Research into use of medicinal cannabis in HIV management
Two talks at the workshop provided different perspectives on use of cannabis and derivatives in the US as medicines.
The first, by Thomas Marcotte from the University of California, San Diego, provided a historical review of the legal changes in the US, including a note that this was a legal medicine for many years.
As of January 2018 there are 30 states with some form of legalised medical marijuana law and 9 states including DC, Guam and Puerto Rico having legalised recreational use. Only 4 states have no form of marijuana legislation. Approximately 60% of the US population live in states with some form of legalised marijuana. showing the importance of the need for research into the effects of cannabis.
The interest in research was taken up again in the 1990s (after the Regan “war on drugs”) and by 2010 US public opinion reached a cross over with a majority supporting legalisation.
The history of legal changes included the Compassionate Use Act in 1996 in California and the Medical Marijuana Research Act in 1999. The Center for Medicinal Cannabis Research (CMCR) was established in 2000 to support high quality research, with funding extended in 2016 by the Adult Use of Marijuana Act.
The CMCR team is notable for including the oncologist Donald Abrams, one of the first HIV specialist doctors, who helped establish the Ward 86 clinic at San Francisco General Hospital in 1983 and who saw the benefits from marijuana for pain relief and as an appetite stimulant to counteract HIV wasting.
However, regulation is complicated as there are more than 100 cannabinoids (including THC as the psychoactive compound) and CBD (a non-intoxicating cannabinoid). Terpenoids modulate how cannabinoids interact with receptor, may act on serotonin, dopamine, etc and are responsible for the distinctive aroma. Flavonoids determine the colour of the plants and are being researched for potential anti-oxidant and anti-inflammatory properties.
A national academies report in 2017 comprehensively reviewed the evidence of medicinal benefits of cannabis although not all claims have good quality evidence. 
- Substantial/conclusive evidence for chronic pain, spasticity of multiple sclerosis and control of nausea.
- Moderate evidence for improving sleep in those with chronic medical conditions (ie chronic pain, fibromyalgia, etc)
- Limited evidence for certain anxiety disorders and PTSD, and promoting appetite and weight gain.
- No or insufficient evidence for treatment of cancers, irritable bowel syndrome, epilepsy, movement disorders due to Huntington Disease or Parkinson Disease and schizophrenia.
Details of these studies were included in the talk, including the recent studies showing a more than 50% reduction in frequency of seizures compared to placebo. 
But the therapeutic window for an effective dose can also important. Some studies reported no effect at a very low dose, benefits with a moderate dose but worsened symptoms with higher doses, for example both for pain relief and for neurocognitive impairment. [4, 5]
Also, in an HIV study, the factors positively associated with “superageing” included higher lifetime cannabis use disorder. Superageing is a recently invented term for people older than 50 who have been protected from the normal expected age-related neurological changes, retaining neurocognitive scores of someone younger than 25, after adjusting for demographics (se, race, education etc). A proposed mechanism for the neuroprotective effect is though activation of the cannabinoid receptors (CB1 and CB2) in the central nervous system. 
This study reported 17% of 734 HIV positive compared to 35% of 123 HIV negative people aged 50 to 64 were superagers. These results can be taken positively – ie that ageing well with HIV is possible, even though the rate was half that of an HIV negative control group.
Other research challenges were also discussed, included the harmful effect of smoking with tobacco. Practical difficulties include the US Drug Enforcement Agency (DEA) treating different formulations of cannabis differently: the plant has the highest restrictions (schedule I, similar to heroin) based on potential harm, whereas some synthetic formulations (nabilone and dronabinol (Syndros) are schedule II and dronabinal (Marinol) is schedule III. However the plant-based Epidox to treat seizures is schedule V (lowest abuse risk) and access to regulated supplies for research, although more than 20 ongoing studies listed on clinicaltrials.gov.
This limits the ability to research any of the many formulations of marijuana that are already widely available including vape, ointments, lotions, oils, drinks, foods and capsules etc. Even comparing smoking compared to ingesting marijuana produces very different pharmacokinetic dynamics for the active ingredient of THC.
Even though there are potential anti-inflammatory and neuroprotective qualities from cannabis use that might could provide cognitive benefit to HIV positive people, larger scale longer-term clinical trials assessing benefits and possible toxicities are still needed,
The second talk was given by Linda Chang from the University of Hawaii looking at the cannabis use from a basic science persepctivee. The review covered at least a dozen studies, including in vitro, animal and human studies, including in HIV positive people, with a focus on evidence for both potential benefits and harms. 
As background, marijuana is apparently the most used drug worldwide including 43 million people in US in last year and 8 million people reporting daily use. Doubling of use over the large decade makes this one of the fasted growing US industries involving multi-billion dollars. Wider access to legal marijuana in the US was reported as being used for medical reasons over the previous year by 26% of HIV positive people compared to 17% of the general population.  These data show the importance of getting accurate results from well-designed studies on potential risks and benefits.
Potential neurprotective effects of cannabinoids linked to endogenous ligands for CB1 and CB1 have the potential to reduce inflammation. This has been supported by research in cell cultures and animal studies, where endocannabinoids directly or indirectly prevented HIV-mediated neuronal cell damage and showed anti-inflammatory effects in rodents and slowed SIV progression and neuroinflammation in macaques. 
However, a recent review of 45 studies looking at potential harm (memory deficits and impairment etc) reported varied results, but included the concern that both HIV and marijuana might independently negatively affect memory, especially with medium to high exposures. 
Research into long-term effects is complicated by duration of both marijuana use, especially if started at a young age and HIV history which might include a period before ART. However, some studies, including MRI and neuroimaging, have reported that HIV positive status isn’t associated with higher risks compared to being HIV negative. 
Another study into chronic use, requiring weekly marijuana use for at least two years, reported that independent of marijuana use, HIV positive participants had slightly higher axonal damage and lesser myelination with radial diffusion, but that the link with inflammation needed further research and mixed effects could be seen. 
- Marcotte T. The Promise and Challenge of Cannabis and Cannabinoids as Medicine. 10th HIV and Ageing Workshop, 9-10 September 2019, New York.
- National Academies Report. Evidence for Therapeutic Benefits of Cannabis (2017).
- Devinsky et al. Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome_. N Engl J Med 2017; 376:2011-2020 DOI: 10.1056/NEJMoa1611618.
- Wallace M et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology. 2007 Nov;107(5):785-96.
- Heaton et al. Cannabis Use and Impaired Cognition in PWH. Rererence tbc,
- Saloner R et al. Neurocognitive superaging in older adults living with HIV: demographic, neuromedical and everyday functioning correlates. J Int Neuropsychol Soc. 2019 May;25(5):507-519. doi: 10.1017/S1355617719000018. Epub 2019 Mar 20.
- Chang LA. Use of cannabis: basic scientist’s perspective. Plenary talk. 10th HIV and Ageing Workshp, 10-11 September 2019, New York.
- Mimiaga MJ et al. Substance Use Among HIV-Infected Patients Engaged in Primary Care in the United States: Findings From the Centers for AIDS Research Network of Integrated Clinical Systems Cohort. American Journal of Public Health (AJPH) 103, 1457-1467, (August 2013), doi.org/10.2105/AJPH.2012.301162.
- Simon L et al. Δ9-tetrahydrocannabinol (Δ9-THC) promotes neuroimmune-modulatory microRNA profile in striatum of simian immunodeficiency virus (SIV)-infected macaques. Journal of Neuroimmune Pharmacology 11(1) DOI: 10.1007/s11481-015-9645-6 2015. (November 2015)
- Skalski LM et al. The impact of marijuana use on memory in HIV-infected patients: a comprehensive review of HIV and marijuana literatures. Curr Drug Abuse Rev, 2016;9(2):126-141. doi: 10.2174/1874473709666160502124503.
- Thames AD et al. Marijuana effects and changes in brain structure and cognitive function among HIV+ and HIV– adults. Drug Alcohol Depend. 2017 Jan 1; 170: 120–127. doi: 10.1016/j.drugalcdep.2016.11.007.
- Chang L et al. Combined and independent effects of chronic marijuana use and HIV on brain metabolites. J Neuroimmune Pharmacol. 2006 Mar; 1(1): 65–76.