindividual variability [53,83]. A phase I study evaluated the interaction between CBD and tacrolimus in 12 healthy participants. The study found that CBD increased tacrolimus Cmax 4.2-fold and AUC0-∞ 3.1-fold (p < 0.0001) without affecting its half-life. These findings suggest that CBD inhibits CYP3A4-mediated metabolism of tacrolimus, which may require dose reduction and frequent therapeutic monitoring in transplant patients using CBD [85].
3.1.7. Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram and escitalopram are metabolized through CYP2C19 and CYP3A4, both of which are inhibited by CBD. Some cases have demonstrated increased plasma concentrations of citalopram with concurrent use of CBD [86]. Data are limited, and further studies are needed on this topic [67].
3.1.8. Tricyclic Antidepressants
Cases of tricyclic antidepressant toxicity after smoking cannabis have been described; however, serum levels were not measured [53,87,88].
3.1.9. Anti-Infectives
Ketoconazole acts as a strong CYP3A4 inhibitor, resulting in increased concentrations of THC (increase in Cmax and AUC of THC, 1.2- and 1.8-fold, respectively) and CBD (increase in Cmax and AUC of CBD, 2- and 2-fold, respectively). Therefore, reducing the dose of ketoconazole is recommended when administered with CBD. Conversely, rifampicin acts as a CYP3A4 inducer. When used concurrently with cannabis, decreases in concentrations of both CBD (reductions in Cmax by 50% and AUC by 60%) and THC (reductions in Cmax by 40% and AUC by 20%) have been observed, necessitating a gradual increase in CBD dose for patients experiencing minimal effects [39,65,67].
Fluconazole acts as a moderate inhibitor of CYP3A4 and a strong inhibitor of CYP2C9, and may increase the systemic exposure of dronabinol and/or its active metabolite, increasing the mean THC Cmax by 22% and mean AUC by 32%. Exposure to the metabolite 11-OH-THC also increased approximately 2.1-fold for Cmax and 2.5-fold for AUC. The Cmax of CBD increased by approximately 40% with fluconazole. All of this can increase cannabis-product-related adverse reactions [39,44,45,46].
3.1.10. Antiretrovirals
Antiretroviral drugs such as indinavir and nelfinavir have shown potential interaction (possible CYP3A4 and CYP2C induction). A 17.4% decrease in the Cmax of indinavir and 14,1% of nelfinavir has been observed in the presence of smoked cannabis [67,89,90].
3.1.11. Proton Pump Inhibitors (PPIs)
Although omeprazole inhibits CYP2C19, no significant alteration in plasma levels of THC and CBD has been found [65].
3.1.12. Psychostimulants
It has been suggested that CBD inhibits enzymes other than CYP, such as CES1 (serine hydrolase), which is involved in the metabolism of drugs like methylphenidate (MPH). However, the co-administration of CBD and MPH has been found to result in insignificant pharmacokinetic changes. Nonetheless, further studies are suggested to evaluate long-term effects [67,91].
3.1.13. Antipsychotics
The administration of smoked cannabis has been documented to increase the clearance of chlorpromazine by 50%, while the co-administration of tobacco and cannabis further increases this clearance by 107% (tobacco smoke acts as an enzyme inducer). Regarding clozapine, a 50% increase in plasma levels has been observed 2–4 weeks after cessation of cannabis consumption (tobacco smoke produces CYP1A2 induction, and clozapine is a substrate of CYP1A2). This can increase sedation and dizziness after stopping smoking, and, therefore, dose adjustments of clozapine are recommended after stopping smoking cannabis [92,93].
3.1.14. Methylxanthine Derivatives
Theophylline and other methylxanthine derivatives are known for common DDI. CBD has been found to inhibit the enzyme CYP1A2 (weak inhibitor), which is responsible for the metabolism of caffeine (theophylline and caffeine are CYP1A2 substrates). This leads to a substantial increase in caffeine’s AUC and half-life, consequently heightening the risk of adverse effects [94]. CBD may increase caffeine exposure by 15% for Cmax and 95% for AUC compared to when caffeine is given alone [39,94].
3.2. Interactions with Drugs of Abuse
Table 6 presents the key interactions between cannabinoid products and drugs of abuse. It details the precipitant substance, observed alterations in cannabinoid pharmacokinetics, and primary clinical effects. Furthermore, the table displays cannabinoids and the observed changes in the pharmacokinetics of the substance of abuse, along with its main clinical effects.
3.3. Pharmacodynamic Interactions (Medicines and Drugs of Abuse)
Cannabis products exhibit additive CNS effects when combined with CNS depressants such as anticonvulsants, barbiturates, ethanol, benzodiazepines, lithium, buspirone, opioids, muscle relaxants, and antihistamines [39,44,45,46]. The symptoms of this interaction may include dizziness, confusion, sedation, and somnolence. Additionally, impairments in attention, judgment, thinking, and psychomotor skills may be exacerbated.
Additionally, additive cardiac effects such as hypertension, hypotension, tachycardia, and syncope have been observed when combined with amphetamines, cocaine, and other sympathomimetics, as well as hypotensors or anticholinergic agents. The concurrent use of amoxapine, amitriptyline, desipramine, or other tricyclic antidepressants can exacerbate drowsiness, hypertension, and tachycardia due to the combined beta-adrenergic and antimuscarinic effects of tricyclics with the beta-adrenergic effects of cannabis. Additive tachycardia and drowsiness may also occur with atropine, scopolamine, some antihistamines, and other anticholinergic agents [34,39]. Moreover, smoking cannabis with disulfiram or fluoxetine can also induce hypomanic reactions. Dronabinol inhibits serotonin uptake in a manner similar to selective serotonin reuptake inhibitors (SSRIs) [92].
Combining cannabis with a nicotine patch has additive effects on the heart rate. Moreover, the effects of oral THC are enhanced by opioid receptor blockade with naltrexone. Cannabis counteracts the stimulant and hyperthermic effects of ecstasy (3,4-methylenedioxymethamphetamine, midomafetamine) [92]. Smoked cannabis plus cisplatin increases the risk of stroke, but the mechanism is unknown [92]. Table 5
Interactions found between cannabis and other medications, including quality of evidence, clinical relevance, risk rating based on the UpToDate classification (A: no interaction, B: no action needed, C: monitor therapy, D: modify regimen, or X: avoid combination) and pharmacokinetic interactions in the prescribing information (Yes/No). Abbreviation: PI, prescription information. NA, not applicable. For other abbreviations, refer to the text (ref., references).
| Drug | Cannabinoid and Pharmacokinetics Mechanism | Observed Pharmacokinetic Findings and Effects | Clinical Effects | Recommendation | Risk Rating/PI | Evidence | Clinical Relevance | Ref. |
|---|---|---|---|---|---|---|---|---|
| Anticoagulants | ||||||||
| Warfarin | CBD, Nabilone, Dronabiol: inhibits the CYP2C9 and CYP3A4 enzymes/Highly protein bound | -No clinical trial with cannabis has been conducted. Out of a total of 10 reported cases, 9 describe variations in INR (90%). A maximum INR variation of +0.4 to +9.61 was described in 8 of the 10 reports. | May increase the risk of bleeding. | Adjust warfarin dosage and closely monitor INR. | C/No | Moderate | Major | [62,63,95] |
| Antiepileptics | ||||||||
| Eslicarbazepine | CBD: Unknown | Eslicarbazepine as an object and CBD as a precipitant | Adverse effects were reported without clear evidence linking them to eslicarbazepine | Adjust eslicarbazepine dosage and, if it is possible, monitor plasma levels | C/No | Strong | Minor | [66,96] |
| -In adult subjects, trough concentrations of eslicarbazepine were elevated. The mean baseline concentration was 14.4 ± 7.4 μg/mL, increasing with CBD in subsequent measurements to 16.8 ± 7.9 μg/mL and 17.8 ± 9.1 μg/mL, demonstrating statistically significant changes. | ||||||||
| Stiripentol | CBD: CYP2C19 inhibition | Stiripentol as an object and CBD as a precipitant | Additive CNS depressant effects | Adjust stiripentol dosage and if it is possible monitor plasma levels | C/Yes | Strong | Minor | [39,65,74] |
| -CBD slight increase in stiripentol levels, with Cmax and the area under the concentration-time curve over the dosing interval (AUCtau) elevated by 2500 ng/mL (32.1%) and 27,000 ng · h/mL (57.6%), respectively. | ||||||||
| CBD as an object and stiripentol as a precipitant medication | ||||||||
| -Minor reductions in CBD major metabolites, 7-OH-CBD which a reduction of 29% and 7-COOH-CBD which decreased by 13%. However, CBD was not affected. | ||||||||
| Valproate | CBD: Unknown/Possible UGT1A9 and UGT2B7 inhibition/Highly protein bound | -AST/ALT levels were significantly higher in participants co-administered with valproate and CBD, with mean AST and ALT levels of 37.1 U/L and 35.3 U/L, respectively. In contrast, participants not taking valproate had lower AST and ALT levels of 23.97 U/L and 23.7 U/L. | May increase ALT and AST levels | Assess liver function before starting CBD and monitor liver function | C/No | Strong | Minor | [66] |
| Analgesics—Opioids | ||||||||
| Buprenorphine | Cannabis recreational: CYP3A4 inhibition | Buprenorphine as an object and CBD as a precipitant | May increase the risk of sedation and somnolence | Adjust buprenorphine dosage and monitor plasma levels of buprenorphine | C/No | Moderate | Significant | [70] |
| -Buprenorphine concentrations were found to be 170% higher in individuals who concurrently use cannabis recreationally. In one case report, a patient experienced a 95% decrease in serum buprenorphine levels upon discontinuing cannabis use. | ||||||||
| Methadone | CBD: CYP3A4 and CYP2C19 inhibition | Methadone as an object and CBD as a precipitant | May increase fatigue and somnolence | Adjust methadone dosage and if it is possible monitor plasma levels | C/No | Weak | Significant | [97] |
| -CBD can inhibit methadone metabolism. The serum methadone levels were measured at 271 ng/mL (2 days after discontinuing CBD), 149 ng/mL (7 days after discontinuing CBD), and 125 ng/mL (14 days after discontinuing CBD) | ||||||||
| Fentanyl | CBD: unknown | CBD as an object and fentanyl as a precipitant medication | Probably not clinically significant | Adjust fentanyl dosage and, if it is possible, monitor plasma levels | C/No | Strong | Lack of relevance | [72] |
| -Plasma concentrations of CBD were not significantly affected. | ||||||||
| Benzodiazepines | ||||||||
| Clobazam | CBD: CYP2C19 inhibition | Clobazam as an object and CBD as a precipitant | May increase the incidence of sedation and somnolence | Adjust clobazam dosage and it is possible, monitor plasma levels | C/Yes | Strong | Minor | [39,53,66,74,75,76,77,78] |
| -CBD increase mean concentrations of N-desmethylclobazam (10–526%). | ||||||||
| CBD as an object and clobazam as a precipitant medication | ||||||||
| -Clobazam may increase exposure to 7-OH-CBD, for which plasma AUC increased by 47%. Clobazam showed a slight increase in CBD exposure, with a trough Cmax of 1.34 ng/mL | ||||||||
| Brivaracetam | CBD: CYP2C19 inhibition | Brivaracetam as an object and CBD as a precipitant | Mild effects, such as diarrhea and somnolence, may occur | Adjust brivaracetam dosage and, if it is possible, monitor plasma levels | C/No | Strong | Significant | [96] |
| -Brivaracetam levels increased by 107% to 280% in patients receiving co-medication of brivaracetam and CBD. | ||||||||
| Immunosuppressants and Proliferation Inhibitors | ||||||||
| Tacrolimus | CBD: CYP3A4 inhibition/Highly protein bound | Tacrolimus as an object and CBD as a precipitant | Nausea, dizziness, and somnolence may appear. Creatinine levels may also increase | Adjust tacrolimus dosage and monitor blood levels of tacrolimus. Dose reduction is warranted when creatinine levels increase | C/No | Strong | Significant | [83,84,85] |
| -A case report showed baseline tacrolimus levels ranged from 3.9 to 8.4 ng/mL. By Day 164, the dose-adjusted tacrolimus level had increased approximately threefold to 13.3 ng/mL. Serum creatinine levels rose to 2.4 mg/dL by Day 124 (baseline 1.2 mg/dL), prompting discontinuation of tacrolimus for a week, after which creatinine levels decreased to 1.5 mg/dL. Attempts to maximize tacrolimus dosage led to a subsequent increase in creatinine levels by Day 282. | ||||||||
| Everolimus | CBD: CYP3A4 inhibition | Everolimus as an object and CBD as a precipitant | May increase the incidence of diarrhea | Adjust everolimus dosage and monitor blood levels | C/No | Moderate | Minor | [79] |
| -Median increase of everolimus AUC by 9.8 ng/mL as compared with baseline | ||||||||
| Sirolimus (convencional) | CBD: | Sirolimus as an object and CBD as a precipitant | May increase the incidence of diarrhea | Adjust sirolimus dosage and, if it is possible, monitor blood levels | D/No | Moderate | Minor | [79] |
| -Median increase of sirolimus AUC by 5.1 ng/mL as compared with baseline | ||||||||
| Cyclosporine | CBD: CYP3A4 inhibition/Highly protein bound drugs | Inconclusive findings: | Probably not clinically significant | Adjust cyclosporine dosage and if it is possible monitor blood levels | C/Yes | Strong | Lack of relevance | [44,45,46,83] |
| Selective serotonin reuptake inhibitors (SSRIs) | ||||||||
| Citalopram | CBD: CYP2C19 and CYP3A4 inhibition | Citalopram as an object and CBD as a precipitant | The reported adverse events were mild | Adjust citalopram or escitalopram dosage and, if it is possible, monitor plasma levels | D/No | Moderate | Minor | [86] |
| -Citalopram plasma concentrations increased from baseline (42 ng/mL) to Week 8 (79 ng/mL). | ||||||||
| Tricyclic antidepressants | ||||||||
| Imipramine | Smoked a marijuana cigarette: unknown | -Serum levels were not measured | Disorientation, restlessness, dizziness, and palpitations may appear, suggestive of tricyclic antidepressants toxicity | Adjust imipramine dosage and, if it is possible, monitor plasma levels | C/No | Strong | NA | [53,88] |
| Antipsychotics | ||||||||
| Clozapine | Cannabis and cigarettes: CYP1A2 induction | Clozapine as an object and cannabis and cigarettes as a precipitant | May increase the risk of hallucinations. | Adjust clozapine dosage and if it is possible, monitor plasma levels | C/No | Weak | Significant | [92,98] |
| -In one case report, a patient stopped the consumption of cannabis and cigarettes, and the plasma levels of clozapine increased by 230%. | ||||||||
| Chlorpromazine | Cannabis and cigarettes: CYP1A2 induction | Chlorpromazine as an object and cannabis and cigarettes as a precipitant | May increase the risk of sedation and somnolence | Adjust chlorpromazine dosage and if it is possible, monitor plasma levels | C/No | Strong | Minor | [93] |
| -Increase the clearance of chlorpromazine by 50%, while co-administration of tobacco and cannabis further increases this clearance by 107%. | ||||||||
| Pimozide | CBD: CYP3A4 inhibitors | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | May produce potentially | Avoid combination | X/No | NA | NA | [99] |
| Bromperidol | Nabilone: Unknown | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | May produce potentially | Avoid combination | X/No | NA | NA | [99] |
| Methotrimeprazine | Dronabinol: Unknown | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | May increase | Avoid combination | X/No | NA | NA | [99] |
| Anti-infectives | ||||||||
| Ketoconazole | Nabiximols: CYP3A4 inhibition | Nabiximols as an object and ketoconazole as a precipitant | Somnolence, malaise, dizziness, anxiety, and disorientation may appear | Adjust ketoconazole dosage and, if it is possible, monitor plasma levels | C/No | Strong | Minor | [65] |
| -In subjects using THC/CBD oromucosal spray alongside ketoconazole, there were increases in Cmax levels of THC from 2.65 to 3.36 ng/mL, CBD from 0.66 to 1.25 ng/mL, and 11-OH-THC from 3.59 to 10.92 ng/mL. Overall, Cmax levels increased by 36% to 87%. | ||||||||
| Rifampicin | Nabiximols: CYP3A4 induction, CYP2C19 inducers | Nabiximols as an object and rifampicin as a precipitant | Few clinical manifestations; headache can occur | Adjust rifampicin dosage and, if it is possible, monitor plasma levels | C/No | Strong | Minor | [65] |
| -When using THC/CBD oromucosal spray alone, Cmax levels were observed as 2.94 ng/mL for THC, 1.03 ng/mL for CBD, and 3.38 ng/mL for 11-hydroxy-THC (11-OH-THC). With co-administration of THC/CBD spray and rifampicin, Cmax levels decreased to 1.88 ng/mL for THC, 0.50 ng/mL for CBD, and 0.45 ng/mL for 11-OH-THC. Overall, Cmax levels were reduced by 26% to 87%. | ||||||||
| Fusidic acid | Dronabinol, Nabilone: CYP3A4 substrates | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | May increase | Modify the regimen of fusidic acid to include aggressive monitoring, empirical adjustments, and consideration of alternative agents | D/No | NA | NA | [99] |
| Fluconazole | Dronabinol: CYP2C9 and CYP3A4 inhibitor | Dronabinol as an object and fluconazole as a precipitant | Can increase cannabis-product-related adverse reactions | Adjust fluconazole dosage and, if it is possible, monitor plasma levels. | C/Yes | Weak | Minor | [39,45,46] |
| -May increase the systemic exposure of dronabinol and/or its active metabolite, increasing THC Cmax by 22% and AUC by 32%. Exposure to the metabolite 11-OH-THC also increased approximately 2.1-fold for Cmax and 2.5-fold for AUC. | ||||||||
| Metronidazole | Dronabinol (Syndros®): Unknown | Dronabinol as an object and metronidazole as a precipitant | Disulfiram-like reaction. May produce potentially | Avoid combination | X/Yes | NA | NA | [45] |
| -The liquid formulation (Syndros®) of dronabinol contains alcohol and Metronidazole can inhibit the metabolism of alcohol. | ||||||||
| Itraconazole | Nabilone, dronabinol: Unknown | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | Can increase cannabis-product-related adverse reactions | Adjust itraconazole dosage and, if it is possible, monitor plasma levels | C/No | NA | NA | [99] |
| Fexinidazole | Dronabinol, Nabilone: CYP3A4 substrates | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | May produce potentially | Avoid combination | X/No | NA | NA | [99] |
| Ordinazole, Secnidazole | Dronabinol: Unknown | No clinical trials with cannabis have been conducted. Considering the metabolism and theoretical principles, a significant interaction may be possible. | May increase | Avoid combination | X/No | NA | NA | [99] |
| Antiretrovirals | ||||||||
| Indinavir | THC cigarettes: Possible CYP3A4 induction | Indinavir as an object and cannabis and THC cigarettes as a precipitant | Probably not clinically significant | Adjust indinavir dosage and, if it is possible, monitor plasma levels | C/No | Strong | Lack of relevance | [89] |
| -Decrease in Cmax of indinavir by 17.4% (n = 11) | ||||||||
| Nelfinavir | THC cigarettes: Possible CYP3A4 induction | Nelfinavir as an object and cannabis and THC cigarettes as a precipitant | Probably not clinically significant | Adjust nelfinavir dosage and, if it is possible, monitor plasma levels | C/No | Strong | Lack of relevance | [89] |
| -Decrease in Cmax of nelfinavir by 14.1% (n = 14) | ||||||||
| Mehtylxanthine derivates | ||||||||
| Caffeine | CBD: CYP1A2 inhibition | Caffeine as an object and CBD as a precipitant | Diarrhea and elevated liver enzymes (AST, ALT, GGT) may appear | No action needed | B/Yes | Strong | Minor | [39,94] |
| -CBD and caffeine co-administration may increase caffeine exposure by +15% for Cmax and +95% for AUC compared to a single administration of caffeine. | ||||||||
| Proton pump inhibitor (PPIs) | ||||||||
| Omeprazole | THC and CBD: CYP3A4 inhibition | THC and CBD as an object and omeprazole as a precipitant | Dizziness may appear | No action needed | B/No | Strong | Lack of relevance | [61,65] |
| -No significant alteration in plasma levels of THC and CBD. | ||||||||
| Psychostimulants | ||||||||
| Methylphenidate (MPH) | CBD: possible serine hydrolase inhibition | MPH as an object and CBD as a precipitant | Probably not clinically significant | No action needed | B/No | Strong | Lack of relevance | [65,91,100] |
| -The geometric mean ratios (GMR) for AUC from time 0 to infinity (AUCinf) and Cmax with CBD co-administration, compared to MPH monotherapy were 1.08 (0.85, 1.37) and 1.09 (0.89, 1.32), respectively. Tmax was longer for CBD (4 h) than MPH (1.25 h). | ||||||||
| Other central nervous system depressants | ||||||||
| Hexobarbital | CBD: possible CYP3A4 inhibition | Hexobarbital as an object and CBD as a precipitant | May increase the risk of sedation and somnolence | Adjust hexobarbital dosage and, if it is possible, monitor plasma levels | Not found/No | Strong | Minor | [101] |
| -CBD reduced hexobarbital clearance by 35%, compared to when it was not administrated, in subjects who consume recreational cannabis regularly. | ||||||||
| Phenobarbital | Dronabinol: possible CYP3A4, CYP2C9 and CYP2C19 induction | Phenobarbital as an object and CBD as a precipitant | Loss of efficacy of cannabis product | Adjust phenobarbital dosage and, if it is possible, monitor plasma levels | C/Yes | Strong | Lack of relevance | [39,58,66] |
| -In co-administration with CBD, no significant changes were found in plasma concentrations of phenobarbital. | ||||||||
| Dronabinol as an object and phenobarbital as a precipitant | ||||||||
| -May reduce the systemic exposure of dronabinol parent drug and/or its active metabolite | ||||||||
| Propofol | CBD: UGT1A9 and UGT2B7 | Inconclusive findings: | May increase the risk of sedation and somnolence | Adjust propofol dosage and, if it is possible, monitor plasma levels | C/Yes | Moderate | NA | [39,102] |
| Other unclassified drugs | ||||||||
| Disulfiram | Dronabinol (Syndros®): Unknown | Dronabinol as an object and Disulfiram as a precipitant | Disulfiram-like reaction. May produce potentially | Avoid combination | X/Yes | NA | NA | [45] |
| -The liquid formulation (Syndros®) of dronabinol contains alcohol, and disulfiram can inhibit the metabolism of alcohol. | ||||||||
| Colchicine, Pralsetinib, Relugolix, Estradiol, Norethindrone, Rimegepant, Tizanidine, Ubrogepant, Venetoclax, Digoxin, Lefamulin, Lemborexant, Afatinib, Berotralstat | CBD: P-glycoprotein/ABCB1 inhibitor | No clinical trials with cannabis have been conducted, but several pharmacokinetic studies have found that the AUC and Cmax of these drugs increase during co-administration with P-glycoprotein inhibitors. | May increase | Modify the regimen of these drugs to include aggressive monitoring, empirical adjustments, and consideration of alternative agents | D/No | NA | NA | [99,103] |
| Bilastine, | CBD: P-glycoprotein/ABCB1 inhibitors | No clinical trials with cannabis have been conducted. but several pharmacokinetic studies have found that the AUC and Cmax of these drugs increase during co-administration with P-glycoprotein inhibitors. | May produce potentially | Avoid combination | X/No | NA | NA | [99] |
| Amifostine, Obinutuzumab | Nabilone: Unknown | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible | May increase | Modify the regimen of these drugs to include aggressive monitoring, empirical adjustments, and consideration of alternative agents | D/No | NA | NA | [99] |
| Lomitapide | CBD: CYP3A4 inhibitors | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | May increase | Modify the regimen of lomitapide to include aggressive monitoring, empirical adjustments, and consideration of alternative agents | D/No | NA | NA | [99] |
| Cilostazol | CBD: CYP2C19 inhibitors | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | May increase | Modify the regimen of cilostazol to include aggressive monitoring, empirical adjustments, and consideration of alternative agents | D/No | NA | NA | [99] |
| Mavacamten | CBD: CYP2C19 inhibitors | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | May produce potentially | Avoid combination | X/No | NA | NA | [99] |
| Fezolinetant | CBD: CYP1A2 inhibitors | No clinical trials with cannabis have been conducted. Considering mechanisms, metabolism, and theoretical principles, a significant interaction may be possible. | May produce potentially | Avoid combination | X/No | NA | NA | [99] |
Overview of cannabis drug interactions with drugs of abuse. Abbreviations (see text): HR heart rate, MAP: mean arterial pressure, BP: blood pressure, T: temperature, EEG: electroencephalogram.
| Drug | Cannabinoid and Pharmacokinetics Mechanism | Observed Pharmacokinetic Findings and Effects | Clinical Effects | References |
|---|---|---|---|---|
| Alcohol | THC, CBN and dronabinol: Unknown | THC as an object and alcohol as a precipitant | May increase HR | [104,105,106,107,108,109,110,111] |
| ||||
| Cocaine | Smoked cannabis: Unknown | Cocaine as an object and smoked cannabis as a precipitant | May increase MAP and HR | [112,113,114,115,116] |
| ||||
| Dextroamphetamine | THC: Unknown | No available information | May increase BP and HR | [117,118] |
| 3,4-metilendioximetanfetamina (MDMA) | THC: Unknown | No pharmacokinetics modifications | May increase BP, HR, and T | [119,120,121] |
| Methylphenidate (MPH) | CBD: possible serine hydrolase inhibition | No pharmacokinetics modifications (for more information, see the Psychostimulants section of Table 5). | May increase HR and BP | [65,100] |
| Nicotine | THC: Unknown | No pharmacokinetics modifications | May increase HR | [122,123,124] |
4. Conclusions
Cannabinoids can interact with therapeutic medications, alcohol, and other substances of abuse. The extensive variety available in the market, combined with the widespread use of cannabinoids for medical conditions, may lead to numerous pharmacokinetic interactions. These interactions predominantly occur within two enzyme families, cytochrome P450 and UGT, as most market medications are metabolized by these enzymes. Despite limited and conflicting data on these interactions, ongoing research is essential. In clinical practice, standardized strategies for managing cannabinoid interactions are lacking; however, practitioners are advised to exercise caution and monitor potential clinical effects that may indicate an interaction with drugs or substances of abuse.
Conceptualization, M.F., E.P., and C.P.-M.; methodology, C.P.-M., M.F., D.A.C.; writing—original draft preparation, D.A.C., E.P., M.F. and C.P.-M.; writing—review and editing, M.F., D.A.C.; visualization, D.A.C.; supervision, M.F., E.P., C.P.-M.; funding acquisition, M.F., E.P., C.P.-M. All authors have read and agreed to the published version of the manuscript.
Not applicable.
Not applicable.
Not applicable.
The authors declare no conflicts of interest.
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Enlarge this image.Figure 3. Influence of cannabinoids on enzyme activity based on prescribing information (? = not fully known).
Cannabis-based products.
| Cannabis-Based Products (Cannabis Preparations) | ||||
|---|---|---|---|---|
| No license for specific medical indications | ||||
| Raw Cannabis | Compounding Preparations | Cannabis-Based Products with | Standardized Cannabis Based Medical Products * | |
| Unheated or | Patient-specific products based on a physician’s prescription prepared by a pharmacist | Flowers | Inflorescences | Bedrocan® (THC approx. 22%, CBD < 1%) |
| Cannabis extract diluted in oil | T10/C2® (THC 10%, CBD 2%) | |||
* Some examples (not all are listed).
Cannabinoid prescription drugs.
| Prescription Drugs | |||||
|---|---|---|---|---|---|
| Terminology | Cannabis-Derived Products | Cannabis-Related Products | |||
| Origin | Compounds occurring naturally in the plant that are extracted directly from the plant | Synthetic compounds created in a laboratory and can be used to manufacture drug products | |||
| Brand name | Epidiolex® | Sativex® | Marinol® | Syndros® | Cesamet® |
| Active principle/substance | CBD | Nabiximols | Dronabinol | Dronabinol | Nabilone |
| Pharmaceutical | Oral solution | Oromucosal spray solution | Oral capsules (Marinol®, Cesamet®) | ||
| Indication | Patients 2 years of age or older with Dravet syndrome. | Muscle spasticity associated with multiple sclerosis. | Anorexia associated with weight loss in patients with acquired immunodeficiency syndrome. | ||
Cannabinoid medication (precipitant) affecting the metabolism of substrate medication (object) with narrow therapeutic index (NTI), based on the medication label.
| Cannabinoid (Precipitant) | CBD (Epidiolex®) | Nabiximols (Sativex®, THC: CBD Equal Quantities) | Dronabinol (Marinol® and Syndros®, Synthetic Form of THC) | Nabilone (Cesamet®, Synthetic Cannabinoid) |
|---|---|---|---|---|
| Can affect the metabolism of substrate medication (object) with a NTI | Inhibits and induces: CYP1A2 and CYP2B6 substrates | Inhibits: CYP3A4, UGT1A9, UGT2B7 substrates | CYP2C9 and CYP3A4 substrates | Weak inhibitor: CYP3A4 and CYP2E1 substrates |
Medications with a narrow therapeutic index (NTI) and cannabinoid medications with high protein binding. Medications in bold have both an NTI and high protein binding. Adapted from Kocis and Vrana (2020).
| Medication with Narrow Therapeutic Index (NTI) | |||
|---|---|---|---|
| Acenocuomarol | Dihydroergotamine | Mephenytoin | |
| Alfentanil | Diphenadione | Mycophenolic acid | |
| Aminophylline | Dofetilide | Nortriptyline | |
| Amiodarone | Dosulepin | Paclitaxel | |
| Amitriptyline | Doxepin | Phenobarbital | |
| Amphotericin B | Ergotamine | Phenprocoumon | |
| Argatroban | Esketamine | Phenytoin | |
| Busulfan | Ethinyl estradiol (oral contraceptives) | Pimozide | |
| Carbamazepine | Ethosuximide | Propofol | |
| Clindamycin | Ethyl biscoumacetate | Quinidine | |
| Clomipramine | Everolimus | Sirolimus | |
| Clonidine | Fentanyl | Tacrolimus | |
| Clorindione | Fluindione | Temsirolimus | |
| Cyclobenzaprine | Fosphenytoin | Theophylline | |
| Cyclosporine | Imipramine | Thiopental | |
| Dabigatran etexilate | Levothyroxine | Tianeptine | |
| Desipramine | Lofepramine | Trimipramine | |
| Dicoumarol | Melitracen | Valproic acid | |
| Digitoxin | Meperidine | Warfarin | |
| Cannabinoid Medication with Protein Binding ≥ 85% * | |||
| Cannabidiol | Nabilone | ||
| Dronabinol | Nabiximols | ||
* Not considered an NTI.
References
1. Hourfane, S.; Mechqoq, H.; Bekkali, A.Y.; Rocha, J.M.; El Aouad, N. A Comprehensive Review on Cannabis sativa Ethnobotany, Phytochemistry, Molecular Docking and Biological Activities. Plants; 2023; 12, 1245. [DOI: https://dx.doi.org/10.3390/plants12061245] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36986932]
2. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (Internet). EU Drug Market: Cannabis—Production. Available online: https://www.emcdda.europa.eu/publications/eu-drug-markets/cannabis/production_en#level-2-section1 (accessed on 1 April 2024).
3. Camí, J.; Farré, M. Drug Addiction. N. Engl. J. Med.; 2003; 349, pp. 975-986. [DOI: https://dx.doi.org/10.1056/NEJMra023160] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12954747]
4. Gorelick, D.A. Cannabis-Related Disorders and Toxic Effects. N. Engl. J. Med.; 2023; 389, pp. 2267-2275. [DOI: https://dx.doi.org/10.1056/NEJMra2212152] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38091532]
5. Nasrin, S.; Watson, C.J.; Perez-Paramo, Y.X.; Lazarus, P. Cannabinoid Metabolites as Inhibitors of Major Hepatic CYP450 Enzymes, with Implications for Cannabis-Drug Interactions. Drug Metab. Dispos.; 2021; 49, pp. 1070-1080. [DOI: https://dx.doi.org/10.1124/dmd.121.000442] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34493602]
6. Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.M.; Denovan-Wright, E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol.; 2015; 172, pp. 4790-4805. [DOI: https://dx.doi.org/10.1111/bph.13250]
7. Sainsbury, B.; Bloxham, J.; Pour, M.H.; Padilla, M.; Enciso, R. Efficacy of cannabis-based medications compared to placebo for the treatment of chronic neuropathic pain: A systematic review with meta-analysis. J. Dent. Anesthesia Pain Med.; 2021; 21, pp. 479-506. [DOI: https://dx.doi.org/10.17245/jdapm.2021.21.6.479] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34909469]
8. Mlost, J.; Bryk, M.; Starowicz, K. Cannabidiol for Pain Treatment: Focus on Pharmacology and Mechanism of Action. Int. J. Mol. Sci.; 2020; 21, 8870. [DOI: https://dx.doi.org/10.3390/ijms21228870]
9. Nichols, J.M.; Kaplan, B.L.F. Immune Responses Regulated by Cannabidiol. Cannabis Cannabinoid Res.; 2020; 5, pp. 12-31. [DOI: https://dx.doi.org/10.1089/can.2018.0073] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32322673]
10. United Nations Office on Drugs and Crime (UNODC) (Internet). Herbal Cannabis for Medical Use: A Spectrum of Regulatory Approaches. 2023; Available online: https://www.unodc.org/res/WDR-2023/WDR23_B3_CH3_Medical_Cannabis.pdf (accessed on 1 May 2024).
11. Qian, Y.; Gurley, B.J.; Markowitz, J.S. The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications. J. Clin. Psychopharmacol.; 2019; 39, pp. 462-471. [DOI: https://dx.doi.org/10.1097/JCP.0000000000001089]
12. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (Internet). Medical Use of Cannabis and Cannabinoids: Questions and Answers for Policymaking. 2018; Available online: https://www.emcdda.europa.eu/publications/rapid-communications/medical-use-of-cannabis-and-cannabinoids-questions-and-answers-for-policymaking_en (accessed on 12 January 2024).
13. Pertwee, R.G. Cannabinoid pharmacology: The first 66 years. Br. J. Pharmacol.; 2006; 147, pp. S163-S171. [DOI: https://dx.doi.org/10.1038/sj.bjp.0706406] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16402100]
14. National Academies of Sciences, Engineering, and Medicine (Internet). Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. 2017; Available online: https://www.ncbi.nlm.nih.gov/books/NBK425767 (accessed on 12 January 2024).
15. Food and Drug Administration (FDA) (Internet). Regulation and Quality Considerations for Cannabis and Cannabis-Derived Compounds. Available online: https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/fda-regulation-and-quality-considerations-cannabis-and-cannabis-derived-compounds (accessed on 12 January 2024).
16. Arellano, A.L.; Papaseit, E.; Romaguera, A.; Torrens, M.; Farré, M. Neuropsychiatric and General Interactions of Natural and Synthetic Cannabinoids with Drugs of Abuse and Medicines. CNS Neurol. Disord.—Drug Targets; 2017; 16, pp. 554-566. [DOI: https://dx.doi.org/10.2174/1871527316666170413104516] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28412920]
17. Boland, R.; Verduin, M.L. Substance Use and Addictive Disorders: Cannabis-Related disorders. Kaplan & Sadock’s Synopsis of Psychiatry; 12th ed. Wolters Kluwer: Philadelphia, PA, USA, 2022; pp. 930-941.
18. Plan Nacional sobre Drogas (PNSD) (National Drug Plan) (Internet). Technical Report on Cannabis. Use Consequences. 2022; Available online: https://pnsd.sanidad.gob.es/profesionales/publicaciones/catalogo/catalogoPNSD/publicaciones/pdf/2022_Technical_Report_Alcohol_2021.pdf (accessed on 12 January 2024).
19. Legare, C.A.; Raup-Konsavage, W.M.; Vrana, K.E. Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals. Pharmacology; 2022; 107, pp. 131-149. [DOI: https://dx.doi.org/10.1159/000521683]
20. World Health Organization (WHO) (Internet). The Health and Social Effects of Nonmedical Cannabis Use. 2016; Available online: https://www.who.int/publications/i/item/9789241510240 (accessed on 15 January 2024).
21. United Nations Office on Drugs and Crime (UNODC) (Internet). World Drug Report 2024. Available online: https://www.unodc.org/unodc/en/data-and-analysis/world-drug-report-2024.html (accessed on 9 May 2024).
22. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (Internet). EU Drug Market: Cannabis—Key Findings and Threat Assessment. Available online: https://www.emcdda.europa.eu/publications/eu-drug-markets/cannabis/key-findings-and-threat-assessment_en (accessed on 1 April 2024).
23. Food and Drug Administration (FDA) (Internet). Cannabis Derived Products Data Acceleration Plan. Available online: https://www.fda.gov/media/153183/download (accessed on 2 April 2024).
24. Matson, T.E.; Carrell, D.S.; Bobb, J.F.; Cronkite, D.J.; Oliver, M.M.; Luce, C.; Ghitza, U.E.; Hsu, C.W.; Campbell, C.I.; Browne, K.C. et al. Prevalence of Medical Cannabis Use and Associated Health Conditions Documented in Electronic Health Records Among Primary Care Patients in Washington State. JAMA Netw. Open; 2021; 4, e219375. [DOI: https://dx.doi.org/10.1001/jamanetworkopen.2021.9375] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33956129]
25. Leung, J.; Chan, G.; Stjepanović, D.; Chung, J.Y.C.; Hall, W.; Hammond, D. Prevalence and self-reported reasons of cannabis use for medical purposes in USA and Canada. Psychopharmacology; 2022; 239, pp. 1509-1519. [DOI: https://dx.doi.org/10.1007/s00213-021-06047-8]
26. Mahabir, V.K.; Merchant, J.J.; Smith, C.; Garibaldi, A. Medical cannabis use in the United States: A retrospective database study. J. Cannabis Res.; 2020; 2, 32. [DOI: https://dx.doi.org/10.1186/s42238-020-00038-w] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33526110]
27. Choi, N.G.; Marti, C.N.; Choi, B.Y. Prevalence of cannabidiol use and correlates in U.S. adults. Drug Alcohol Depend. Rep.; 2024; 13, 100289. [DOI: https://dx.doi.org/10.1016/j.dadr.2024.100289] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39831101]
28. Chapin, M.R.; Kane-Gill, S.L.; Li, X.; Abanyie, K.; Taneja, S.B.; Egbert, S.; Paine, M.F.; Boyce, R.D. Part 1: Evaluation of Pediatric Cannabis–Drug Interaction Reports. Pharmacol. Res. Perspect.; 2025; 13, e70046. [DOI: https://dx.doi.org/10.1002/prp2.70046]
29. Chapin, M.R.; Kane-Gill, S.L.; Li, X.; Abanyie, K.; Taneja, S.B.; Egbert, S.; Paine, M.F.; Boyce, R.D. Part 2: Drug Interactions Involving Cannabis Products in Persons Aged 18 and Over: A Summary of Published Case Reports and Analysis of the FDA Adverse Event Reporting System. Pharmacol. Res. Perspect.; 2025; 13, e70047. [DOI: https://dx.doi.org/10.1002/prp2.70047]
30. Bardhi, K.; Coates, S.; Watson, C.J.; Lazarus, P. Cannabinoids and drug metabolizing enzymes: Potential for drug-drug interactions and implications for drug safety and efficacy. Expert Rev. Clin. Pharmacol.; 2022; 15, pp. 1443-1460. [DOI: https://dx.doi.org/10.1080/17512433.2022.2148655]
31. Lucas, C.J.; Galettis, P.; Schneider, J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br. J. Clin. Pharmacol.; 2018; 84, pp. 2477-2482. [DOI: https://dx.doi.org/10.1111/bcp.13710]
32. Grotenhermen, F. Pharmacokinetics and Pharmacodynamics of Cannabinoids. Clin. Pharmacokinet.; 2003; 42, pp. 327-360. [DOI: https://dx.doi.org/10.2165/00003088-200342040-00003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12648025]
33. Cox, E.J.; Maharao, N.; Patilea-Vrana, G.; Unadkat, J.D.; Rettie, A.E.; McCune, J.S.; Paine, M.F. A marijuana-drug interaction primer: Precipitants, pharmacology, and pharmacokinetics. Pharmacol. Ther.; 2019; 201, pp. 25-38. [DOI: https://dx.doi.org/10.1016/j.pharmthera.2019.05.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31071346]
34. Health Canada: Government of Canada (Internet). Information for Health Care Professionals: Cannabis (Marihuana, Mariju-Ana) and the Cannabinoids. 2018; Available online: https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/information-medical-practitioners/information-health-care-professionals-cannabis-cannabinoids.html (accessed on 20 September 2024).
35. Stinchcomb, A.L.; Valiveti, S.; Hammell, D.C.; Ramsey, D.R. Human skin permeation of Δ8-tetrahydrocannabinol, cannabidiol and cannabinol. J. Pharm. Pharmacol.; 2004; 56, pp. 291-297. [DOI: https://dx.doi.org/10.1211/0022357022791] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15025853]
36. Valiveti, S.; Hammell, D.C.; Earles, D.C.; Stinchcomb, A.L. In vitro/in vivo correlation studies for transdermal Δ8-THC development. J. Pharm. Sci.; 2004; 93, pp. 1154-1164. [DOI: https://dx.doi.org/10.1002/jps.20036] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15067692]
37. McGilveray, I.J. Pharmacokinetics of Cannabinoids. Pain Res. Manag.; 2005; 10, pp. 15A-22A. [DOI: https://dx.doi.org/10.1155/2005/242516]
38. Chayasirisobhon, S. Mechanisms of Action and Pharmacokinetics of Cannabis. Perm. J.; 2021; 25, 19.200. [DOI: https://dx.doi.org/10.7812/TPP/19.200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33635755]
39. Agencia Española del Medicamento y Productos Sanitarios (AEMPS) (Spanish Agency for Medicines and Health Products) (Internet) Product Information Sativex®, Epidyolex®. Available online: https://cima.aemps.es/cima/publico/home.html (accessed on 12 January 2024).
40. Huestis, M.A.; Cone, E.J. Differentiating new marijuana use from residual drug excretion in occasional marijuana users. J. Anal. Toxicol.; 1998; 22, pp. 445-454. [DOI: https://dx.doi.org/10.1093/jat/22.6.445]
41. Heuberger, J.A.A.C.; Guan, Z.; Oyetayo, O.-O.; Klumpers, L.; Morrison, P.D.; Beumer, T.L.; van Gerven, J.M.A.; Cohen, A.F.; Freijer, J. Population Pharmacokinetic Model of THC Integrates Oral, Intravenous, and Pulmonary Dosing and Characterizes Short- and Long-term Pharmacokinetics. Clin. Pharmacokinet.; 2015; 54, pp. 209-219. [DOI: https://dx.doi.org/10.1007/s40262-014-0195-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25316574]
42. Babayeva, M.; Loewy, Z.G. Cannabis Pharmacogenomics: A Path to Personalized Medicine. Curr. Issues Mol. Biol.; 2023; 45, pp. 3479-3514. [DOI: https://dx.doi.org/10.3390/cimb45040228]
43. Wright, J.A.; Huang, L.; Katamesh, B.E.; Yadav, S.; Singla, A.; Vincent, A. Hypothesized pharmacogenomic and medication influences on tetrahydrocannabinol and cannabidiol metabolism in a cohort of unselected oral cannabis users. J. Cannabis Res.; 2025; 7, 1. [DOI: https://dx.doi.org/10.1186/s42238-024-00256-6]
44. Food and Drug Administration (FDA) (Internet). Label Cesamet®, Syndros®, Marinol®. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018677s011lbl.pdf (accessed on 12 January 2024).
45. Food and Drug Administration (FDA) (Internet). Label Syndros®. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/205525Orig1s009lbledt.pdf (accessed on 12 January 2024).
46. Food and Drug Administration (FDA) (Internet). Label Marinol®. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018651s029lbl.pdf (accessed on 12 January 2024).
47. Grotenhermen, F.; Müller-Vahl, K. The therapeutic potential of cannabis and cannabinoids. Dtsch. Arztebl. Int.; 2012; 109, pp. 495-501. [DOI: https://dx.doi.org/10.3238/arztebl.2012.0495] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23008748]
48. Foster, B.C.; Abramovici, H.; Harris, C.S. Cannabis and Cannabinoids: Kinetics and Interactions. Am. J. Med.; 2019; 132, pp. 1266-1270. [DOI: https://dx.doi.org/10.1016/j.amjmed.2019.05.017]
49. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders; 5th ed. DSM V American Psychiatric Association: Washington, DC, USA, 2013; pp. 509-519.
50. Chu, F.; Cascella, M. Cannabinoid Hyperemesis Syndrome; StatPearls Publishing: Treasure Island, FL, USA, 2023; Available online: https://www.ncbi.nlm.nih.gov/books/NBK549915 (accessed on 3 July 2024).
51. Lawn, W.; Trinci, K.; Mokrysz, C.; Borissova, A.; Ofori, S.; Petrilli, K.; Bloomfield, M.; Haniff, Z.R.; Hall, D.; Fernandez-Vinson, N. et al. The acute effects of cannabis with and without cannabidiol in adults and adolescents: A randomised, double-blind, placebo-controlled, crossover experiment. Addiction; 2023; 118, pp. 1282-1294. [DOI: https://dx.doi.org/10.1111/add.16154] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36750134]
52. Vandrey, R.; Budney, A.; Hughes, J.; Liguori, A. A within-subject comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and both substances. Drug Alcohol Depend.; 2008; 92, pp. 48-54. [DOI: https://dx.doi.org/10.1016/j.drugalcdep.2007.06.010]
53. Nachnani, R.; Knehans, A.; Neighbors, J.D.; Kocis, P.T.; Lee, T.; Tegeler, K.; Trite, T.; Raup-Konsavage, W.M.; Vrana, K.E. Systematic review of drug-drug interactions of delta-9-tetrahydrocannabinol, cannabidiol, and Cannabis. Front. Pharmacol.; 2024; 15, 1282831. [DOI: https://dx.doi.org/10.3389/fphar.2024.1282831] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38868665]
54. Lopera, V.; Rodríguez, A.; Amariles, P. Clinical Relevance of Drug Interactions with Cannabis: A Systematic Review. J. Clin. Med.; 2022; 11, 1154. [DOI: https://dx.doi.org/10.3390/jcm11051154]
55. Zhu, H.-J.; Wang, J.-S.; Markowitz, J.S.; Donovan, J.L.; Gibson, B.B.; Gefroh, H.A.; DeVane, C.L. Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. J. Pharmacol. Exp. Ther.; 2006; 317, pp. 850-857. [DOI: https://dx.doi.org/10.1124/jpet.105.098541] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16439618]
56. Kocis, P.T.; Vrana, K.E. Delta-9-Tetrahydrocannabinol and Cannabidiol Drug-Drug Interactions. Med. Cannabis Cannabinoids; 2020; 3, pp. 61-73. [DOI: https://dx.doi.org/10.1159/000507998] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34676340]
57. Zamarripa, C.A.; Spindle, T.R.; Surujunarain, R.; Weerts, E.M.; Bansal, S.; Unadkat, J.D.; Paine, M.F.; Vandrey, R. Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered with Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial. JAMA Netw. Open; 2023; 6, e2254752. [DOI: https://dx.doi.org/10.1001/jamanetworkopen.2022.54752] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36780161]
58. Vaughn, D.; Kulpa, J.; Paulionis, L. Preliminary Investigation of the Safety of Escalating Cannabinoid Doses in Healthy Dogs. Front. Veter. Sci.; 2020; 7, 51. [DOI: https://dx.doi.org/10.3389/fvets.2020.00051] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32118071]
59. Arkell, T.R.; Kevin, R.C.; Stuart, J.; Lintzeris, N.; Haber, P.S.; Ramaekers, J.G.; McGregor, I.S. Detection of Δ9 THC in oral fluid following vaporized cannabis with varied cannabidiol (CBD) content: An evaluation of two point-of-collection testing devices. Drug Test. Anal.; 2019; 11, pp. 1486-1497. [DOI: https://dx.doi.org/10.1002/dta.2687] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31442003]
60. Ertl, N.; Freeman, T.P.; Mokrysz, C.; Ofori, S.; Borissova, A.; Petrilli, K.; Curran, H.V.; Lawn, W.; Wall, M.B. Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks. Neuropsychopharmacology; 2024; 49, pp. 1640-1651. [DOI: https://dx.doi.org/10.1038/s41386-024-01891-6]
61. MacDonald, E.; Adams, A. The Use of Medical Cannabis with Other Medications: A Review of Safety and Guidelines—An Update (Internet): Canadian Agency for Drugs and Technologies in Health. 2019; Available online: https://www.ncbi.nlm.nih.gov/books/NBK549545/ (accessed on 8 June 2024).
62. Damkier, P.; Lassen, D.; Christensen, M.M.H.; Madsen, K.G.; Hellfritzsch, M.; Pottegård, A. Interaction between warfarin and cannabis. Basic Clin. Pharmacol. Toxicol.; 2019; 124, pp. 28-31. [DOI: https://dx.doi.org/10.1111/bcpt.13152]
63. Smythe, M.A.; Wu, W.; Garwood, C.L. Anticoagulant drug–drug interactions with cannabinoids: A systematic review. Pharmacother. J. Hum. Pharmacol. Drug Ther.; 2023; 43, pp. 1327-1338. [DOI: https://dx.doi.org/10.1002/phar.2881]
64. Treyer, A.; Reinhardt, J.K.; Eigenmann, D.E.; Oufir, M.; Hamburger, M. Phytochemical Comparison of Medicinal Cannabis Extracts and Study of Their CYP-Mediated Interactions with Coumarinic Oral Anticoagulants. Med. Cannabis Cannabinoids; 2023; 6, pp. 21-31. [DOI: https://dx.doi.org/10.1159/000528465] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36814687]
65. 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, 236. [DOI: https://dx.doi.org/10.1186/2193-1801-2-236]
66. Gaston, T.E.; Bebin, E.M.; Cutter, G.R.; Liu, Y.; Szaflarski, J.P. The Uab Cbd Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia; 2017; 58, pp. 1586-1592. [DOI: https://dx.doi.org/10.1111/epi.13852] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28782097]
67. Ho, J.J.Y.; Goh, C.; Leong, C.S.A.; Ng, K.Y.; Bakhtiar, A. Evaluation of potential drug–drug interactions with medical cannabis. Clin. Transl. Sci.; 2024; 17, e13812. [DOI: https://dx.doi.org/10.1111/cts.13812]
68. Critchley, D.; Szaflarski, J.; Patsalos, P.; Gidal, B.; VanLandingham, K.; Morrison, G. Drug-drug Interaction Studies with Coadministration of Cannabidiol (CBD) and Clobazam, Valproate, Stiripentol or Midazolam in Healthy Volunteers and Adults with Epilepsy. Epilepsy Behav.; 2019; 101, 106735. [DOI: https://dx.doi.org/10.1016/j.yebeh.2019.08.010]
69. Benowitz, N.L.; Jones, R.T. Effects of delta-9-tetrahydrocannabinol on drug distribution and metabolism Antipyrine, pentobarbital, and ethanol. Clin. Pharmacol. Ther.; 1977; 22, pp. 259-268. [DOI: https://dx.doi.org/10.1002/cpt1977223259]
70. 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, pp. 847-856. [DOI: https://dx.doi.org/10.1007/s00406-019-01091-0] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31907614]
71. Abrams, D.I.; Couey, P.; Shade, S.B.; Kelly, M.E.; Benowitz, N.L. Cannabinoid–Opioid Interaction in Chronic Pain. Clin. Pharmacol. Ther.; 2011; 90, pp. 844-851. [DOI: https://dx.doi.org/10.1038/clpt.2011.188] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22048225]
72. Manini, A.F.; Yiannoulos, G.; Bergamaschi, M.M.; Hernandez, S.; Olmedo, R.; Barnes, A.J.B.; Winkel, G.; Sinha, R.; Jutras-Aswad, D.; Huestis, M.A. et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J. Addict. Med.; 2015; 9, pp. 204-210. [DOI: https://dx.doi.org/10.1097/ADM.0000000000000118]
73. Schulze Westhoff, M.S.; Massarou, C.; Bleich, S.; Heck, J.; Jendretzky, K.F.; Glahn, A.; Schröder, S. Drug interactions in a sample of inpatients diagnosed with cannabis use disorder. J. Neural Transm.; 2025; [DOI: https://dx.doi.org/10.1007/s00702-025-02884-5]
74. 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, pp. 1009-1031. [DOI: https://dx.doi.org/10.1002/cpdd.665] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30791225]
75. Devinsky, O.; Patel, A.D.; Thiele, E.A.; Wong, M.H.; Appleton, R.; Harden, C.L.; Greenwood, S.; Morrison, G.; Sommerville, K. GWPCARE1 Part A Study Groupet al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology; 2018; 90, pp. e1204-e1211. [DOI: https://dx.doi.org/10.1212/WNL.0000000000005254]
76. Geffrey, A.L.; Pollack, S.F.; Bruno, P.L.; Thiele, E.A. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia; 2015; 56, pp. 1246-1251. [DOI: https://dx.doi.org/10.1111/epi.13060]
77. Patsalos, P.N.; Szaflarski, J.P.; Gidal, B.; VanLandingham, K.; Critchley, D.; Morrison, G. Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs. Epilepsia; 2020; 61, pp. 1854-1868. [DOI: https://dx.doi.org/10.1111/epi.16674] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32918835]
78. VanLandingham, K.E.; Crockett, J.; Taylor, L.; Morrison, G. A Phase 2, Double-Blind, Placebo-Controlled Trial to Investigate Potential Drug-Drug Interactions Between Cannabidiol and Clobazam. J. Clin. Pharmacol.; 2020; 60, pp. 1304-1313. [DOI: https://dx.doi.org/10.1002/jcph.1634]
79. Ebrahimi-Fakhari, D.; Agricola, K.D.; Tudor, C.; Krueger, D.; Franz, D.N. Cannabidiol Elevates Mechanistic Target of Rapamycin Inhibitor Levels in Patients With Tuberous Sclerosis Complex. Pediatr. Neurol.; 2020; 105, pp. 59-61. [DOI: https://dx.doi.org/10.1016/j.pediatrneurol.2019.11.017] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31924480]
80. Wray, L.; Berwaerts, J.; Critchley, D.; Hyland, K.; Chen, C.; Thai, C.; Tayo, B. Pharmacokinetic Drug-Drug Interaction With Coadministration of Cannabidiol and Everolimus in a Phase 1 Healthy Volunteer Trial. Clin. Pharmacol. Drug Dev.; 2023; 12, pp. 911-919. [DOI: https://dx.doi.org/10.1002/cpdd.1262]
81. Moadel, D.; Chism, K. Medical Marijuana-Induced Tacrolimus Toxicity. Psychosomatics; 2019; 60, pp. 603-605. [DOI: https://dx.doi.org/10.1016/j.psym.2019.01.009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30819507]
82. Hauser, N.; Sahai, T.; Richards, R.; Roberts, T. High on Cannabis and Calcineurin Inhibitors: A Word of Warning in an Era of Legalized Marijuana. Case Rep. Transplant.; 2016; 2016, 4028492. [DOI: https://dx.doi.org/10.1155/2016/4028492]
83. Cuñetti, L.; Manzo, L.; Peyraube, R.; Arnaiz, J.; Curi, L.; Orihuela, S. Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay. Transplant. Proc.; 2018; 50, pp. 461-464. [DOI: https://dx.doi.org/10.1016/j.transproceed.2017.12.042] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29579828]
84. Leino, A.D.; Emoto, C.; Fukuda, T.; Privitera, M.; Vinks, A.A.; Alloway, R.R. Evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus. Am. J. Transplant.; 2019; 19, pp. 2944-2948. [DOI: https://dx.doi.org/10.1111/ajt.15398] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31012522]
85. So, G.C.; Lu, J.B.L.; Koyama, S.; Cheng, Y.; Gisch, D.L.; McClara, K.; Dexter, P.R.; Sharfuddin, A.A.; Etkins, J.; Tillman, E.M. et al. A Phase I Trial of the Pharmacokinetic Interaction Between Cannabidiol and Tacrolimus. Clin. Pharmacol. Ther.; 2024; 117, pp. 716-723. [DOI: https://dx.doi.org/10.1002/cpt.3504] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39601108]
86. Anderson, L.L.; Doohan, P.T.B.; Oldfield, L.; Kevin, R.C.; Arnold, J.C.; Berger, M.; Amminger, G.P.; McGregor, I.S. Citalopram and Cannabidiol. J. Clin. Psychopharmacol.; 2021; 41, pp. 525-533. [DOI: https://dx.doi.org/10.1097/JCP.0000000000001427] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34121064]
87. Wilens, T.E.; Biederman, J.; Spencer, T.J. Case study: Adverse effects of smoking marijuana while receiving tricyclic antidepressants. J. Am. Acad. Child Adolesc. Psychiatry; 1997; 36, pp. 45-48. [DOI: https://dx.doi.org/10.1097/00004583-199701000-00016] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9000780]
88. Kizer, K.W. Possible interaction of TCA and marijuana. Ann. Emerg. Med.; 1980; 9, 444. [DOI: https://dx.doi.org/10.1016/S0196-0644(80)80163-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7406260]
89. Kosel, B.W.; Aweeka, F.T.; Benowitz, N.L.; Shade, S.B.; Hilton, J.F.; Lizak, P.S.; Abrams, D.I. The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS; 2002; 16, pp. 543-550. [DOI: https://dx.doi.org/10.1097/00002030-200203080-00005]
90. Drugs.com: Drugs Interaction Checker 2021. Available online: https://www.drugs.com/drug_interactions.html (accessed on 2 September 2024).
91. Markowitz, J.S.; De Faria, L.; Zhang, Q.; Melchert, P.W.; Frye, R.F.; Klee, B.O.; Qian, Y. The Influence of Cannabidiol on the Pharmacokinetics of Methylphenidate in Healthy Subjects. Med. Cannabis Cannabinoids; 2022; 5, pp. 199-206. [DOI: https://dx.doi.org/10.1159/000527189] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36467779]
92. Preston, C. Stockley’s Drug Interactions; 12th ed. Pharmaceutical Press: London, UK, 2019.
93. Chetty, M.; Miller, R.; Moodley, S.V. Smoking and body weight influence the clearance of chlorpromazine. Eur. J. Clin. Pharmacol.; 1994; 46, pp. 523-526. [DOI: https://dx.doi.org/10.1007/BF00196109]
94. Thai, C.; Tayo, B.; Critchley, D. A Phase 1 Open-Label, Fixed-Sequence Pharmacokinetic Drug Interaction Trial to Investigate the Effect of Cannabidiol on the CYP1A2 Probe Caffeine in Healthy Subjects. Clin. Pharmacol. Drug Dev.; 2021; 10, pp. 1279-1289. [DOI: https://dx.doi.org/10.1002/cpdd.950] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33951339]
95. Udomuksorn, W.; Saowaneepitak, N.; Dolthammasiri, P.; Ruanglertboon, W.; Limsuwanchote, S.; Wiriyapongsukit, S.; Tungsukruthai, S. Unveiling the impact of water-boiled cannabis on warfarin: A case report of atrial fibrillation patients after cannabis legalization in Thailand. Toxicol. Rep.; 2024; 13, 101838. [DOI: https://dx.doi.org/10.1016/j.toxrep.2024.101838] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39703766]
96. Klotz, K.A.; Grob, D.; Hirsch, M.; Metternich, B.; Schulze-Bonhage, A.; Jacobs, J. Efficacy and Tolerance of Synthetic Cannabidiol for Treatment of Drug Resistant Epilepsy. Front. Neurol.; 2019; 10, 1313. [DOI: https://dx.doi.org/10.3389/fneur.2019.01313] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31920934]
97. Madden, K.; Tanco, K.; Bruera, E. Clinically Significant Drug-Drug Interaction Between Methadone and Cannabidiol. Pediatrics; 2020; 145, e20193256. [DOI: https://dx.doi.org/10.1542/peds.2019-3256] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32444381]
98. Zullino, D.; Delessert, D.; Eap, C.; Preisig, M.; Baumann, P. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int. Clin. Psychopharmacol.; 2002; 17, pp. 141-143. [DOI: https://dx.doi.org/10.1097/00004850-200205000-00008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11981356]
99. UpToDate. Drug Interactions, Search Results in UpToDate; UpToDate, Inc.: Waltham, MA, USA, 2024; Available online: https://www.uptodate.com (accessed on 2 September 2024).
100. Kollins, S.H.; Schoenfelder, E.N.; English, J.S.; Holdaway, A.; Van Voorhees, E.; O’brien, B.R.; Dew, R.; Chrisman, A.K. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults. J. Subst. Abus. Treat.; 2015; 48, pp. 96-103. [DOI: https://dx.doi.org/10.1016/j.jsat.2014.07.014]
101. Benowitz, N.L.; Nguyen, T.-L.; Jones, R.T.; Herning, R.I.; Bachman, J. Metabolic and psychophysiologic studies of cannabidiol-hexobarbital interaction. Clin. Pharmacol. Ther.; 1980; 28, pp. 115-120. [DOI: https://dx.doi.org/10.1038/clpt.1980.139]
102. Imasogie, N.; Rose, R.V.; Wilson, A. High quantities: Evaluating the association between cannabis use and propofol anesthesia during endoscopy. PLoS ONE; 2021; 16, e0248062. [DOI: https://dx.doi.org/10.1371/journal.pone.0248062] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33661987]
103. Food and Drug Administration (FDA) (Internet). Colchicine (Colcrys®), Label Information. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022351lbl.pdf (accessed on 12 September 2024).
104. Hartman, R.L.; Brown, T.L.; Milavetz, G.; Spurgin, A.; Pierce, R.S.; Gorelick, D.A.; Gaffney, G.; Huestis, M.A. Cannabis effects on driving lateral control with and without alcohol. Drug Alcohol Depend.; 2015; 154, pp. 25-37. [DOI: https://dx.doi.org/10.1016/j.drugalcdep.2015.06.015] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26144593]
105. Bosker, W.M.; Theunissen, E.L.; Conen, S.; Kuypers, K.P.C.; Jeffery, W.K.; Walls, H.C.; Kauert, G.F.; Toennes, S.W.; Moeller, M.R.; Ramaekers, J.G. A placebo-controlled study to assess Standardized Field Sobriety Tests performance during alcohol and cannabis intoxication in heavy cannabis users and accuracy of point of collection testing devices for detecting THC in oral fluid. Psychopharmacology; 2012; 223, pp. 439-446. [DOI: https://dx.doi.org/10.1007/s00213-012-2732-y] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22581391]
106. Ramaekers, J.G.; Theunissen, E.L.; de Brouwer, M.; Toennes, S.W.; Moeller, M.R.; Kauert, G. Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users. Psychopharmacology; 2011; 214, pp. 391-401. [DOI: https://dx.doi.org/10.1007/s00213-010-2042-1]
107. Lenné, M.G.; Dietze, P.M.; Triggs, T.J.; Walmsley, S.; Murphy, B.; Redman, J.R. The effects of cannabis and alcohol on simulated arterial driving: Influences of driving experience and task demand. Accid. Anal. Prev.; 2010; 42, pp. 859-866. [DOI: https://dx.doi.org/10.1016/j.aap.2009.04.021]
108. Chait, L.D.; Perry, J.L. Acute and residual effects of alcohol and marijuana, alone and in combination, on mood and performance. Psychopharmacology; 1994; 115, pp. 340-349. [DOI: https://dx.doi.org/10.1007/BF02245075] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7871074]
109. Adams, A.J.; Brown, B.; Haegerstrom-Portnoy, G.; Flom, M.C.; Jones, R.T. Marijuana, alcohol, and combined drug effects on the time course of glare recovery. Psychopharmacology; 1978; 56, pp. 81-86. [DOI: https://dx.doi.org/10.1007/BF00571413]
110. Perez-Reyes, M.; Hicks, R.E.; Bumberry, J.; Jeffcoat, A.R.; Cook, C.E. Interaction between marihuana and ethanol: Effects on psychomotor performance. Alcohol. Clin. Exp. Res.; 1988; 12, pp. 268-276. [DOI: https://dx.doi.org/10.1111/j.1530-0277.1988.tb00193.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2837105]
111. Toennes, S.W.; Schneider, K.; Kauert, G.F.; Wunder, C.; Moeller, M.R.; Theunissen, E.L.; Ramaekers, J.G. Influence of ethanol on cannabinoid pharmacokinetic parameters in chronic users. Anal. Bioanal. Chem.; 2010; 400, pp. 145-152. [DOI: https://dx.doi.org/10.1007/s00216-010-4449-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21116612]
112. Foltin, R.W.; Fischman, M.W.; Pedroso, J.J.; Pearlson, G.D. Marijuana and cocaine interactions in humans: Cardiovascular consequences. Pharmacol. Biochem. Behav.; 1987; 28, pp. 459-464. [DOI: https://dx.doi.org/10.1016/0091-3057(87)90506-5]
113. Van Wel, J.H.P.; Kuypers, K.P.C.; Theunissen, E.L.; Toennes, S.W.; Spronk, D.B.; Verkes, R.J.; Ramaekers, J.G. Single doses of THC and cocaine decrease proficiency of impulse control in heavy cannabis users. Br. J. Pharmacol.; 2013; 170, pp. 1410-1420. [DOI: https://dx.doi.org/10.1111/bph.12425] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24106872]
114. Foltin, R.W.; Fischman, M.W. Effects of the combination of cocaine and marijuana on the task-elicited physiological response. NIDA Res. Monogr.; 1989; 95, pp. 359-360. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2640994]
115. Murray, C.H.; Haney, M.; Foltin, R.W.; Manubay, J.; Bedi, G.; Cooper, Z.D. Smoked cannabis reduces peak cocaine plasma levels and subjective effects in a controlled drug administration study of polysubstance use in men. Drug Alcohol Depend.; 2022; 243, 109757. [DOI: https://dx.doi.org/10.1016/j.drugalcdep.2022.109757] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36608482]
116. Lukas, S.E.; Sholar, M.; Kouri, E.; Fukuzako, H.; Mendelson, J.H. Marihuana smoking increases plasma cocaine levels and subjective reports of euphoria in male volunteers. Pharmacol. Biochem. Behav.; 1994; 48, pp. 715-721. [DOI: https://dx.doi.org/10.1016/0091-3057(94)90338-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7938127]
117. Evans, M.A.; Martz, R.; Rodda, B.E.; Lemberger, L.; Forney, R.B. Effects of marihuana-dextroamphetamine combination. Clin. Pharmacol. Ther.; 1976; 20, pp. 350-358. [DOI: https://dx.doi.org/10.1002/cpt1976203350] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/782773]
118. Zalcman, S.; Liskow, B.; Cadoret, R.; Goodwin, D. Marijuana and amphetamine: The question of interaction. Am. J. Psychiatry; 1973; 130, pp. 707-708. [DOI: https://dx.doi.org/10.1176/ajp.130.6.707]
119. Dumont, G.J.; Kramers, C.; Sweep, F.C.; Touw, D.J.; van Hasselt, J.G.; de Kam, M.; van Gerven, J.M.; Buitelaar, J.K.; Verkes, R.J. Cannabis coadministration potentiates the effects of “ecstasy” on heart rate and temperature in humans. Clin. Pharmacol. Ther.; 2009; 86, pp. 160-166. [DOI: https://dx.doi.org/10.1038/clpt.2009.62]
120. Lansbergen, M.M.; Dumont, G.J.H.; van Gerven, J.M.A.; Buitelaar, J.K.; Verkes, R.-J. Acute effects of MDMA (3,4-methylenedioxymethamphetamine) on EEG oscillations: Alone and in combination with ethanol or THC (delta-9-tetrahydrocannabinol). Psychopharmacology; 2011; 213, pp. 745-756. [DOI: https://dx.doi.org/10.1007/s00213-010-2031-4]
121. Dumont, G.; van Hasselt, J.; de Kam, M.; van Gerven, J.; Touw, D.; Buitelaar, J.; Verkes, R. Acute psychomotor, memory and subjective effects of MDMA and THC co-administration over time in healthy volunteers. J. Psychopharmacol.; 2011; 25, pp. 478-489. [DOI: https://dx.doi.org/10.1177/0269881110376687] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20817749]
122. Penetar, D.M.; Kouri, E.M.; Gross, M.M.; McCarthy, E.M.; Rhee, C.K.; Peters, E.N.; Lukas, S.E. Transdermal nicotine alters some of marihuana’s effects in male and female volunteers. Drug Alcohol Depend.; 2005; 79, pp. 211-223. [DOI: https://dx.doi.org/10.1016/j.drugalcdep.2005.01.008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16002030]
123. Hunault, C.C.; Mensinga, T.T.; de Vries, I.; Kelholt-Dijkman, H.H.; Hoek, J.; Kruidenier, M.; Leenders, M.E.C.; Meulenbelt, J. Delta-9-tetrahydrocannabinol (THC) serum concentrations and pharmacological effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg THC. Psychopharmacology; 2008; 201, pp. 171-181. [DOI: https://dx.doi.org/10.1007/s00213-008-1260-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18695931]
124. Hunault, C.C.; Mensinga, T.T.; Böcker, K.B.E.; Schipper, C.M.A.; Kruidenier, M.; Leenders, M.E.C.; de Vries, I.; Meulenbelt, J. Cognitive and psychomotor effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg delta-9-tetrahydrocannabinol (THC). Psychopharmacology; 2009; 204, pp. 85-94. [DOI: https://dx.doi.org/10.1007/s00213-008-1440-0] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19099294]
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Details
; Pérez-Mañá, Clara 1
; Farré, Magí 1
; Papaseit, Esther 1 1 Department of Clinical Pharmacology, Hospital Universitari Germans Trias I Pujol, Institut de Recerca Germans Trias i Pujol (IGTP), Carretera de Canyet, s/n, 08916 Badalona, Spain;