New research suggests that cannabis use by people in care for opioid addiction might improve their treatment outcomes and reduce their risk of being exposed to fentanyl in the contaminated unregulated drug supply.
In a paper published today in the peer-reviewed journal Drug and Alcohol Dependence, researchers from the BC Centre on Substance Use (BCCSU) and University of British Columbia (UBC) found that 53 per cent of the 819 study participants in Vancouver’s Downtown Eastside were intentionally or inadvertently using fentanyl, despite being on opioid agonist treatments (OAT) like methadone or buprenorphine/naloxone.
These evidence-based treatments aim to support people who want to eliminate their use of unregulated opioids, however, these findings suggest people may be supplementing their treatment through the unregulated drug supply, putting them at risk of overdose.
However, researchers found that those in the study who had urine tests positive for THC (the primary psychoactive component of cannabis) were approximately 10 per cent less likely to have fentanyl-positive urine, putting them at lower risk of a fentanyl overdose.
“These new findings suggest that cannabis could have a stabilizing impact for many patients on treatment, while also reducing the risk of overdose,” said Dr. Eugenia Socías, a clinician scientist at BCCSU and lead author of the study.
“With overdoses continuing to rise across the country, these findings highlight the urgent need for clinical research to evaluate the therapeutic potential of cannabinoids as adjunctive treatment to OAT to address the escalating opioid overdose epidemic.”
Untreated opioid use disorder is a key driver of the overdose crisis in BC and across the United States and Canada, and expanding access to evidence-based addiction care like OAT has been identified as an urgent need and a key part of BC’s response.
Research has found that without access to and rapid scale-up of take home naloxone, overdose prevention services, and OAT, the number of overdose deaths in B.C. would be 2.5 times as high.
However, while more British Columbians diagnosed with an opioid use disorder are being connected to evidence-based treatments, retention on these medications remains a challenge. People who are retained in OAT face much lower risks of dying from an overdose, acquiring HIV or suffering other harms of drug use compared to people who are out of treatment.
Cannabis may play an important role in supporting retention on OAT. Previous research from the BCCSU found that individuals initiating OAT who reported using cannabis on a daily basis were approximately 21 per cent more likely to be retained in treatment at six months than non-cannabis users.
This was the first study to find a beneficial link between high-intensity cannabis use and retention in treatment among people initiating OAT.
The findings published today add to an emerging body of research suggesting cannabis could have a stabilizing impact for many patients on treatment, while also reducing the risk of overdose.
Researchers from BCCSU will soon be able to confirm these preliminary results, as the Canadian Institutes of Health Research, Canada’s federal health research funder, recently approved funding for a Vancouver-based pilot study evaluating the feasibility and safety of cannabis as an adjunct therapy to OAT.
“Scientists are only just beginning to understand the role cannabis might play in supporting people’s wellbeing, particularly those who use other substances,” says Dr. M-J Milloy, study co-author and the Canopy Growth professor of cannabis science at UBC, who will lead the new study with Dr. Socías.
“This study will help us understand if and how cannabis might have a role in addressing the overdose crisis.”
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 .
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 .
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.  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 . 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 , which decreased fourteen days after CBD was discontinued.
Some authors  concluded that morphine and methadone analgesia was greater in mice lacking Pgp. Hassan et al.  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 , 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 , 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 , 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.
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 .
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) . 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  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 .
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 .
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 . 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 . 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 , 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.
Regarding efflux transporters in the brain, recent studies supported a low possibility that Pgp affects these drugs .
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.
Antiepileptic drugs are used worldwide to treat several disorders other than epilepsy, such as neuropathic pain, migraine, and bipolar disorder . The first-line options for the treatment of various neuropathic pain conditions are carbamazepine, gabapentin, and pregabalin .
Pregabalin and gabapentin share a similar mechanism of action, and both undergo renal excretion . 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  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.  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 , 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 , 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 , 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 , 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. .
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  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 , 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  and in the prevention of migraine with aura . Lamotrigine is predominantly metabolized by glucuronidation (UGT1A4 and UGT2B7), and it also undergoes elimination by a minor elimination pathway that involves CYP450 enzymes .
This minor route converts the drug to a reactive arene oxide metabolite . Such intermediate metabolite, if not effectively detoxified, can result in cellular damage . Skin injuries, Stevens-Johnson syndrome, and toxic epidermal necrolysis are all reported adverse events related to lamotrigine use , mainly when the drug is coadministered with valproic acid [111–113], a well-known inhibitor of the glucuronidation pathway.
Cannabinoids can act inhibiting UGTs  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 , 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.
reference link: https://www.hindawi.com/journals/bmri/2020/3902740/tab2/
More information: M. Eugenia Socías et al, Cannabis use is associated with reduced risk of exposure to fentanyl among people on opioid agonist therapy during a community-wide overdose crisis, Drug and Alcohol Dependence (2020). DOI: 10.1016/j.drugalcdep.2020.108420