Donald Abrams is a San Francisco oncologist who has instigated significant cannabis research, including early studies on the safety of combining cannabis with HIV therapy or opioids. He laid out the potential of cannabis in cancer care in a recent piece titled “Should Oncologists recommend cannabis?” In a word, yes. Amidst Abrams’s summary of the science, he makes a number of often overlooked observations. Cannabis for cancer care is not new – the oldest example in which it may have been used is the Siberian Ice Maiden, the 2700-year-old remains of a Siberian woman who had breast cancer and cannabis on her corpse. Moving to the modern day, pure THC has been approved since 1986 for nausea related to chemotherapy, and recent research supports the use of cannabis rather than isolate THC for nausea. Interestingly, however, early studies did not show that THC helped patients gain weight. (And, in fact, recent research indicates that regular cannabis use can lead to lower BMI.) Through Abrams’s interaction with patients, he has found that many people prefer inhaling cannabis to the modern anti-emetic drugs (like Zofran/Ondansetron), thanks to fewer or more manageable side effects with cannabis. Pain is often what drives people to try cannabis. There is reasonable evidence that THC numbs peripheral neuropathic pain. CBD has less clinical evidence for pain but appears best for pain secondary to inflammation. Doctors often cite the lack of clinical trials as reason to distrust cannabis, but “[t]he absence of evidence… is not evidence of absence of effect.” Although clinicians worry about recommending cannabis in the absence of specific guidelines, Abrams maintains that cannabis “is both safe and effective and really does not require a package insert.” There is much to learn about cannabis therapeutics, but uncertainty is not cause for withholding medicine.
CBD for Epilepsy in New South Wales
Part of why doctors remain wary of cannabis medicine is the lack of randomized, double-blind, placebo controlled trials — the gold standard for medical research. Because of cannabis’ status as an illicit drug, research is often relegated to retrospective surveys, which are useful but more likely to be biased. But there are methods in between these two schemes, such as open-label trials. In an open label study, patients are not blinded to which medicine they receive and the protocol is often less strict. Australian scientists recently published an open label study of Epidiolex in pediatric epilepsy. The forty children involved had extreme cases: they had uncountably many daily seizures, and the typical child had already tried nine different medications, yet was younger than nine years old. Around 18-30% of children were “much improved” or “very much improved” by CBD treatment, depending on whether their caregivers or physicians were asked. This rate of improvement is similar to, but slightly lower than, previous trials of Epidiolex. No one’s seizures stopped entirely with CBD treatment, which normally happens in about 10% of cases. A few side effects were highlighted — many patients had somnolence, especially those taking CBD with clobazam. Two kids on both valproate and CBD had altered liver function. One patient was thought to have an increase of seizures due to CBD treatment, though it is difficult to discern given the severity of their initial condition.
Transplant Among Cannabis Users
Candidates for organ transplant are thoroughly screened, and illicit substance use is usually disqualifying. But cannabis is well established as a medicine (as it has been for millennia) and should not prevent patients from receiving a necessary transplant. Doctors at a pediatric hospital in Delaware recently described the thought process around allowing or prohibiting cannabis use. An adolescent woman was managing her anxiety with cannabis and had a kidney disease. The transplant team’s main concerns were the possibility of aspergillus infection and PCP contamination on cannabis. The fear with aspergillus is that patients on immunosuppressive medication will be more susceptible to harm. But there have only been three established cases of aspergillus infection from cannabis in the past 30 years. And the concern about PCP is hard to understand — there are no reports of people accidentally using PCP-laced cannabis. To ensure the safety of her cannabis, the patient was not placed on the transplant list until she enrolled in her state medical cannabis program. But the doctors discuss how even this requirement is problematic — not every state has a medical cannabis program, and the ones that do don’t always protect cannabis-using patients from discrimination. A more realistic concern is that a transplant patient may use isolate CBD in high doses. Moreover, as Project CBD has highlighted, states like California allow «¼ of the [cannabis product to be] covered by mold», which can hardly be considered sufficient protection. Finally, the doctors highlight data indicating that cannabis is safe in transplant patients. Studies that compare cannabis users to non-users find equivalent rates of complications. And cannabinoids are even being studied to prevent graph versus host disease, a life-threatening reaction to organ rejection.
Cannabinoids for Nausea
Preventing nausea is a common medical use of cannabis. But nausea is a multi-faceted feeling. Motion sickness, morning sickness, the flu, or chemotherapy all cause slightly different versions of this discomfort. Scientists at the University of Guelph, led by Linda Parker, have spearheaded our understanding of how CBD, THC, CBDA, and THCA exert their anti-nausea effects. They focus particularly on anticipatory nausea, a severe malaise produced while expecting chemo or another sickening situation. This placebo-like discomfort is hard to treat with typical anti-emetics, but cannabinoids often work, at least in animal models. A new publication by Erin Rock and others at the University of Guelph adds to this literature. They inhibited FAAH, thus preventing the breakdown of anandamide, OEA, and PEA. Blocking FAAH prevented nausea, apparently because OEA and PEA activated the gene-regulator PPARa. This effect was seen in a previous study from this group, where FAAH inhibition prevented nausea through both PPARa and CB1. In their new study, they demonstrated that PPARa’s medical effect can be produced in a single brain region — injecting a tiny amount of FAAH inhibitor into the ventral pallidum was sufficient to suppress nausea. Why is it worth examining the mechanisms of cannabinoids in such detail? Well, because it’s a complicated situation, and the more we understand, the better we can harness cannabinoids in treating nausea. From previous research, it appears that THC synergizes with CBD and CBDA, while CBG and CBD may interfere with each other.
Hemp is a bioaccumulator — it tends to absorb heavy metals from soil, leaving the ground clean by collecting contaminants in its body. When intended for human consumption, this is obviously a problem. But as a means for cleansing land of industrial toxins, hemp is quite promising. Chinese scientists recently published their research on hemp’s biological reaction to lead in the soil. They examined how cells in two hemp varietals responded to high levels of lead, comparing a lead-sensitive fiber-type plant to a lead-tolerant seed-type plant. Both plants were affected by lead in the soil, changing the expression of roughly 300-400 proteins. The common changes altered the plants“ generation of energy, worsened their assimilation of raw materials (like carbon and nitrogen), and altered the breakdown of damaged proteins. But the hardy hemp variety was less affected than the lead-sensitive one — 6x fewer proteins were altered in the lead-resistant plant than the more sensitive strain. These results shed some light on the adaptations required for cannabis to successfully tolerate contaminated soil.
CB1 Protects Against Pesticide Toxicity
Organophosphates are a class of insecticides like chlorpyrifos and soman. Sarin, used as a chemical weapon, is also an organophosphate. Many of these are neurotoxic, owing to their ability to amplify the neurotransmitter acetylcholine, which paralyzes insects and causes their death. A recent study from medical researchers in Maryland and Pennsylvania described the human toxicity in detail and explained why cannabinoids may be protective for humans. These toxic insecticides promoted a process called long-term depression (LTD), wherein the neural connections in a certain brain region are suppressed. The elevated levels of acetylcholine activate what are called muscarinic receptors, whose activity prompts endocannabinoid release, telling the neuron to calm down because its signal has been heard. LTD is usually promoted by the cannabinoids that cause a high, so the researchers thought that endocannabinoid activity might be dysregulated by organophosphates, allowing excessive neural activity and brain damage. When CB1 receptors were blocked, the harms were amplified — nearly all the pesticide-exposed mammals died within two hours. This is worth noting, because a common pesticide synergist, piperonyl butoxide (PBO), is known to inhibit CB1 receptors. PBO potentiates pesticides by strongly inhibiting cytochrome P450 enzymes, which slows pesticide metabolism in insects. But if the concentration is high enough to also block CB1 receptors, it may amplify their harms to humans as well. California regulators have previously warned about the risks of organophosphate contamination on cannabis.
Enough to Drink?
Researchers have modulated cannabinoid CB1 receptors in addiction treatment in order to affect cravings, the formation of habits, one’s sensitivity to triggers, withdrawal symptoms, and the pleasure one derives from drug use. Now scientists at the National Institute on Alcohol Abuse and Alcoholism have added a new factor to the list: feeling satiated. As the paper published in Cell Metabolism describes, suppressing CB1 activity outside of the central nervous system reduces mice’s desire to drink. Though we used to believe that the brain is the only major hub of neural activity, we now know that the gut acts as a «second brain.» Connecting our diet to our minds, the enteric nervous system links the gut to the brain with 5 times more neural connections than in the whole of a human spine. In the same way that eating satiates hunger, feedback from diet can aggravate or resolve psychological distress. The recent paper delves into detail on one possible mechanism. CB1 receptors exist on cells in the stomach that produce ghrelin, a hunger-inducing hormone. Ghrelin also stimulates a desire to drink, and drinking, in turn, suppresses the release of ghrelin. Activating CB1 receptors contributes to «the munchies» that cannabis enthusiasts know well, but this could also cause a desire to drink. Blocking CB1 with a peripherally restricted antagonist, one that doesn’t get into the brain, significantly reduced mice’s drinking. Practically, there isn’t much evidence that cannabis users drink more. There is reason to believe that chronic cannabis use decreases CB1 activity in fatty tissue, which would have similar effects as a peripherally restricted CB1 inhibitor.
Cannabinoids for Alzheimer's
Cannabinoids have been proposed for numerous neurodegenerative disorders. As a matter of fact, scientists employed by the US government filed a patent in 2001 for Cannabinoids as antioxidants and neuroprotectants, citing their potential for treating Alzheimer’s disease among others. Researchers at the Salk Institute for Biological Studies recently examined isolate cannabinoids and their combination in a preclinical assay of neuroprotection. They checked 11 cannabinoids“ effects on 5 measures of cellular stress that are relevant to Alzheimer’s. Many cannabinoids (CBDV, CBG, Δ8-THC, etc) prevented oxidant-induced cell death. The acid cannabinoids did not show much promise in these models — CBGA was actually cytotoxic at large concentrations, and CBDA and THCA were generally less effective at preventing cellular stress (than their neutral counterparts, CBD and THC). On average, Δ8-THC, Δ9-THC, CBD, CBC, and CBN were potent and effective neuroprotectants in nearly every test. Combining THC with CBN had a synergistic neuroprotective effect. The combination of THC and CBD was additive, but not synergistic.
Driving Under the Influence of Cannabis
Driving under the influence of cannabis (DUIC) is framed as a major risk associated with legalizing cannabis. Studies on cannabis and driving suggest that lighting up before getting behind the wheel increases crash risk between 25-40%. This is equal to the effect of having a single drink one hour before driving. So although policy around DUIC needs to be decided, the danger does not warrant stalling medical or recreational legalization while impairment limits are determined. Doctors at a hospital in Vancouver recently published a prospective study meant to determine how THC in the blood is associated with the likelihood of causing a crash. These are somewhat flawed measures — blood levels of THC aren’t equal to the THC concentration in the brain, and
culpability inflates the supposed risk. But these measures can be a good proxy, in the absence of better data. The doctors found that low levels of THC (less than 5 ng THC/ml in the blood) was not associated with crashes. Higher levels of THC did not lead to a statistically significant effect, but appeared to fall in line with past research showing a slightly increased risk. Scientists are still trying to determine why the danger is not higher. It may be that cannabis replaces recreational alcohol use, so the total number of car crashes decrease. There is also evidence that stoned drivers drive slower and less aggressively, making up for some impairment in their reaction time. The Canadian researchers also tried to discern the effect of combining alcohol and cannabis. This couldn’t be reasonably analyzed in their data, however, the current evidence suggests that this is a quite dangerous combination.
"Changing Demographics of Marijuana Initiation"
The development of legal cannabis is associated with lower teen use and higher adult use. But many scientists, hesitant to give up a lifetime of prohibition, spin their data to emphasize danger. One study from 2017 had shown that attending college is a risk factor for trying cannabis, and suggested that political acceptance of cannabis is promoting use among college students. But this interpretation was taken to task by a scientist at Washington University in St. Louis. The total levels of cannabis use have not changed much since 2000. The increase in college cannabis initiation is matched by a decrease in the number of high school students trying cannabis for the first time. In other words, college may now be a
risk factor for trying marijuana because of a successful public health effort to reduce use among high schoolers. They simply wait a few years longer before trying cannabis for the first time. As the commentary points out,
Given that later initiation is associated with decreased risk for drug-related problems, there may even be a case for cautious optimism.