HIV antiretrovirals as drugs of abuse
From around 2008, an unusual new street drug has been appearing in South Africa, containing HIV antiretroviral (ARV) efavirenz. Reports have described robberies of both clinics and HIV patients, often by those high on the drug intending to sell them on to the ‘cooks’.
Vice magazine reporter Hamilton Morris has been investigating various drugs for the publication, and in this installment covered whoonga, or nyaope as it’s also known in the country. I don’t have a lot of time for videos concerning psychedelic states, and at times his breathless reverence for drugs is grating. In fairness to Morris however, he is one of a minority of scientifically literate reporters in media today, and in this case the topic is an obscure and interesting one which would be unlikely to receive such an in-depth analysis in other mainstream media outlets.
Morris visited pharmacologist John Schetz at the University of North Texas, and analysed the drug under ‘simulated smoking’ (essentially condensing the combustion products for characterisation, though this brief section of the film went easy on the detail).
Eagle-eyed chemists might have noticed that the diagram above shows a bit of a non-event (the molecules on either side of the top arrow are identical). Like I say, the chemistry side was lacking. This flashed up for a few seconds, and a brief mention that it’s not known how the biological effects of this molecule may differ when smoked from the regular, ingested ARV.
Also covered are behavioural experiments in mice, which seemed quite rudimentary, though I’m not so strong on pharmacology so can’t exactly suggest any better trials. Mice conditioned to react differently to LSD (pressing one lever rather than the other which would be used for saline) were given efavirenz and acted similarly to those administered LSD — taken to mean that efavirenz was a psychedelic. The presence of a ‘head twitch response' in such mice provided further evidence for the hypothesis.
In Neuropsychopharmacology last year, a group led by Schetz published the work, affirming that The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties. They cited anecdotal reports relating to both “HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects”.
Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABAA and 5-HT2A receptors. In rodents, interaction with the 5-HT2A receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz’s behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT2A receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT2A-knockout, mice. Despite having GABAA-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz’s prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT2A receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication.
Antiretrovirals I’ve read about all have quite frightening side-effects (myo- and neuropathy), and one that messes with the patient’s mind must only compound a patient’s problems. The authors note a study some 15 years ago which described HIV patients recovering from drug abuse having experienced ‘flashbacks’ on efavirenz, and side-effects ranging from vivid dreaming to psychosis as part of a HIV treatment regimen.
What’s worse, there have been reports that the activity is leading to entirely preventable ‘pretreatment immunity’ — with 7 to 8% of HIV-positive individuals presenting for ART with resistance.
Diversion of antiretroviral drugs, in addition to affecting adherence, reduces drug supply and limits access to treatment. Criminal behaviour related to diversion of antiretroviral drugs endangers patients and health-care providers and deters people from getting tested or seeking treatment. Finally, the recreational use of antiretroviral drugs further stigmatises HIV-infected patients and their communities and could undermine donor willingness to fund antiretroviral drug treatment.
In addition to these effects, when untreated HIV-infected people are exposed to antiretroviral drugs recreationally, they are at risk for acquiring resistance. Mutations that confer resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as efavirenz are among the most common in people with pretreatment resistance. Antiretroviral drugs including efavirenz have been detected in serum samples from some HIV-infected individuals with pretreatment resistance who deny a history of treatment.
The only 2 papers regarding the drug by its street name come from a group led by David Grelotti, epidemiologist and MD at the Harvard School of Public Health, a brief report published December 2013 based on interviews, and a longer paper this year:
Efavirenz is a NNRTI used in first-line treatment of HIV in South Africa. In the context of high HIV prevalence (including estimates that 24.7 % of 15–49 year-olds in KwaZulu-Natal are infected with HIV), recreational use of ARVs may expose untreated HIV-infected individuals to ARVs and promote ARV resistance.
…respondents reported that whoonga is prepared with household cleaning products and rat poison and that whoonga may be mixed with dagga (marijuana).
Any resistance to efavirenz would likely also confer resistance to other NNRTIs because of cross-class resistance risks. Because NNRTIs are the mainstay of HIV treatment regimens in South Africa, any behavior linked to increased NNRTI resistance may compromise treatment response and must be taken quite seriously.
Watch Morris’s film ‘Getting High on HIV Medication’ here, and read his blog here, which covers a little more chemistry than his films