CBD Oil And Lamotrigine


Buy CBD Oil Online

Potential Pharmacokinetic Drug-Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain This is an open access article distributed under the Creative Commons Attribution License, There’s reason to believe that, as safe as CBD has been shown when used alone, it may have the potential to negatively react with other medications to create some unintended side effects.

Potential Pharmacokinetic Drug-Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Choosing an appropriate treatment for chronic pain remains problematic, and despite the available medication for its treatment, still, many patients complain about pain and appeal to the use of cannabis derivatives for pain control. However, few data have been provided to clinicians about the pharmacokinetic drug-drug interactions of cannabinoids with other concomitant administered medications. Therefore, the aim of this brief review is to assess the interactions between cannabinoids and pain medication through drug transporters (ATP-binding cassette superfamily members) and/or metabolizing enzymes (cytochromes P450 and glucuronyl transferases).

1. Introduction

A drug-drug interaction (DDI) occurs when one drug alters the clinical effect of another. Drug interactions occur on pharmacodynamic and pharmacokinetic levels. In the first case, one drug may alter the sensitivity or responsiveness to another drug. Pharmacokinetic DDIs occur when a drug alters the absorption or disposition (distribution and elimination) of a concomitantly administered drug. This change can lead to an altered quantity of drug at the site of action affecting the magnitude and duration of the effect. In this scenario, a drug is a perpetrator referring to the one that causes an effect on the substrate drug, for example, by inducing or inhibiting drug-metabolizing enzymes. Although DDIs are often associated with toxicity or therapeutic failure [1], sometimes they can produce beneficial effects to the patient (i.e., improving the bioavailability of a drug and producing additive or synergistic effects) [2]. In any case, clinicians must be familiar with DDIs in order to improve prescribing tools.

During the last 5 years, a dramatic rise in the use of cannabis led to an increased number of patients taking it simultaneously with their previous medication. This situation could result in several problems as cannabinoids may be classified as either perpetrators or substrates depending on the concomitant drugs leading to altered exposure, adverse events, and/or lack of clinical efficacy. However, scarce evidence is available about cannabis drug interactions with potential implications in clinical efficacy and safety.

The endocannabinoid system has been recognized as a potential therapeutic target. Either highly purified cannabidiol (such as Epidiolex recently approved in the United States for use in Lennox–Gastaut or Dravet syndrome) or formulations with different Δ 9 -tetrahydrocannabinol (THC) to cannabidiol (CBD) ratios (such as Sativex, an oromucosal spray for the treatment of multiple sclerosis-associated spasticity) are being investigated for other disease states. Although the use of cannabinoids for the treatment of pain is supported by some controlled clinical trials [3–5], currently and according to systematic reviews and meta-analysis [6–8], there is only moderate evidence to support the use of cannabinoids in treating chronic pain and larger and higher quality clinical trials are needed. Despite this fact, chronic pain relief is by far the most common condition cited by patients using cannabis for medical purposes and very little is known about potential pharmacokinetic interactions with common medication prescribed for chronic pain.

Nowadays, even cannabinol (CBN), a byproduct of THC degradation, is being studied for its analgesic effect [9].

CBD, THC, and CBN are extensively metabolized in the liver and in the intestine. Mainly CYP2C19 and, to a lesser extent, CYP3A4 are implicated in CBD biotransformation [10, 11]. CBD can also undergo direct conjugations via UDP-glucuronosyltransferase (UGT) enzymes, such as UGT1A9, UGT2B7, and UGT2B17 [12, 13]. THC biotransformation is primarily dependent on CYP2C9 and CYP3A4 isoenzymes [14], but UGT enzymes play a critical role in metabolizing THC metabolites (THC-OH, THC-COOH) as well [12]. CBN is metabolized by CYP2C9 and CYP3A4 and can also undergo direct glucuronidation by hepatic UGT1A9 and the extrahepatic UGT1A7, UGT1A8, and UGT1A10 [12, 14].

CBD is not only a substrate but also an inhibitor of CYP450 enzymes and UGTs. In addition, some isoenzymes of the cytochrome P450 system or UGTs are also subjected to inhibition by THC and CBN [11, 15–25].

Regarding the inducing activity of cannabinoids, smoked cannabis may increase the clearance of drugs metabolized by CYP1A2 [24, 25], resulting in lower concentrations of these drugs and perhaps in therapeutic failure.

Furthermore, in vitro and animal studies have shown that CBD, THC, and CBN interact in some way with ATP-binding cassette superfamily: breast cancer-resistant protein (Bcrp) and glycoprotein P (Pgp). Thus, a significant impact on the absorption and disposition of other coadministered drugs that are also substrates of these transporters may be expected. According to some preclinical studies [26–29], CBD inhibits Pgp and Bcrp. Even though inhibitors are often substrates, different in vitro and animal studies show that CBD is not a Pgp substrate [30, 31] and it acts provoking a downregulation in Pgp expression. THC and CBN could also deregulate Pgp, Bcrp, and multidrug-resistant protein (MRP) 1-4 expression [15]. An overview of the effect of cannabinoids on CYP450 isoenzymes, UGTs, and efflux transporters is summarized in Table 1 .

Table 1

Effect of cannabinoids on CYP450 isoenzymes, UGTs, and efflux transporters.

Cannabinoids CYP P450 isoenzymes UGTs Modulation of efflux transporter expression
CBD Inhibition of CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2B6, CYP3A4, and CYP2D6 Inhibition of UGT1A9 and 2B7 Deregulation of Pgp, BCRP, and MRP1-4 transporter expression
THC Inhibition of CYP3A4, CYP2D6, and CYP2C9 THC-OH, THC-COOH (metabolites) can compete with glucuronidation pathways
CBN Inhibition of CYP3A4, CYP2D6, and CYP2C9 Inhibition of UGT1A7, 1A8, and 1A9

BCRP: breast cancer resistance proteins; CBD: cannabidiol; CBN: cannabinol; CYP: cytochrome; MRP: multidrug resistance proteins; Pgp: glycoprotein P; THC: Δ 9 -tetrahydrocannabinol; THC-OH: 11-hydroxy-tetrahydrocannabinol; THC-COOH: 11-nor-9-carboxy-tetrahydrocannabinol; UGTs: UDP glucuronosyltransferases.

As cannabinoids are often used as add-on therapy, the occurrence of DDIs seems more plausible. Therefore, their use in the therapy could interfere with the disposition of other drugs that undergo the same metabolic pathways. Nonetheless, few studies in humans have been carried out and reported in the literature about DDIs of cannabinoids with other prescribed medications [32–34] and some of them are only case reports [35–37].

Although in vitro or animal studies about DDIs should not be extrapolated to human beings, healthcare providers should be aware of clinically important DDIs leading in some cases to therapeutic improvement or in other cases to therapeutic failure or toxicity. Therefore, this review addresses a comprehensive overview of potential pharmacokinetic interactions affecting drug metabolism enzymes such as cytochrome P450 or UGTs and membrane efflux transporters between cannabinoids and drugs used for chronic pain.

2. Methodology

Electronic databases of published scientific literature were the main source for this review. The in vitro and in vivo research findings and clinical case reports were searched from PubMed, Google Scholar, and Cochrane Library. Some studies were identified with Google search. Additional articles of interest were obtained through cross-referencing of published literature. The primary key terms used were “pharmacokinetics,” “drug interactions,” “cannabinoids,” “metabolizing enzymes,” “efflux transporters,” and “chronic pain medication.” Only English language papers were taken into consideration.

3. Drug-Drug Interactions

3.1. Cannabinoids-Opioids

The conventional opioids most commonly used for chronic pain management are morphine, oxycodone, codeine, methadone, tramadol, and fentanyl. Most opioids exert an analgesic effect through binding to the μ opioid receptor except for tramadol and methadone that include both opioid and nonopioid components [38, 39].

Morphine is glucuronidated via UGT2B7 to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), being the latter a highly active analgesic [40].

Oxycodone is metabolized in the liver by CYP3A4/5 and CYP2D6. An active metabolite (oxymorphone) is formed by CYP2D6 [41, 42]. Oxycodone glucuronidation is carried out by UGT2B7 and UGT2B4 while oxymorphone is glucuronidated mostly by UGT2B7 [43].

CBD inhibits UGT2B7, and thus, a lower M6G to morphine ratio should be expected and less analgesic potency. Moreover, CBD, THC, and CBN inhibit CYP2D6 affecting oxymorphone formation and thus reducing analgesic effect. Therefore, if the interactions mentioned above take place, perhaps less analgesia would be seen with the combination of cannabis and these two opioids. However, several studies in the literature report that cannabis enhances the analgesic effects of opioids, thereby allowing for lower doses [44–47]. Furthermore, Abrams et al. [48] found that vaporized cannabis given to patients with chronic pain on opioid therapy (morphine or oxycodone) increased the analgesic effect of opioids but no significant differences were observed in the mean plasma concentration-time curves for morphine and oxycodone with and without cannabis treatment. These authors suggested pharmacodynamic interactions between opioids and cannabinoids. However, as opioid delivery to the brain is influenced by ATP-binding cassette transporters [49–51], a pharmacokinetic interaction should not be neglected.

Several cytochrome P450 enzymes are involved in methadone metabolism: CYP3A4, CYP2B6, and CYP2C19 and, to a lesser extent, CYP2C9, CYP2C8, and CYP2D6. It has become clear nowadays that CYP2B6, rather than CYP3A4, is the predominant P450 responsible for clinical methadone disposition [52]. CBD is a strong inhibitor of CYP2B6, so increased levels of this opioid and a greater analgesic potency might be observed. An increased plasma level of methadone was observed in a pediatric patient receiving CBD [36], which decreased fourteen days after CBD was discontinued.

Some authors [53] concluded that morphine and methadone analgesia was greater in mice lacking Pgp. Hassan et al. [54] found that oxycodone is a Pgp substrate in vivo. Some studies [50, 55, 56] suggested that this efflux transporter limits the entry of some opiates into the brain and that administration of Pgp inhibitors or drugs that downregulate Pgp expression can increase the sensitivity to these opiates. This fact, rather than enzyme inhibition by cannabinoids, could be the explanation of augmented analgesic potency of opiates, and the need of lowering their doses in the presence of cannabinoids as efflux transporters are deregulated by cannabinoids. This could be the case for morphine, oxycodone, and methadone as they are substrates of efflux transporters.

Neither codeine nor tramadol is Pgp substrates [51, 57]. The polymorphic CYP2D6 regulates the O-demethylation of codeine and tramadol to more potent metabolites: morphine and O-desmethyl-tramadol, respectively. Tramadol undergoes another metabolic pathway catalyzed by CYP3A4 and CYP2B6.

According to some authors [58], if the subject is a poor metabolizer, inadequate analgesia can be observed. If CBD, THC, or CBN inhibition of CYP2D6 predominates, the analgesic effects of tramadol and codeine will be reduced. However, the fate of the active metabolites has to be taken into account as well. O-desmethyl-tramadol undergoes inactivation by UGT2B7 and UGT1A8 [59], and morphine as stated before is a Pgp substrate. If cannabinoids interfere in the elimination of these metabolites either by inhibiting UGT2B7 or by deregulating efflux transporter expression, the result will be the opposite. Further studies are necessary in order to assess cannabinoid influence on codeine and tramadol.

Fentanyl is mainly metabolized by CYP3A4 and is a Pgp substrate [50, 60]. Although some authors found no interaction between fentanyl given intravenously and CBD [61], plasma levels of fentanyl were undetectable before and after the administration of CBD. Therefore, deeper research is necessary in order to conclude on a possible pharmacokinetic interaction.

To sum up, if opioids and/or their active metabolite levels are increased when taken along with cannabinoids, an enhanced analgesic activity can be observed.

3.2. Cannabinoids-Acetaminophen

Acetaminophen (paracetamol) is a drug with analgesic and antipyretic properties widely used for pain relief. Although its analgesic effect is weaker in comparison with nonsteroidal anti-inflammatory drugs (NSAIDs), it can be considered as a first-line option among nonopioids due to a more favorable safety profile. However, high concentrations can induce liver damage, and therefore, daily doses should not exceed 4 g [62].

Acetaminophen glucuronidation by UGT1A1, UGT1A6, UGT1A9, and UGT2B15 is the main biotransformation pathway, and only a minor fraction of the drug is oxidized to the highly reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) [63]. Acetaminophen-induced liver toxicity with the concomitant use of phenytoin or phenobarbital or with the use of tyrosine kinase inhibitors was reported in the literature [64, 65]. The interaction is assumed to be due to competition or inhibition of UGT activities. A recent study [66] revealed that the coadministration of a cannabidiol-rich cannabis extract and acetaminophen results in alterations in the livers of aged female mice. As cannabinoids can inhibit UGTs, a higher concentration of acetaminophen might be expected. When glucuronidation is compromised, acetaminophen is directed towards the formation of the reactive metabolite NAPQI resulting in liver damage.

Moreover, acetaminophen is a MRP2 substrate so deregulation of this transporter by the concomitant use of cannabinoids can result in higher levels of the drug as well [67].

3.3. Cannabinoids-Antidepressants

Mixed-action antidepressants (serotonin and norepinephrine-reuptake inhibitors) such as duloxetine, amitriptyline, and venlafaxine are a mainstay in the treatment of many chronic pain conditions [68].

Elimination of duloxetine is mainly through hepatic metabolism involving CYP1A2 and to a lesser extent CYP2D6. There is evidence that coadministration of duloxetine with CYP1A2 and CYP2D6 inhibitors increased duloxetine levels [69]. As stated before, CBD is an inhibitor of CYP1A2 and THC, CBD, and CBN inhibit CYP2D6, so if cannabinoids are used as a concomitant medication, an increase in duloxetine plasma levels may be seen.

Venlafaxine relies on CYP2D6 for conversion to O-desmethylvenlafaxine (major active metabolite). Further conversion of this metabolite involves CYP2C19 and CYP3A4. Venlafaxine is also metabolized by CYP2C19, CYP2C9, and CYP3A4 but to a lesser extent [70]. As all the enzymes implied in venlafaxine and its active metabolite biotransformation are inhibited by cannabinoids, the clinical implication is difficult to predict. Several studies evaluating CYP2D6 polymorphism [71–73] concluded that higher venlafaxine and lower O-desmethylvenlafaxine levels in poor metabolizers resulted in a reduced clinical response with an increased risk for side effects in comparison with extensive metabolizers. Polymorphisms in the CYP2C19 genes that result in decreased enzymatic activity have also been documented [74, 75]. Therefore, elevated venlafaxine levels caused by the potential inhibition of cannabinoids of its metabolic pathway can affect drug response and its side-effect profile.

Amitriptyline is metabolized mostly by CYP2D6, CYP3A4, and CYP2C19, the latter leading to the formation of nortriptyline (active metabolite). Other isozymes involved in amitriptyline metabolism are CYP1A2 and CYP2C9. Based on dosing recommendations made by the Clinical Pharmacogenetics Implementation Consortium in 2016 according to CYP2D6 and/or CYP2C19 variants of individuals [76], if the level of amitriptyline and its active metabolites are too high as happening in poor metabolizers, there is an increased risk of toxicity. Certain drugs as cannabinoids inhibit the activity of these isoenzymes and make normal metabolizers resemble poor metabolizers.

See also  CBD Oil Michigan

Regarding efflux transporters in the brain, recent studies supported a low possibility that Pgp affects these drugs [77].

To sum up, drug interactions between cannabinoids and antidepressants, if they occur, may be due to metabolizing enzyme inhibition. This inhibition may increase the levels of the antidepressants or their active metabolites resulting in side effects such as the serotonin syndrome, hyponatraemia [78–80], hemorrhagic events [81–84], and QT interval prolongation among others [85, 86]. In the case of duloxetine and amitriptyline, as both drugs are metabolized by CYP1A2, chronic smoked cannabis use may result in lower concentrations of these drugs and perhaps lower efficacy.

3.4. Cannabinoids-Anticonvulsants

Antiepileptic drugs are used worldwide to treat several disorders other than epilepsy, such as neuropathic pain, migraine, and bipolar disorder [87]. The first-line options for the treatment of various neuropathic pain conditions are carbamazepine, gabapentin, and pregabalin [88].

Pregabalin and gabapentin share a similar mechanism of action, and both undergo renal excretion [89]. Based on the renal elimination of these drugs, no DDIs between these gabapentinoids and cannabinoids should be expected. With regard to efflux transporters, some authors’ results [90] suggested that a combined treatment of pregabalin with Pgp inhibitors enables the prolongation of dose interval of this drug. However, no studies in literature found increased pregabalin levels in the brain with the use of Pgp inhibitors.

Although Gaston et al. [32] did not find changes in carbamazepine levels when administered with cannabis, they focused the study on CBD as the perpetrator drug and carbamazepine as the substrate but information is lacking about the influence of concomitant carbamazepine on CBD plasma levels. Carbamazepine is a well-known inducer of CYP3A4 [91], and therefore, THC, CBD, and CBN metabolism could be affected leading to lower plasma concentrations of these cannabinoids.

Although there is insufficient evidence to support the use of valproic acid for neuropathic pain and fibromyalgia [92], it is sometimes used for these purposes in the clinical practice. Valproic acid is metabolized by three different routes: glucuronidation (UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15) and β-oxidation (using carnitine as a carrier) in the mitochondria (major pathways) and a minor route (ω-oxidation) leading the latter to the formation of a hepatotoxic metabolite (4-en-VPA) [93, 94]. According to some studies [95], valproic acid inhibited UGT1A9 in an uncompetitive manner and UGT2B7 competitively. Glucuronidation is also involved in CBD metabolism being CBD an inhibitor of UGT1A9 and UGT2B7. On the one hand, if cannabinoid concentrations are high, perhaps CBD may impair valproic acid glucuronidation, and thus, valproic acid clearance may be reduced. The higher concentrations of valproic acid induce carnitine depletion [96], and this could increase the ω-oxidation route leading to a higher concentration of 4-en-VPA (hepatotoxic metabolite). This last fact could result in incorrect ammonium elimination and thus hyperammonemia [97–99]. On the other hand, valproic acid inhibits UGT1A9 and UGT2B7, both involved in cannabinoid elimination. Perhaps, this inhibition plays the main role and higher concentrations of cannabinoids could be seen in turn. This fact could be supported by the observation made by Gaston et al. [32]. Although these researchers did not measure CBD levels, they did not find a significant change in the valproate levels with increasing doses of CBD but a rise in aspartate transaminase (AST) and/or alanine transaminase (ALT) levels after CBD treatment. These authors concluded that CBD enhances the negative effects of valproic acid on liver functions, but perhaps, valproic acid is the one that intensifies CBD hepatotoxicity augmenting its blood levels. Research done in mice [100] showed that CBD treatment increases liver-to-body weight, ALT, AST, and total bilirubin. In clinical trials carried out recently, some authors [101–103] found elevated liver enzymes in 5-20% of patients treated with CBD, and some patients had to be withdrawn from the studies due to serious hepatic complications. So the combination of CBD with other drugs that exhibit hepatotoxicity and interact with CBD should be of great concern. Valproic acid is not a substrate of Pgp or MRPs [104], so interactions with cannabinoids at this level are unlikely.

Regarding lamotrigine, although the evidence of its efficacy in chronic pain is unconvincing, it can have some effect in patients with painful HIV-related neuropathy [105] and in the prevention of migraine with aura [106]. Lamotrigine is predominantly metabolized by glucuronidation (UGT1A4 and UGT2B7), and it also undergoes elimination by a minor elimination pathway that involves CYP450 enzymes [107]. This minor route converts the drug to a reactive arene oxide metabolite [108]. Such intermediate metabolite, if not effectively detoxified, can result in cellular damage [109]. Skin injuries, Stevens-Johnson syndrome, and toxic epidermal necrolysis are all reported adverse events related to lamotrigine use [110], mainly when the drug is coadministered with valproic acid [111–113], a well-known inhibitor of the glucuronidation pathway. Cannabinoids can act inhibiting UGTs [114] in the same way valproic acid does. So, in the absence of the major pathway, lamotrigine can be bioactivated to the arene oxide and an increased risk of skin reactions in patients could be expected. In addition, lamotrigine is a substrate of Pgp and BCRP [115], so downregulation of their expression provoked by cannabinoids can intensify the drug effect.

A comprehensive overview of the potential interactions discussed in the text is summarized in Table 2 .

Table 2

Drugs commonly used in chronic pain, their main metabolic pathways, efflux transporter implication, and the result of potential interaction with cannabinoids.

Drugs Efflux transporter substrate Metabolic pathway Potential cannabinoid interaction
Morphine Yes UGT2B7 Augmented analgesic potency due to efflux transporters downregulation. Dose reduction may be required.
Codeine No CYP2D6 Possible augmented analgesia provoked by the active metabolite (morphine) by downregulation of efflux transporter expression. Dose reduction may be required.
Oxycodone Yes CYP3A4/5, CYP2D6, UGT2B7, and UGT2B4 Augmented analgesia due to parent drug or active metabolite by efflux transporter downregulation and/or enzyme inhibition. Dose reduction may be required.
Methadone Yes CYP3A4, CYP2B6, CYP2C19, CYP2C9, CYP2C8, and CYP2D6 Augmented analgesia due to enzyme inhibition and/or efflux transporter downregulation. Dose reduction may be required.
Tramadol No CYP2D6, CYP2B6, and CYP3A Possible augmented analgesia due to inhibition of metabolism of active metabolite. Dose reduction may be required.
Fentanyl Yes CYP3A4 Possible augmented analgesia due to inhibition of metabolism and/or efflux transporter downregulation.
Acetaminophen Yes UGT1A1, UGT1A6, UGT1A9, and UGT2B15 Higher levels of acetaminophen due to UGT inhibition and/or efflux transporter downregulation and thus possible hepatotoxicity. Monitor adverse effects.
Duloxetine No CYP1A2, CYP2D6 Higher concentration of antidepressant due to metabolizing enzyme inhibition. Dose reduction may be required.
Smoked cannabis may increase clearance of duloxetine. Monitor for loss of efficacy with chronic marijuana use.
Venlafaxine No CYP2D6, CYP2C19, CYP2C9, and CYP3A4 Higher concentration of antidepressant due to metabolizing enzyme inhibition. Dose reduction may be required.
Amitriptyline No CYP2D6, CYP3A4, CYP2C19, CYP1A2, and CYP2C9 Higher concentration of parent drug and/or active metabolites due to metabolizing enzyme inhibition. Dose reduction may be required.
Smoked cannabis may increase clearance of amitriptyline. Monitor for loss of efficacy with chronic marijuana use.
Valproic acid No UGT1A3, A4, A6, A8, A9, A10, UGT2B7, UGT2B15, and β-oxidation in the mitochondria (using carnitine as carrier) Possible higher levels of valproic acid by inhibition of UGTs or higher levels of cannabinoids due to valproic acid UGT inhibition. In both cases, the interaction could result in hepatic damage. Monitor adverse effects.
Lamotrigine Yes UGT1A4, UGT2B7 Higher levels of lamotrigine by UGT inhibition and/or downregulation of efflux transporters. Possible cutaneous reactions. Dose reduction may be required.

4. Conclusion

Data on significant DDIs between cannabinoids and other medications is still limited and most of it comes from in vitro and animal studies. The results obtained in the literature may be of help, but they cannot be extrapolated to human beings. Given that the widespread use of cannabinoids will certainly continue, further research in humans is essential to clarify DDIs in order to fully understand their relevance in the clinical setting.

Conflicts of Interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.


1. Abubakar A. R., Chedi B. A. Z., Mohammed K. G., Haque M. Drug interaction and its implication in clinical practice and personalized medicine. National Journal of Physiology, Pharmacy and Pharmacology. 2015; 5 (5):343–349. doi: 10.5455/njppp.2015.5.2005201557. [CrossRef] [Google Scholar]

2. Gerber W., Steyn J. D., Kotzé A. F., Hamman J. H. Beneficial pharmacokinetic drug interactions: a tool to improve the bioavailability of poorly permeable drugs. Pharmaceutics. 2018; 10 (3):p. 106. doi: 10.3390/pharmaceutics10030106. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

3. Andreae M. H., Carter G. M., Shaparin N., et al. Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data. The Journal of Pain. 2015; 16 (12):1221–1232. doi: 10.1016/j.jpain.2015.07.009. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

4. Vučković S., Srebro D., Vujović K. S., Vučetić Č., Prostran M. Cannabinoids and pain: new insights from old molecules. Frontiers in Pharmacology. 2018; 9, article 1259 doi: 10.3389/fphar.2018.01259. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

5. Whiting P. F., Wolff R. F., Deshpande S., et al. Cannabinoids for medical use: a systematic review and meta-analysis. Journal of the American Medical Association. 2015; 313 (24):2456–2473. doi: 10.1001/jama.2015.6358. [PubMed] [CrossRef] [Google Scholar]

6. Johal H., Devji T., Chang Y., Simone J., Vannabouathong C., Bhandari M. Cannabinoids in chronic non-cancer pain: a systematic review and meta-analysis. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders. 2020; 13 :13. doi: 10.1177/1179544120906461. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

7. Cameron E. C., Hemingway S. L. Cannabinoids for fibromyalgia pain: a critical review of recent studies (2015–2019) Journal of Cannabis Research. 2020; 2 (1, article 19) doi: 10.1186/s42238-020-00024-2. [CrossRef] [Google Scholar]

8. Mücke M., Phillips T., Radbruch L., Petzke F., Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews. 2018; 3 (3) doi: 10.1002/14651858.cd012182.pub2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

9. Wong H., Cairns B. E. Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain. Archives of Oral Biology. 2019; 104 :33–39. doi: 10.1016/j.archoralbio.2019.05.028. [PubMed] [CrossRef] [Google Scholar]

10. Jiang R., Yamaori S., Takeda S., Yamamoto I., Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sciences. 2011; 89 (5-6):165–170. doi: 10.1016/j.lfs.2011.05.018. [PubMed] [CrossRef] [Google Scholar]

11. Zendulka O., Dovrtělová G., Nosková K., et al. Cannabinoids and cytochrome P450 interactions. Current Drug Metabolism. 2016; 17 (3):206–226. doi: 10.2174/1389200217666151210142051. [PubMed] [CrossRef] [Google Scholar]

12. Mazur A., Lichti C. F., Prather P. L., et al. Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids. Drug Metabolism and Disposition. 2009; 37 (7):1496–1504. doi: 10.1124/dmd.109.026898. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

13. Ujváry I., Hanuš L. Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis and Cannabinoid Research. 2016; 1 (1):90–101. doi: 10.1089/can.2015.0012. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

14. Watanabe K., Yamaori S., Funahashi T., Kimura T., Yamamoto I. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sciences. 2007; 80 (15):1415–1419. doi: 10.1016/j.lfs.2006.12.032. [PubMed] [CrossRef] [Google Scholar]

15. Alsherbiny M. A., Li C. G. Medicinal cannabis-potential drug interactions. Medicines. 2019; 6 (1):p. 3. doi: 10.3390/medicines6010003. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

16. Arellano A. L., Papaseit E., Romaguera A., Torrens M., Farre M. Neuropsychiatric and general interactions of natural and synthetic cannabinoids with drugs of abuse and medicines. CNS & Neurological Disorders Drug Targets. 2017; 16 (5):554–566. doi: 10.2174/1871527316666170413104516. [PubMed] [CrossRef] [Google Scholar]

17. Stout S. M., Cimino N. M. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metabolism Reviews. 2013; 46 (1):86–95. doi: 10.3109/03602532.2013.849268. [PubMed] [CrossRef] [Google Scholar]

18. Yamaori S., Ebisawa J., Okushima Y., Yamamoto I., Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sciences. 2011; 88 (15-16):730–736. doi: 10.1016/j.lfs.2011.02.017. [PubMed] [CrossRef] [Google Scholar]

19. Yamaori S., Okamoto Y., Yamamoto I., Watanabe K. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metabolism and Disposition. 2011; 39 (11):2049–2056. doi: 10.1124/dmd.111.041384. [PubMed] [CrossRef] [Google Scholar]

20. Opitz B. J., Ostroff M. L., Whitman A. C. The potential clinical implications and importance of drug interactions between anticancer agents and cannabidiol in patients with cancer. Journal of Pharmacy Practice. 2020; 33 (4):506–512. doi: 10.1177/0897190019828920. [PubMed] [CrossRef] [Google Scholar]

21. Brown J. D., Winterstein A. G. Potential adverse drug events and drug-drug interactions with medical and consumer cannabidiol (CBD) use. Journal of Clinical Medicine. 2019; 8 (7):p. 989. doi: 10.3390/jcm8070989. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

22. Qian Y., Gurley B. J., Markowitz J. S. The potential for pharmacokinetic interactions between cannabis products and conventional medications. Journal of Clinical Psychopharmacology. 2019; 39 (5):462–471. doi: 10.1097/JCP.0000000000001089. [PubMed] [CrossRef] [Google Scholar]

23. Rong C., Carmona N. E., Lee Y. L., et al. Drug-drug interactions as a result of co-administering Δ 9 -THC and CBD with other psychotropic agents. Expert Opinion on Drug Safety. 2017; 17 (1):51–54. doi: 10.1080/14740338.2017.1397128. [PubMed] [CrossRef] [Google Scholar]

24. Antoniou T., Bodkin J., Ho J. M. W. Drug interactions with cannabinoids. CMAJ. 2020; 192 (9, article E206) doi: 10.1503/cmaj.191097. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

25. Kocis P. T., Vrana K. E. Delta-9-tetrahydrocannabinol and cannabidiol drug-drug interactions. Medical Cannabis and Cannabinoids. 2020:1–13. doi: 10.1159/000507998. [CrossRef] [Google Scholar]

26. Feinshtein V., Erez O., Ben-Zvi Z., et al. Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study. American Journal of Obstetrics and Gynecology. 2013; 209 (6):573.e1–573.e15. doi: 10.1016/j.ajog.2013.08.005. [PubMed] [CrossRef] [Google Scholar]

27. Holland M. L., Lau D. T. T., Allen J. D., Arnold J. C. The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids. British Journal of Pharmacology. 2007; 152 (5):815–824. doi: 10.1038/sj.bjp.0707467. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

28. Holland M. L., Panetta J. A., Hoskins J. M., et al. The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells. Biochemical Pharmacology. 2006; 71 (8):1146–1154. doi: 10.1016/j.bcp.2005.12.033. [PubMed] [CrossRef] [Google Scholar]

29. Zhu H. J., Wang J. S., Markowitz J. S., et al. Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. The Journal of Pharmacology and Experimental Therapeutics. 2006; 317 (2):850–857. doi: 10.1124/jpet.105.098541. [PubMed] [CrossRef] [Google Scholar]

30. Brzozowska N., Li K. M., Wang X. S., et al. ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice. PeerJ. 2016; 4, article e2081 doi: 10.7717/peerj.2081. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

See also  Five CBD Gummies

31. Feinshtein V., Erez O., Ben-Zvi Z., et al. Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines. PeerJ. 2013; 1, article e153 doi: 10.7717/peerj.153. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

32. 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 (9):1586–1592. doi: 10.1111/epi.13852. [PubMed] [CrossRef] [Google Scholar]

33. 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 (8):1246–1251. doi: 10.1111/epi.13060. [PubMed] [CrossRef] [Google Scholar]

34. 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. Clinical Pharmacology in Drug Development. 2019; 8 (8):1009–1031. doi: 10.1002/cpdd.665. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

35. Grayson L., Vines B., Nichol K., Szaflarski J. P. An interaction between warfarin and cannabidiol, a case report. Epilepsy & Behavior Case Reports. 2018; 9 :10–11. doi: 10.1016/j.ebcr.2017.10.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

36. Madden K., Tanco K., Bruera E. Clinically significant drug-drug interaction between methadone and cannabidiol. Pediatrics. 2020; 145 (6, article e20193256) doi: 10.1542/peds.2019-3256. [PubMed] [CrossRef] [Google Scholar]

37. 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. American Journal of Transplantation. 2019; 19 (10):2944–2948. doi: 10.1111/ajt.15398. [PubMed] [CrossRef] [Google Scholar]

38. Raffa R. B., Friderichs E., Reimann W., Shank R. P., Codd E. E., Vaught J. L. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. The Journal of Pharmacology and Experimental Therapeutics. 1992; 260 (1):275–285. [PubMed] [Google Scholar]

39. Baldo B. A. Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects. Archives of Toxicology. 2018; 92 (8):2457–2473. doi: 10.1007/s00204-018-2244-6. [PubMed] [CrossRef] [Google Scholar]

40. Osborne R., Joel S., Trew D., Slevin M. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clinical Pharmacology and Therapeutics. 1990; 47 (1):12–19. doi: 10.1038/clpt.1990.2. [PubMed] [CrossRef] [Google Scholar]

41. Lalovic B., Phillips B., Risler L. L., Howald W., Shen D. D. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metabolism and Disposition. 2004; 32 (4):447–454. doi: 10.1124/dmd.32.4.447. [PubMed] [CrossRef] [Google Scholar]

42. Lalovic B., Kharasch E., Hoffer C., Risler L., Liuchen L., Shen D. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clinical Pharmacology and Therapeutics. 2006; 79 (5):461–479. doi: 10.1016/j.clpt.2006.01.009. [PubMed] [CrossRef] [Google Scholar]

43. Coffman B. L., King C. D., Rios G. R., Tephly T. R. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268) Drug Metabolism and Disposition. 1998; 26 (1):73–77. [PubMed] [Google Scholar]

44. Degenhardt L., Lintzeris N., Campbell G., et al. Experience of adjunctive cannabis use for chronic non-cancer pain: findings from the Pain and Opioids IN Treatment (POINT) study. Drug and Alcohol Dependence. 2015; 147 :144–150. doi: 10.1016/j.drugalcdep.2014.11.031. [PubMed] [CrossRef] [Google Scholar]

45. Haroutounian S., Ratz Y., Ginosar Y., et al. The effect of medicinal cannabis on pain and quality-of-life outcomes in chronic pain. The Clinical Journal of Pain. 2016; 32 (12):1036–1043. doi: 10.1097/AJP.0000000000000364. [PubMed] [CrossRef] [Google Scholar]

46. Reiman A., Welty M., Solomon P. Cannabis as a substitute for opioid-based pain medication: patient self-report. Cannabis and Cannabinoid Research. 2017; 2 (1):160–166. doi: 10.1089/can.2017.0012. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

47. Cooper Z. D., Bedi G., Ramesh D., Balter R., Comer S. D., Haney M. Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. Neuropsychopharmacology. 2018; 43 (10):2046–2055. doi: 10.1038/s41386-018-0011-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

48. Abrams D. I., Couey P., Shade S. B., Kelly M. E., Benowitz N. L. Cannabinoid-opioid interaction in chronic pain. Clinical Pharmacology and Therapeutics. 2011; 90 (6):844–851. doi: 10.1038/clpt.2011.188. [PubMed] [CrossRef] [Google Scholar]

49. Chaves C., Remiao F., Cisternino S., Decleves X. Opioids and the blood-brain barrier: a dynamic interaction with consequences on drug disposition in brain. Current Neuropharmacology. 2017; 15 (8):1156–1173. doi: 10.2174/1570159X15666170504095823. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

50. Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance. Current Topics in Medicinal Chemistry. 2011; 11 (9):1157–1164. doi: 10.2174/156802611795371288. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

51. Yang J., Reilly B., Davis T., Ronaldson P. Modulation of opioid transport at the blood-brain barrier by altered ATP-binding cassette (ABC) transporter expression and activity. Pharmaceutics. 2018; 10 (4):p. 192. doi: 10.3390/pharmaceutics10040192. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

52. Gadel S., Friedel C., Kharasch E. D. Differences in methadone metabolism by CYP2B6 variants. Drug Metabolism and Disposition. 2015; 43 (7):994–1001. doi: 10.1124/dmd.115.064352. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

53. Thompson S. J., Koszdin K., Bernards C. M. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology. 2000; 92 (5):1392–1399. doi: 10.1097/00000542-200005000-00030. [PubMed] [CrossRef] [Google Scholar]

54. Hassan H. E., Myers A. L., Lee I. J., Coop A., Eddington N. D. Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel’s tissue distribution in Sprague Dawley rats. Journal of Pharmaceutical Sciences. 2007; 96 (9):2494–2506. doi: 10.1002/jps.20893. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

55. Rodriguez M., Ortega I., Soengas I., Suarez E., Lukas J. C., Calvo R. Effect of P-glycoprotein inhibition on methadone analgesia and brain distribution in the rat. The Journal of Pharmacy and Pharmacology. 2004; 56 (3):367–374. doi: 10.1211/0022357022782. [PubMed] [CrossRef] [Google Scholar]

56. Wang J. S., Ruan Y., Taylor R. M., Donovan J. L., Markowitz J. S., DeVane C. L. Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice. Psychopharmacology. 2004; 173 (1-2):132–138. doi: 10.1007/s00213-003-1718-1. [PubMed] [CrossRef] [Google Scholar]

57. Kanaan M., Daali Y., Dayer P., Desmeules J. Uptake/efflux transport of tramadol enantiomers and O-desmethyl-tramadol: focus on P-glycoprotein. Basic & Clinical Pharmacology & Toxicology. 2009; 105 (3):199–206. doi: 10.1111/j.1742-7843.2009.00428.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

58. Kumar S., Kundra P., Ramsamy K., Surendiran A. Pharmacogenetics of opioids: a narrative review. Anaesthesia. 2019; 74 (11):1456–1470. doi: 10.1111/anae.14813. [PubMed] [CrossRef] [Google Scholar]

59. Gong L., Stamer U. M., Tzvetkov M. V., Altman R. B., Klein T. E. PharmGKB summary: tramadol pathway. Pharmacogenetics and Genomics. 2014; 24 (7):374–380. doi: 10.1097/FPC.0000000000000057. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

60. Smith H. S. Opioid metabolism. Mayo Clinic Proceedings. 2009; 84 (7):613–624. doi: 10.1016/S0025-6196(11)60750-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

61. Manini A. F., Yiannoulos G., Bergamaschi M. M., et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. Journal of Addiction Medicine. 2015; 9 (3):204–210. doi: 10.1097/ADM.0000000000000118. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

62. Jaeschke H. Acetaminophen: dose-dependent drug hepatotoxicity and acute liver failure in patients. Digestive Diseases. 2015; 33 (4):464–471. doi: 10.1159/000374090. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

63. Mazaleuskaya L. L., Sangkuhl K., Thorn C. F., FitzGerald G. A., Altman R. B., Klein T. E. PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenetics and Genomics. 2015; 25 (8):416–426. doi: 10.1097/FPC.0000000000000150. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

64. Kostrubsky S. E., Sinclair J. F., Strom S. C., et al. Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicological Sciences. 2005; 87 (1):146–155. doi: 10.1093/toxsci/kfi211. [PubMed] [CrossRef] [Google Scholar]

65. Liu Y., Ramírez J., Ratain M. J. Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors. British Journal of Clinical Pharmacology. 2011; 71 (6):917–920. doi: 10.1111/j.1365-2125.2011.03911.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

66. Ewing L. E., McGill M. R., Yee E. U., et al. Paradoxical patterns of sinusoidal obstruction syndrome-like liver injury in aged female CD-1 mice triggered by cannabidiol-rich cannabis extract and acetaminophen co-administration. Molecules. 2019; 24 (12):p. 2256. doi: 10.3390/molecules24122256. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

67. Hassany M., Hassanzadeh Khayat M., Behravan J., Kasaeeian J. Expression of drug pump protein MRP2 in lipopolysaccharide-treated rats and its impact on the disposition of acetaminophen. Iranian Journal of Pharmaceutical Research. 2011; 10 (4):855–859. [PMC free article] [PubMed] [Google Scholar]

68. Leo R. J., Khalid K. Antidepressants for chronic pain. Current Psychiatry. 2019; 18 (2):9–22. [Google Scholar]

69. Knadler M. P., Lobo E., Chappell J., Bergstrom R. Duloxetine. Clinical Pharmacokinetics. 2011; 50 (5):281–294. doi: 10.2165/11539240-000000000-00000. [PubMed] [CrossRef] [Google Scholar]

70. Sangkuhl K., Stingl J. C., Turpeinen M., Altman R. B., Klein T. E. PharmGKB summary: venlafaxine pathway. Pharmacogenetics and Genomics. 2014; 24 (1):62–72. doi: 10.1097/FPC.0000000000000003. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

71. Shams M. E. E., Arneth B., Hiemke C., et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. Journal of Clinical Pharmacy and Therapeutics. 2006; 31 (5):493–502. doi: 10.1111/j.1365-2710.2006.00763.x. [PubMed] [CrossRef] [Google Scholar]

72. Veefkind A. H., Haffmans P. M. J., Hoencamp E. Venlafaxine serum levels and CYP2D6 genotype. Therapeutic Drug Monitoring. 2000; 22 (2):202–208. doi: 10.1097/00007691-200004000-00011. [PubMed] [CrossRef] [Google Scholar]

73. Wijnen P. A. H. M., Limantoro I., Drent M., Bekers O., Kuijpers P. M. J. C., Koek G. H. Depressive effect of an antidepressant: therapeutic failure of venlafaxine in a case lacking CYP2D6 activity. Annals of Clinical Biochemistry. 2009; 46 (6):527–530. doi: 10.1258/acb.2009.009003. [PubMed] [CrossRef] [Google Scholar]

74. Jornil J., Nielsen T. S., Rosendal I., et al. A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine. Forensic Science International. 2013; 226 (1-3):e26–e31. doi: 10.1016/j.forsciint.2012.12.020. [PubMed] [CrossRef] [Google Scholar]

75. Vinetti M., Haufroid V., Capron A., Classen J. F., Marchandise S., Hantson P. Severe acute cardiomyopathy associated with venlafaxine overdose and possible role of CYP2D6 and CYP2C19 polymorphisms. Clinical Toxicology. 2011; 49 (9):865–869. doi: 10.3109/15563650.2011.626421. [PubMed] [CrossRef] [Google Scholar]

76. Hicks J. K., Sangkuhl K., Swen J. J., et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clinical Pharmacology and Therapeutics. 2017; 102 (1):37–44. doi: 10.1002/cpt.597. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

77. Zheng Y., Chen X., Benet L. Z. Reliability of in vitro and in vivo methods for predicting the effect of P-glycoprotein on the delivery of antidepressants to the brain. Clinical Pharmacokinetics. 2016; 55 (2):143–167. doi: 10.1007/s40262-015-0310-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

78. Rottmann C. N. SSRIs and the syndrome of inappropriate antidiuretic hormone secretion. The American Journal of Nursing. 2007; 107 (1):51–58. doi: 10.1097/00000446-200701000-00022. [PubMed] [CrossRef] [Google Scholar]

79. Roxanas M., Hibbert E., Field M. Venlafaxine hyponatraemia: incidence, mechanism and management. The Australian and New Zealand Journal of Psychiatry. 2007; 41 (5):411–418. doi: 10.1080/00048670701261202. [PubMed] [CrossRef] [Google Scholar]

80. Yoshida K., Aburakawa Y., Suzuki Y., Kuroda K., Kimura T. Acute hyponatremia resulting from duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion. Internal Medicine. 2019; 58 (13):1939–1942. doi: 10.2169/internalmedicine.2346-18. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

81. de Abajo F. J. Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients. Drugs & Aging. 2011; 28 (5):345–367. doi: 10.2165/11589340-000000000-00000. [PubMed] [CrossRef] [Google Scholar]

82. Hackam D. G., Mrkobrada M. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology. 2012; 79 (18):1862–1865. doi: 10.1212/WNL.0b013e318271f848. [PubMed] [CrossRef] [Google Scholar]

83. Hougardy D. M. C., Egberts T. C. G., van der Graaf F., Brenninkmeijer V. J., Derijks L. J. J. Serotonin transporter polymorphism and bleeding time during SSRI therapy. British Journal of Clinical Pharmacology. 2008; 65 (5):761–766. doi: 10.1111/j.1365-2125.2008.03098.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

84. Jiang H. Y., Chen H. Z., Hu X. J., et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2015; 13 (1):42–50.e3. doi: 10.1016/j.cgh.2014.06.021. [PubMed] [CrossRef] [Google Scholar]

85. Letsas K., Korantzopoulos P., Pappas L., Evangelou D., Efremidis M., Kardaras F. QT interval prolongation associated with venlafaxine administration. International Journal of Cardiology. 2006; 109 (1):116–117. doi: 10.1016/j.ijcard.2005.03.065. [PubMed] [CrossRef] [Google Scholar]

86. Yekehtaz H., Farokhnia M., Akhondzadeh S. Cardiovascular considerations in antidepressant therapy: an evidence-based review. The Journal of Tehran Heart Center. 2013; 8 (4):169–176. [PMC free article] [PubMed] [Google Scholar]

87. Sidhu H. S., Sadhotra A. Current status of the new antiepileptic drugs in chronic pain. Frontiers in Pharmacology. 2016; 7 :p. 276. doi: 10.3389/fphar.2016.00276. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

88. Goodyear-Smith F., Halliwell J. Anticonvulsants for neuropathic pain: gaps in the evidence. The Clinical Journal of Pain. 2009; 25 (6):528–536. doi: 10.1097/AJP.0b013e318197d4cc. [PubMed] [CrossRef] [Google Scholar]

89. Bockbrader H. N., Wesche D., Miller R., Chapel S., Janiczek N., Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clinical Pharmacokinetics. 2010; 49 (10):661–669. doi: 10.2165/11536200-000000000-00000. [PubMed] [CrossRef] [Google Scholar]

90. Mukae T., Fujita W., Ueda H. P-glycoprotein inhibitors improve effective dose and time of pregabalin to inhibit intermittent cold stress-induced central pain. Journal of Pharmacological Sciences. 2016; 131 (1):64–67. doi: 10.1016/j.jphs.2016.01.002. [PubMed] [CrossRef] [Google Scholar]

91. Patsalos P. N., Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. The Lancet Neurology. 2003; 2 (6):347–356. doi: 10.1016/S1474-4422(03)00409-5. [PubMed] [CrossRef] [Google Scholar]

92. Gill D., Derry S., Wiffen P. J., Moore R. A. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews. 2011; 2011 (10, article CD009183) doi: 10.1002/14651858.CD009183.pub2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

93. Siemes H., Nau H., Schultze K., et al. Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity. Epilepsia. 1993; 34 (2):332–346. doi: 10.1111/j.1528-1157.1993.tb02419.x. [PubMed] [CrossRef] [Google Scholar]

94. Ghodke-Puranik Y., Thorn C. F., Lamba J. K., et al. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenetics and Genomics. 2013; 23 (4):236–241. doi: 10.1097/FPC.0b013e32835ea0b2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

95. Ethell B. T., Anderson G. D., Burchell B. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases. Biochemical Pharmacology. 2003; 65 (9):1441–1449. doi: 10.1016/S0006-2952(03)00076-5. [PubMed] [CrossRef] [Google Scholar]

96. Ohtani Y., Endo F., Matsuda I. Carnitine deficiency and hyperammonemia associated with valproic acid therapy. The Journal of Pediatrics. 1982; 101 (5):782–785. doi: 10.1016/S0022-3476(82)80320-X. [PubMed] [CrossRef] [Google Scholar]

97. Vázquez M., Fagiolino P., Mariño E. L. Concentration-dependent mechanisms of adverse drug reactions in epilepsy. Current Pharmaceutical Design. 2013; 19 (38):6802–6808. doi: 10.2174/1381612811319380012. [PubMed] [CrossRef] [Google Scholar]

98. Vázquez M., Fagiolino P., Maldonado C., et al. Hyperammonemia associated with valproic acid concentrations. BioMed Research International. 2014; 2014 :7. doi: 10.1155/2014/217269. 217269 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

See also  Mother Nature's CBD Gummies

99. Maldonado C., Guevara N., Queijo C., González R., Fagiolino P., Vázquez M. Carnitine and/or acetylcarnitine deficiency as a cause of higher levels of ammonia. BioMed Research International. 2016; 2016 :8. doi: 10.1155/2016/2920108. 2920108 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

100. Ewing L. E., Skinner C. M., Quick C. M., et al. Hepatotoxicity of a cannabidiol-rich cannabis extract in the mouse model. Molecules. 2019; 24 (9, article 1694) doi: 10.3390/molecules24091694. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

101. Devinsky O., Cross J. H., Wright S. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. The New England Journal of Medicine. 2017; 377 (7):699–700. [PubMed] [Google Scholar]

102. Devinsky O., Patel A. D., Cross J. H., et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. The New England Journal of Medicine. 2018; 378 (20):1888–1897. doi: 10.1056/NEJMoa1714631. [PubMed] [CrossRef] [Google Scholar]

103. Thiele E. A., Marsh E. D., French J. A., et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018; 391 (10125):1085–1096. doi: 10.1016/S0140-6736(18)30136-3. [PubMed] [CrossRef] [Google Scholar]

104. Baltes S., Fedrowitz M., Tortós C. L., Potschka H., Löscher W. Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays. The Journal of Pharmacology and Experimental Therapeutics. 2006; 320 (1):331–343. doi: 10.1124/jpet.106.102491. [PubMed] [CrossRef] [Google Scholar]

105. Wiffen P. J., Derry S., Moore R. A. Lamotrigine for acute and chronic pain. Cochrane Database of Systematic Reviews. 2011; 16 (2, article CD006044) doi: 10.1002/14651858. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

106. Buch D., Chabriat H. Lamotrigine in the prevention of migraine with aura: a narrative review. Headache. 2019; 59 (8):1187–1197. doi: 10.1111/head.13615. [PubMed] [CrossRef] [Google Scholar]

107. Rowland A., Elliot D. J., Williams J. A., Mackenzie P. I., Dickinson R. G., Miners J. O. In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction. Drug Metabolism and Disposition. 2006; 34 (6):1055–1062. doi: 10.1124/dmd.106.009340. [PubMed] [CrossRef] [Google Scholar]

108. Maggs J. L., Naisbitt D. J., Tettey J. N. A., Pirmohamed M., Park B. K. Metabolism of lamotrigine to a reactive arene oxide intermediate. Chemical Research in Toxicology. 2000; 13 (11):1075–1081. doi: 10.1021/tx0000825. [PubMed] [CrossRef] [Google Scholar]

109. Naisbitt D. J. Drug hypersensitivity reactions in skin: understanding mechanisms and the development of diagnostic and predictive tests. Toxicology. 2004; 194 (3):179–196. doi: 10.1016/j.tox.2003.09.004. [PubMed] [CrossRef] [Google Scholar]

110. Wang X. Q., Lv B., Wang H. F., et al. Lamotrigine-induced severe cutaneous adverse reaction: update data from 1999–2014. Journal of Clinical Neuroscience. 2015; 22 (6):1005–1011. doi: 10.1016/j.jocn.2015.01.016. [PubMed] [CrossRef] [Google Scholar]

111. Lalic M., Cvejic J., Popovic J., et al. Lamotrigine and valproate pharmacokinetics interactions in epileptic patients. European Journal of Drug Metabolism and Pharmacokinetics. 2009; 34 (2):93–99. doi: 10.1007/BF03191157. [PubMed] [CrossRef] [Google Scholar]

112. Vázquez M., Maldonado C., Guevara N., et al. Lamotrigine-Valproic Acid Interaction Leading to Stevens–Johnson Syndrome. Case Reports in Medicine. 2018; 2018 :5. doi: 10.1155/2018/5371854. 5371854 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

113. Yalcin B., Karaduman A. Stevens–Johnson syndrome associated with concomitant use of lamotrigine and valproic acid. Journal of the American Academy of Dermatology. 2012; 43 (5):703–706. [PubMed] [Google Scholar]

114. Johannessen Landmark C., Brandl U. Pharmacology and drug interactions of cannabinoids. Epileptic Disorders. 2020; 22 (1):S16–S22. [PubMed] [Google Scholar]

115. Römermann K., Helmer R., Löscher W. The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2) Neuropharmacology. 2015; 93 :7–14. doi: 10.1016/j.neuropharm.2015.01.015. [PubMed] [CrossRef] [Google Scholar]

What Kind of Drug Interactions Can Happen with CBD?

Many consumers are increasingly turning to CBD products as a natural alternative to everything from chronic pain relief to the treatment of ADHD, anxiety, and more. While CBD, one of the many compounds inherent to the cannabis sativa plant, may offer a nice alternative to current treatments, including prescription drugs, it’s important to be smart about how CBD could potentially interact with any other medications you’re taking.

7 Common CBD Oil Drug Interactions

  • Antidepressants, such as Fluoxetine or Prozac
  • Any drug that causes drowsiness, including antipsychotics and benzodiazepines
  • Warfarin
  • Macrolide antibiotics like Erythromycin and Clarithromycin
  • Amiodarone
  • Levothyroxine
  • Seizure Medications Like Clobazam, Lamotrigine and Vaproate

CBD has many exciting possibilities when it comes to therapeutic treatment, but it’s important to remember that the research around is in the very early stages. Because researchers haven’t fully explored CBD’s mechanism of action (yet), it can be sometimes be hard to predict whether it will have interactions with other medications, both over-the-counter and prescriptions. What behaves as a safe and natural remedy for one patient could have unintended negative interactions with another patient, depending on the other compounds in the patient’s system.

While we’ll outline some of the most common CBD oil drug interactions, it’s always important to visit with your doctor or consult with a pharmacist if you have any concerns about potential negative side effects.

Does CBD Interact with Medications?

There’s reason to believe that, as safe as CBD has been shown when used alone, it may have the potential to negatively react with other medications to create some unintended side effects.

CBD may at times react with over-the-counter medications, herbal products, and some prescription medications, which underscores the necessity of talking with a doctor or pharmacist before trying CBD products if you’re regularly taking a drug for a heart condition, pain or another medical condition. Some medications should never be taken with CBD, while others can be modified or reduced in order to decrease the chance of a negative CBD drug interaction. And while CBD information for medical professionals is in early phases, your doctor is still the best equipped to provide sound advice about how to safely use CBD for your particular medical condition.

According to Nina M. Bemben, PharmD, BCPS —a specialist in drug interactions—CBD, along with many other medications and compounds, are broken down for the body’s use by the liver enzyme family known as Cytochrome p450. Because CBD acts as an inhibitor to certain CYP enzymes, it could cause other medications in the body to be broken down more slowly—which, unless your doctor lowers your dosage, could lead to increased side effects. On the other hand, CBD can induce other CYP enzymes, which may lead to a faster drug metabolism, resulting in reduced efficacy unless the dosage is increased.

While much research is needed on exactly how CBD behaves within our bodies and how it interacts with various other medications, here’s a good general rule to remember: if you take a drug with a label that features a grapefruit juice warning, it’s a good idea to steer clear of any CBD product while you take that drug. Why? According to the U.S. Food and Drug Administration , a medication with this warning, taken together with grapefruit or grapefruit juice, can manifest at a higher than intended concentration within the blood, potentially causing adverse events.

What does this have to do with CBD? A class of chemicals present in grapefruit juice, known as furanocoumarins, inhibit the enzyme CYP3A4—in much the same way CBD does, resulting in a slower metabolization of medications. So, if you’re taking a medication that features a grapefruit warning, there’s a good chance CBD may cause a few issues with that drug as well. More than 85 different drugs react negatively with grapefruit, including many of the following—you’ll notice a distinct overlap between this list and the list of drugs that commonly have a CBD drug interaction:

  • Antibiotics and antimicrobials
  • Anticancer medications
  • Antihistamines
  • Antiepileptic drugs
  • Blood pressure medications
  • Blood thinners
  • Cholesterol medications
  • Corticosteroids
  • Erectile dysfunction medications
  • GI medications, such as those used to treat nausea and GERD
  • Heart rhythm medications
  • Immunosuppressants
  • Mental health medications, such as to treat anxiety, depression, or mood disorders
  • Pain management medications
  • Prostate medications

The good news? Based on what we know about how CBD is metabolized, there doesn’t seem to be much concern over potential reactions to nonsteroidal anti-inflammatory drugs and/or other prescription medications used to treat the symptoms of arthritis. More good news: there are no reports of any life-threatening interactions that over-the-counter CBD products have had with any herbal, OTC, or prescription drug. Commonly reported side effects have included drowsiness, nausea, diarrhea, dry mouth, a decrease in medication efficacy and changes in appetite or weight.

With the help of your doctor, it’s possible to add CBD to your therapeutic regimen, even if you’re taking another prescription medication that could interact negatively with CBD. It may just be a question of adjusting dosage, monitoring liver function and/or carefully watching for side effects.

We also want to stress that you should never forego your current medication to try CBD without talking with your doctor first. Some medications will need the dosage slowly tapered down in order to safely discontinue use, while others may require careful monitoring.

7 Common CBD Oil Drug Interactions

Let’s take a closer look at common medications CBD oil may negatively interact with:

1. Antidepressants, such as Fluoxetine or Prozac

Some common medications prescribed for depression, such as Fluoxetine and Prozac, when combined with CBD, may increase drowsiness or dizziness. This can be dangerous for patients who are older or who otherwise experience mobility issues, as it may increase the chances for a dangerous or even life-threatening fall.

2. Any drug that causes drowsiness, including antipsychotics and benzodiazepines

Any drug that causes drowsiness, which is a surprisingly large collection, has the potential to combine with CBD for an intensified effect. Anyone who is taking these types of medications combined with CBD is at an increased risk for impaired judgment, falls, and other dangerous situations that result from excessive drowsiness.

3. Warfarin and Clopidogrel

Warfarin is a fairly common drug prescribed as a blood thinner. The most reliable information we have about CBD’s potential interaction with Warfarin comes from studies of the only FDA-approved CBD product, Epidiolex, which is a prescription treatment for rare forms of epilepsy. Epidiolex has been shown to increase blood levels of Warfarin by approximately 30 percent. With this increase comes a higher risk of excessive bleeding. Clopidogrel also interacts with CBD.

4. Macrolide antibiotics like Erythromycin and Clarithromycin

These types of antibiotics are widely prescribed for the treatment of bacterial infections. Because CBD has the ability to slow down or speed up the metabolism of antibiotics by our CPY450 enzymes, taking antibiotics in conjunction with CBD may mean you end up with a higher dose of drugs in your system than is either safe or effective.

5. Amiodarone

Amiodarone is often prescribed to address irregular heart rhythm. CBD metabolism often is slowed down when taken in combination with Amiodarone, resulting in elevated levels of both medications in your system if they’re used together. In addition, both CBD and amiodarone can cause an elevation in liver enzymes, and the effect is exacerbated when the two are taken together.

6. Levothyroxine

Levothyroxine is a commonly prescribed thyroid medication. In fact, it is likely the most popular drug prescribed for thyroid issues. When CBD and levothyroxine are taken together, they are forced to compete within the CPY450 enzyme pathways for effective drug metabolism. This kind of drug interaction could cause thyroxine to accumulate, which could result in hyperthyroidism. In addition, when thyroid medications and CBD products are taken too closely together, some patients may experience short-term anxiety and mild nausea.

Seizure medications, like Clobazam, Lamotrigine and Vaproate
Clobazam, Lamotrigine, and Vaproate often are prescribed for patients experiencing seizures, either due to epilepsy or other health conditions. In some cases, CBD has increased the Clobazam levels of children treated with both Clobazam and CBD for epilepsy.

Does CBD Consumption Method Matter?

The manner in which you consume CBD absolutely has an effect on its potential to negatively react with other medications you take. Inhaling CBD, for example, deposits the compound almost immediately into your bloodstream, which allows it to reach peak concentration within 30 minutes. This delivery method avoids the liver’s metabolism, but may still increase the chances that CBD will negatively react with other medications already in your system.

Edible CBD vehicles, like soft chews, CBD gummies, etc., take longer to absorb and reach peak concentration, but they also have the potential to reach a highly concentrated enough level that negative interactions are possible. The same is true for a CBD oil or emulsion tincture .

CBD topicals, such as balms, creams, CBD lotion, etc., are the least likely to react negatively with other medications in your bloodstream because absorption through the skin decreases the amount of CBD that may eventually make its way into your bloodstream.

Other factors that influence both the occurrence and severity of a CBD interaction with other pharmaceutical drugs may include the age of the patient, the dosage amount of both CBD, and the interacting drug, plus any existing underlying medical conditions. Older patients may be at higher risk of potential negative drug interaction for a couple of reasons: first, as we age, the time our bodies take to process compounds like CBD and other medications increases, and second, older patients are more likely to take multiple medications on a regular basis.

Your doctor can help you figure out what type of CBD and dosage may be right for you, considering your medical profile and any medications you already take on a regular basis.

Create a CBD Treatment Plan with Your Medical Team Today!

CBD shows great promise in being able to offer patients relief from a wide variety of medical conditions, but it’s still in the early stages of research. If you want to try CBD, but are already taking a medication to treat your condition, make sure to confer with your doctor before adding CBD to your treatment plan or before using CBD to replace any of your current medications.

Your doctor can help you develop a plan that will let you enjoy the highest therapeutic effect of CBD with the fewest possible side effects. And when you’re ready to purchase high quality, responsible CBD products, our team at Farmer & Chemist is here to help—we have a broad variety of CBD oils, creams, gummies, and more. Our team of pharmacists and pharmacy technicians are also available to answer any questions you may have about the appropriate use of CBD, as well as any potential drug interaction you need to speak to your doctor about.

How useful was this post?

Click on a star to rate it!

Average rating 3 / 5. Vote count: 1

No votes so far! Be the first to rate this post.