cbd and hivDecember 15, 2021
There are no known interactions between NNRTIs and some of the recreational drugs such as GHB, MDMA, mephedrone, methamphetamine or poppers.
This applies to some, but not all anti-HIV drugs. Similarly it only affects some recreational drugs.
Taking ketamine with NNRTIs may lower levels of ketamine. Similarly, levels of erectile dysfunction drugs may be lowered. This applies to efavirenz, etravirine, and nevirapine.
If you use recreational drugs or think you may in the future, a frank discussion with your HIV doctor or HIV pharmacist can give you a better understanding of the risks, based on your own situation. If you don’t want to stop or can’t stop using recreational drugs, switching to an HIV treatment with less potential for interactions might be an option.
Non-nucleoside reverse transcriptase inhibitor, the family of antiretrovirals which includes efavirenz, nevirapine, etravirine, doravirine and rilpivirine. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to and block HIV reverse transcriptase (an HIV enzyme), preventing HIV from replicating.
Non-nucleoside reverse transcriptase inhibitors.
Some interactions may have an effect after some time taking the drugs, while on other occasions they could have an effect the first time they are used.
Poppers may also interact with erectile dysfunction drugs, causing a potentially dangerous drop in blood pressure. This may be more likely if you are also taking ritonavir or cobicistat.
The two anti-HIV drugs most likely to be involved in harmful interactions with recreational drugs are ritonavir ( Norvir ) and cobicistat ( Tybost ) .
Increased exposure to cannabis is reported when taken with etravirine ( Intelence) and efavirenz (Sustiva , also in Atripla).
The potential for interactions with several other substances is considered to be low. This includes alcohol, poppers, heroin and other opioids.
A risky combination of drugs, when drug A interferes with the functioning of drug B. Blood levels of the drug may be lowered or raised, potentially interfering with effectiveness or making side-effects worse. Also known as a drug-drug interaction.
Nonetheless, recreational drugs are rarely sold in a pure form, so it is hard to know what they contain. They may have been ‘cut’ with other substances and may contain larger or smaller quantities of the active ingredient than expected. Predicting how recreational drugs will interact with HIV medications is not straightforward.
There is a limited number of studies on interactions between GHB and anti-HIV drugs. These studies reported higher exposure to GHB, which may lead to higher levels of GHB. Due to the close relation between GHB and GBL, the same effects may occur with GBL.
Both of these are boosting agents, taken to boost levels of other antiretrovirals. Adding a small dose of one of these agents makes the liver break down the primary drug more slowly, so that it stays in the body for longer or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.
Taking cocaine with some NNRTIs may lead to higher levels of cocaine. This applies to efavirenz (Sustiva , also in Atripla), nevirapine (Viramune) and etravirine (Intelence) . A different kind of interaction may occur with rilpivirine (Edurant).
Ritonavir and cobicistat.
Amyl, butyl or isobutyl nitrite, are recreational drugs sniffed during sex to both intensify the experience and relax anal sphincter muscles.
The first four weeks of taking a new HIV treatment combination, when your body gets used to the new drugs, are likely to be the riskiest time for interactions.
If your HIV treatment includes a protease inhibitor, you are probably taking either ritonavir ( Norvir ) or cobicistat ( Tybost ). Protease inhibitors include darunavir (Prezista), atazanavir (Reyataz) and lopinavir (Kaletra) .
Recreational drugs have a wide range of impacts on physical and mental health, both in the short and long term. You can find more detailed information on their effects and legal status on the FRANK website (www.talktofrank.com).
The boosting mechanism can also affect recreational drugs. The liver processes the recreational drug more slowly, resulting in the recreational drug staying in the body for longer or in greater concentrations. Sometimes this can cause serious side effects or an overdose.
When two drugs are taken at the same time, their interaction can affect the drugs’ effectiveness and side effects.
A dangerous interaction is possible between ritonavir or cobicistat and several recreational drugs:
Drugs without significant interactions.
Heavy use of ketamine can lead to damage to the liver and bile ducts. Overdoses of erectile dysfunction drugs are dangerous for the heart. An overdose of benzodiazepines could result in the person passing out.
“The first four weeks of taking a new HIV treatment combination, when your body gets used to the new drugs, are likely to be the riskiest time for interactions.”
Cobicistat is also taken with the integrase inhibitor elvitegravir (Vitekta). It is included in the combination pills Stribild (with elvitegravir, tenofovir disoproxil and emtricitabine), Genvoya (with elvitegravir, tenofovir alafenamide and emtricitabine), Rezolsta (with darunavir), Evotaz (with atazanavir) and Symtuza (with darunavir, cobicistat, tenofovir alafenamide and emtricitabine).
Ritonavir is also in a combination pill used to treat hepatitis C called Viekirax (with ombitasvir and pariteprevir).
Drug use can interfere with sleeping patterns and routines, making missed doses of your HIV treatment more likely.
Experts judge the potential for interactions with the first five drugs listed to be ‘moderate’ and with the last four to be ‘high’. There have been a handful of documented cases of deaths and serious side effects in people taking ritonavir alongside crystal meth, MDMA or ketamine.
The University of Liverpool’s HIV Drug Interactions website (www.hiv-druginteractions.org) publishes a table summarising the likely interactions.
If you are not sure which medications you are taking, staff at your HIV clinic can tell you.
Cannabis may hold many potential therapeutic benefits for people living with HIV due to its promising anti-inflammatory and antifibrotic effects. Before adequately powered interventional studies can be designed to study cannabis as a therapy for specific conditions associated with chronic inflammation and fibrosis, a key first step will be to demonstrate that cannabinoid use in a clinical trial is feasible and that they have a favourable safety and tolerability profile. As such, we propose a proof-of-concept pilot study to examine the feasibility, safety and tolerability of cannabinoid oils consumed orally in people living with HIV on effective ART. As a secondary objective, we will examine the effect of cannabinoid oils on immune profiles, including levels inflammatory markers associated with HIV disease progression and frequencies of activated and senescent CD4 and CD8 T cells. Frequencies of regulatory T cells and various subsets of Th17 will also be assessed. Finally, an exploratory objective will be to study the effect of cannabinoid oils on markers of HIV persistence and the composition of the gastrointestinal microbiome.
Within 1 hour of being drawn, blood from the CVIS will be transferred to the laboratory at the Research Institute of the McGill University Health Centre (RI-MUHC) (in the adjacent, connected building), and the plasma will be separated from PBMCs by Ficoll density centrifugation by an experienced laboratory personnel. PBMCs and plasma will be stored in liquid nitrogen tanks at the RI-MUHC laboratory until time for analysis. Patients will be contacted the day before their clinic visit to remind them when a stool specimen is due. They will be instructed to record the time of the provision of the sample on the paper bag containing the sterile container and store it in a refrigerator (−4°C) until brought to the clinic. Once at the CVIS, the stool specimen will be placed in a large fridge designated specifically for the storage of stool specimens.
†If participant tests positive for hepatitis B and C, he or she will no longer be eligible for the study. If participant tests positive for syphilis, he or she will be treated for syphilis according to clinical care guidelines and will still be eligible to participate in the study. The need for syphilis treatment and follow-up testing (usually in 6 and 12 months) will be discussed between the sponsor and the investigator at the CVIS. It will be up to the investigator to ensure proper follow-up and management of the syphilis, as this is part of standard of care.
Since the advent of ART, people living with HIV now have a longevity that approaches that of their HIV-uninfected counterparts but have a higher burden of non-communicable comorbidities including cardiovascular, pulmonary, renal and hepatic diseases. 1 2 Heightened inflammation in people living with HIV despite ART is believed to be the driving before behind the increased rates of non-infectious comorbidities. Similarly, chronic immune activation fosters HIV persistence. 10–15 As cannabinoids possesses both anti-inflammatory and antifibrotic properties, 19 cannabinoids may represent a feasible method to reduce immune activation and enhance immune profile. This, in turn, may hasten the progression of non-opportunistic complications associated with HIV. Although some studies have examined whether there are beneficial effects on inflammation resulting from treatment with integrase inhibitors compared with PIs, between PIs and non-nucleoside reverse transcriptase inihibitors, between specific nucleoside reverse transcriptase inhibitors, or with maraviroc in ART-naïve patients, to date insufficient to conclude that any class of antiretrovirals is superior to other classes of antiretrovirals with regards to effects on inflammation. 75 Furthermore, cannabis may induce cytochrome P450 (CYP) 1A2 via activation of the aromatic hydrocarbon receptor. 76 CYP3A4 inducers and inhibitors alter the pharmacokinetics of Δ9-THC and CBD when administered as Δ9-THC/CBD oromucosal spray. To date only one study has ever examined the effects of cannabinoids on the pharmacokinetics of antiretrovirals. Kosel et al studied the pharmacokinetics of smoked marijuana and dronabinol in people living with HIV receiving either indinavir and nelfinavir (two PIs no longer used due to their toxicity and adverse effect profiles). 77 Individuals on stable regimens of indinavir 800 mg every 8 hours or nelfinavir 750 mg three times daily were randomised to one of three treatment arms: (1) 3.95% THC marijuana cigarettes; (2) dronabinol 2.5 mg capsules; or (3) placebo capsules given three times daily. Although there were statistically significant decreases in maximum concentration (Cmax) of indinavir in the smoked marijuana arm, the size of the changes in the pharmacokinetic parameters of both indivnavir and nelfinavir was sufficiently small not to impose any short-term clinical consequence. 77 Furthermore, the investigators concluded that use of marijuana or dronabinol is unlikely to impact ART. 77 For these reasons and based on clinical experience at our clinic, we have not precluded individuals on any particular antiretroviral regimens from participating in this study.
The study medications are TN-TC11LM and TN-TC19LM capsules that contain THC:CBD in a ratio of 1:1 (2.5 mg/2.5 mg) and 1:9 (5 mg/45 mg), respectively. These study drugs are being provided by Tilray, and the active pharmaceutical ingredients are extracted from the cannabis plant and purified according to pharmaceutical standards (>98%). Participants will be advised to gradually increase the number of capsules they take based on the suggested titration scheme presented in tables 1 and 2 , until a daily maximum is reached. These maximum amounts are composed of 10 capsules of TN-TC11LM (25 mg THC/25 mg CBD total per day) or 3 capsules of TN-TC19LM (15 mg THC: 135 mg CBD for TN-CT19L) per day. These doses were selected as in a clinical trial for neuropathic pain; doses equivalent to 2.5 mg of THC were well tolerated. 34 More recently, among patients (ages 2–55 years) with the Lennox-Gastaut syndrome, CBD at a dose of 10 or 20 mg per kg per day resulted in greater reductions in the frequency of drop seizures than placebo and was well tolerated overall other than for an increase liver aminotransferase concentrations. 60 Due to person-to-person variability in the ability to metabolise and tolerate cannabinoids, 61 we have opted for patients to titrate their dose of medication to a range where they are comfortable as the titration method of dosing has proven successful in other clinical trials involving cannabinoids. 34.
The study medications and doses were chosen after a lengthy review of the existing literature and discussion with experts in the field of pain management. A high degree of interindividual variability in metabolism following administration of cannabinoids is observed due to polymorphisms in cytochrome isoenzymes. 61 Given that the therapeutic doses of cannabinoids are highly variable between individuals, a dose titration schedules are usually recommended. When used to treat specific conditions, persons may be told to increase the dose until they achieve adequate symptom relief without adverse effects. This method was observed to work well when used in the first cohort study on the long-term safety of medicinal cannabis for non-cancer chronic pain in seven Canadian clinics. 34.
§Review individual POMS questionnaires completed at visits 2 and 6 with each participant.
The primary objective is to evaluate the safety and tolerability of TN-TC11LM and TN-TC19LM oral capsules in PLWHIV on effective ART. The primary between group comparison is the percentage of participants without any signs of significant toxicity; percentage of participants who are able to complete the study and scores on the WHOQOLHIV-BREF Scale, EQ-D5 and POMS questionnaires from week 0 to week 12 are secondary outcomes that will also be compared between groups. The secondary objective is to determine the effect of TN-TC11LM and TN-TC19LM oral capsules on frequency of activated T-cells and markers of inflammation association with HIV disease progression. Exploratory objectives are to determine the effect of TN-TC11LM and TN-TC19LM oral capsules on: (1) the size of the peripheral HIV reservoir and (2) the composition of the gastrointestinal bacterial and fungal microbiome.
At the screening visit, clinical information will be collected from each participant including age, ethnicity, sexual orientation, list of current medications, dosage, date of treatment initiation, any antimicrobials taken in the previous 6 months, psychiatric disorders, duration of HIV infection, current ART regimen and duration of ART regimen months, ART history, CD4+ T cells count within the past 3 months, nadir CD4+ T cells count, CD4/CD8 ratio, duration of plasma viral load suppression and any pre-existing medical conditions, signs or symptoms. Information will also be collected on whether the individual consumed cannabis in the past, the form(s) in which it was consumed, frequency of use and reasons for use.
Gastrointestinal microbiome composition.
The capsules used will contain both Δ9-tetrahydrocannabinol and cannabidiol, thus improving tolerability.
For the primary endpoint, the proportions of participants without any signs of significant toxicity (grades 0–2 scores on the WHO toxicity scale), proportions of participants who complete the study and scores on the WHOQOLHIV-BREF, EQ-5D and POMS questionnaires will be examined using descriptive statistics. We will also compare these proportions for group 1 versus group 2 using a Fisher’s exact test. For quality of life and mood measures, we will use analysis of covariance with 12-week score as outcome and baseline score as covariate and treatment as independent variable. With regards to the POMS questionnaire, we will consider only overall scores (and not subscores) due to the small sample size that would make comparisons of the subscale inappropriate.
A stool sample without preservative will be collected from each participant at the beginning of the study prior to consuming the capsules and during the final week (week 12) of capsule consumption. Specimens will be stored at −80°C until analysed in batch, as previously described. 68 Bacterial DNA will be extracted with PCR amplified targeting of the 16S rRNA gene using universal primers that flank the V3–V4 region of the 16S gene modified with the addition of TruSeq Illumina adapters, also as previously outlined. 69 Internal transcribed spacer for fungal DNA extraction will be used for fungi. PCR amplification, PCR amplicon quantification and sequencing will be performed as previously described. 68 69.
In addition, we decided to make our objective examining the ability of TN-TC11LM and TN-TC91LM capsules to reduce the HIV reservoir, through the reduction of systemic inflammation, an exploratory objective. It is unclear if 3 months of treatment will be long enough to produce any meaningful reduction in the size of the HIV reservoir. Furthermore, it is unclear what reduction in reservoir size is required to have a meaningful effect on clinical outcomes. As mentioned earlier, we will consider a 50% decrease in the number of HIV-infected cells at baseline versus week 12 to be a significant reduction in the reservoir based on a study by Hill et al . 71 To our knowledge, there is no other randomised clinical trial examining the effect of cannabinoids on inflammation and HIV reservoir size in people living with HIV.
After eligibility is confirmed and written informed consent obtained, participants will be randomised to either TN-TC11LM (group 1) or TN-TC19LM (group 2) capsules, which contain THC:CBD in a ratio of 1:1 and 1:9, respectively. Prior to study commencement, a statistician unassociated with the study will develop a randomisation scheme using SAS and input into a password-protected web-based randomisation system. Variable block sizes of 2 and 4 will be used. Participants will be assigned to either group 1 versus group 2 based on the predesignated allocation code. As this is an unblinded study, participants and study staff will be aware of the group to which the participant has been randomised. A computerised audit trail will track date and time of allocation, patient study identification number and treatment allocation. The randomisation group will be recorded in the study log, which will be accessible to the sponsor/medical manager and study coordinator.
*If urine test is positive, perform serum pregnancy test.
Group 2: high CBD dose TN-TC19LM (5 mg THC/45 mg CBD capsules). This group will be advised to start by taking one capsule once daily for 1 week (5 mg THC/45 mg CBD) and increase the number of capsules as tolerated to a maximum of 10 capsules daily by week 5 (25 mg THC/225 mg CBD total). Participants will record the times and dates of all capsules consumed in a log book.
Scheduled visits will occur to monitor safety and tolerability, as per the visit schedule depicted in table 3 . Visits will include physical exam with vital signs, weight, occurrence of adverse events (AEs; and concomitant medications) and the presence of common symptoms associated with cannabinoids including dizziness, nausea, headaches, appetite or mood changes. At visits, blood for some or all of the following will be collected: CD4+ T cells count, CD8+ T cells, CD4/CD8 ratio, plasma viral load, complete blood count, AST, ALT, ALP, total bilirubin, urea, creatinine and blood glucose, T cell activation and inflammatory markers and testing for syphilis if the participant tested positive during the 4 weeks prior to beginning consuming the study capsules. A stool sample for analysis of the bacterial and fungal microbiome assessment will also be collected prior to beginning the study capsules. Participants will be enrolled in the study for up to 15 weeks but will consume capsules for a period of 12 weeks. Participants will undergo screening tests and eligibility assessment within 4 weeks prior to initiating study capsules. Participants will then undergo assessments after the first week of capsule consumption and every 2 weeks thereafter. A second stool sample for bacterial and fungal microbiome analysis will be collected during the final week of capsule consumption. The final visit will occur 2 weeks after study drug cessation.
Study staff at the CVIS will conduct chart reviews of prospective people living with HIV ahead of their clinic visits to determine which persons have had suppressed viral load for at least 3 years on ART. The patient chart will be flagged, and if the treating HIV physician believes the person to be suitable for the study, the physician or study staff will approach potential trial participants at their clinic visit. The trial staff will inform the patients about the trial and invite him or her for eligibility screening and possible trial enrolment. Participant eligibility will be documented and written informed consent obtained for eligible patients by the study coordinator. The study coordinator will systematically document all individuals who have been approached for the study in addition to reasons for acceptance and refusal to participate in the study. Individuals who wish to discuss their participation in the study with their treating physician and/or family and friends will have the opportunity to do and may enrol their next scheduled clinic visit. Following enrolment, participants will be followed during the study by the principal investigator and study coordinator at the CVIS.