Interactions with recreational drugs

Anyone who has studied information sheets regarding antiretroviral (ARV) drugs knows that these drugs can have significant interactions with many other prescribed drugs. It is much harder to find reliable advice about interactions between ARVs and recreational drugs.

The issue came to the fore in autumn 1996 when an HIV-positive man in London died after taking ecstasy. An autopsy found that he had unusually high levels of ecstasy in his blood, which may be partially explained by the fact that he was also taking full-dose ritonavir (Norvir). Ecstasy is not the only illegal drug that might interact dangerously with prescription drugs and ritonavir is not the only anti-HIV drug that may interact with illegal drugs.

Drug companies generate much of their data on drug interactions to satisfy regulatory authorities for commercial product licensing. Results from clinical trials concentrate on interactions with other prescribed drugs in the regimen of persons using the investigational drug. These well-studied patterns of interaction are not the norm. More often, drug company researchers decide which interactions are most likely, based on the way their drug is metabolised.

Even for some prescribed drugs that are regularly used by a substantial number of people with HIV, such as the heroin-substitute methadone, surprisingly little reliable research on interactions with anti-HIV drugs has been conducted. Most of the guidelines on possible interactions are 'informed guesswork' based on the way the drugs in question are metabolised by liver enzymes.

It is generally even harder to find any published guidance on possible antiretroviral (ARV) interactions with illegal/recreational drugs. That information also comes through 'informed guesswork' and anecdotal information.

Several additional problems complicate information gathering. Researchers are often unsure how some illegal drugs are metabolised in the body. Available information may relate to the pure form of the drug, such as the chemical 3,4-methylenedioxymethamphetamine (MDMA; ecstasy), but ‘street' drugs are rarely pure. For example, an ecstasy tablet may well contain methylenedioxyethamphetamine (MDE) or methylenedioxyamphetamine (MDA), rather than MDMA. The same applies to amphetamines and lysergic acid diethylamide (LSD). Additionally, doses in street drugs are not controlled. Reaction to ecstasy varies depending on whether a tablet contains pure MDMA or one that contains just a small amount.

Drug companies and governments are not anxious to be seen as condoning illegal drug use and that has hampered research on this subject. Many warnings and recommendations concerning interactions with illegal drugs are based on isolated case reports, rather than prospective or controlled studies. Anecdotal information is not usually suitable for extrapolation to the wider population.

Several of these issues were relevant to the ritonavir/ecstasy case. No formal interaction studies had taken place, although knowledge of the metabolism of the two drugs made it likely that ritonavir would increase the ecstasy level two- to threefold. In the London case, it was reported that the patient had taken no more than 2.5 ecstasy tablets, yet at postmortem, he had blood levels of MDMA equivalent to taking 22 tablets.

Alternatively, if due to genetic factors this person metabolised MDMA poorly, that would have a bearing on the case. Abbott Laboratories has subsequently suggested that abnormally high peak levels of ritonavir during the early weeks of therapy may cause elevations in ecstasy levels if it is taken at this time. London’s Chelsea and Westminster Hospital has reported two admissions due to adverse reactions to ecstasy among people taking protease inhibitors.

Below are specific examples of some, but not all types of interactions. Pharmacists, particularly those with an interest in HIV care, are likely to be the best source of information regarding drug interactions between approved and illicit drugs.  

Tobacco and marijuana may reduce levels of atazanavir (Reyataz) in the body, whilst tobacco and alcohol may lower efavirenz (Sustiva or Stocrin) levels in individuals who carry specific genetic variations. A US study found that atazanavir trough levels (the lowest level between doses) were significantly reduced in people who used tobacco or marijuana, with trough levels below the effective therapeutic range in many users.

In the same study, efavirenz trough concentrations were significantly lower amongst tobacco and alcohol users who had a particular genetic variation in the gene encoding CYP2B6, a liver enzyme that plays a role in efavirenz metabolism.¹

Levels of MDMA, the key ingredient in ecstasy tablets, are likely to increase two- to threefold when taken alongside ritonavir, although the elevation is dependent on the amount of MDMA in the ecstasy tablet.

Some doctors have suggested that anyone taking a ritonavir-boosted protease inhibitor should avoid taking ecstasy during the first four weeks of starting the protease inhibitor, and thereafter resume taking ecstasy at a dose of one-quarter or one-half of a pill, increasing the amount on subsequent occasions if there is no severe reaction . The risk of overdose is probably highest during the early weeks of taking ritonavir, due to abnormal peak levels of ritonavir during this period.

Drugs which induce the CYP3A4 enzyme - nevirapine, efavirenz and tipranavir - may reduce MDMA levels.

Levels of the recreational drug gamma-hydroxybutyrate (GHB, liquid ecstasy) may be increased to life-threatening levels if it is taken alongside a protease inhibitor, according to a single case report from Seattle. A 29-year-old man receiving treatment with ritonavir and saquinavir became unconscious after taking half a teaspoonful of GHB. He had also taken a half teaspoonful of GHB and two ecstasy tablets in the preceding 24 hours. The man had not experienced adverse reactions to GHB or ecstasy prior to protease inhibitor treatment. Reporting doctors suggested that ritonavir and saquinavir slowed down metabolism of both drugs and caused the near-fatal reaction.

Usual symptoms of GHB overdose include vomiting, breathing problems, seizures, stupor, and coma. The dose normally associated with severe distress is greater than 50mg/kg of body weight. In this case, the dose was estimated to be less than 10mg/kg body weight.²

In 2000, Australian doctors reported what they believed to be a fatal interaction between ritonavir and methamphetamine, commonly known as 'crystal' or 'crystal meth'. A 49-year-old Melbourne man taking ritonavir, soft gel saquinavir, and d4T (stavudine, Zerit) was found dead the morning after injecting methamphetamine and sniffing amyl nitrite (poppers). A toxicology analysis showed that the dead man had methamphetamine levels of 0.5mg/l in his blood, a level seen in many overdose cases.

Methamphetamine is metabolised by the liver enzyme CYP2D6, which is inhibited by ritonavir. The protease inhibitor could have slowed the metabolism of methamphetamine, thus causing the overdose. The authors speculate that amyl nitrite use could have had a contributing role because amyl nitrite is metabolised to nitric oxide, another cytochrome P450 inhibitor.³

Interactions between AZT and methadone have been studied. Methadone increases by roughly twofold the levels of AZT, so people taking both drugs need only take half the standard dose of AZT to get the same anti-HIV effect.

The NNRTIs efavirenz and nevirapine induce (speed up) methadone metabolism and this can result in substantially decreased levels of methadone . A study among patients in Dublin reported that nevirapine reduced methadone levels by 46% within two to three weeks of commencing the NNRTI. Patients began to report opiate withdrawal symptoms eight to ten days after starting nevirapine, but it is not recommended that methadone dosage be increased at the same time as starting nevirapine. Instead, it may be better to monitor withdrawal symptoms and increase the methadone dose if withdrawal does begin to occur.⁴ 

Within 24 hours of taking efavirenz, systemic exposure to methadone is reduced by about 60%. Dosage adjustment should not take place immediately because the neurological side-effects of efavirenz may be mistaken for opiate withdrawal. Monitoring methadone levels closely and increasing methadone dosing in 10mg increments as needed is recommended for patients initiating an NNRTI-based regimen.

Nelfinavir (Viracept) and methadone are both metabolised via cytochrome P450 enzymes and may have pharmacokinetic interactions that require dose adjustments of methadone. Theoretically, this interaction should result in reduced methadone levels, but the majority of participants in two studies did not experience withdrawal or the need to increase the methadone maintenance dose.⁵

Ritonavir reduces blood levels of both methadone and heroin; ritonavir-boosted protease inhibitors have shown widely varying effects on methadone levels, so the best advice is to monitor carefully for methadone withdrawal and increase the dose accordingly.

There have been no published case reports of drug interactions between ketamine and antiretroviral therapy; however, there is a theoretical basis for suspecting an interaction. Ketamine is primarily metabolised by a number of CYP450 isoenzymes. PIs and NNRTIs (particularly ritonavir, nelfinavir, and efavirenz) could  theoretically affect ketamine metabolism, causing increased blood levels of this drug. Should that occur, consequences might include symptoms such as respiratory depression, loss of consciousness, and hallucinations. The practical advice for those on antiretroviral therapy wishing to use ketamine is to do so cautiously, especially when taking with CYP450 inhibitors, such as ritonavir .

Taking ritonavir with sildenafil (Viagra) results in a significant increase in sildenafil blood levels. In theory, the same could be anticipated when sildenafil is taken with all other PIs. The consequence of this interaction is an increased risk of sildenafil-related side-effects such as headache, dizziness, indigestion, nasal congestion, and altered vision. Significant drug interactions are not thought to occur when sildenafil is taken with NNRTIs or NRTIs.

CYP3A4 seems to be one of the major isoenzymes for PCP metabolism. It would be expected that concurrent use of PCP with PIs, and possibly efavirenz also, might result in elevated PCP concentrations and resultant toxicity. Patients using PCP who are also receiving treatment with antiretrovirals should do so with caution and be advised of the theoretical increased risk of PCP-related adverse effects.

The safest solution is not to mix protease inhibitors and/or NNRTIs with recreational drugs. Talking to a pharmacist beforehand would be the next best step for those who decide to combine ARVs with recreational drugs. Forewarned is somewhat more helpful than hindsight in this case. 

Often, definitive answers are not to be had to questions concerning recreational drugs and ARVs, as the research has simply not been done. In the absence of clinical trials, an educated insight is still an advantage over learning through personal experience. For example, anecdotal accounts indicate that a significant number of people taking ritonavir are also using ecstasy or other drugs without experiencing any problems. Nevertheless, the case of Philip Kay, the HIV-positive man in London who died after taking ecstasy, highlights the possibility that some unlucky individuals may suffer potentially fatal interactions.

Some doctors recommend leaving as many hours as possible between a dose of a protease inhibitor and a drug such as ecstasy. There is no hard evidence that this will reduce the risk of an interaction, but it is unlikely to increase the risk either. Skipping the protease inhibitor dose is never a good idea, as it may lead to drug resistance.

Recreational drug use may have other consequences aside from interactions. They can make it harder to remember to take ARVs on schedule (and according to any dietary requirement) and also lead to risk-taking behaviours.