An “orphan receptor” is the term for a receptor in the body whose natural activator is not known. GPR55 is a G-protein coupled orphan receptor that interacts with the other cannabinoid system. CBD appears to inhibit GPR55, while endocannabinoids may activate it. Researchers in the UK and Italy collaborated on a study of GPR55 in pancreatic cancer. Activating GPR55 increased the proliferation and metastasis of cancer cells, while inhibiting GPR55 with CBD or another molecule slowed tumor progression. Mice treated with CBD and the chemo gemcitabine survived nearly three times longer than the mice that didn’t receive CBD. Since CBD affects many different proteins, it’s hard to be sure that GPR55 is the main reason for CBD’s protective activity. The scientists emphasize that CBD and gemcitabine — which are both approved for use in humans — should be tested in clinical trials. Previous research has shown that activating GPR55 stimulates the immune system, opposing the anti-inflammatory immuno-modulating effect of the CB2 cannabinoid receptor.
THC & Night Sweats
The first medical use of THC allowed by the FDA was the 1985 approval of isolate THC (Marinol) to treat nausea and vomiting from chemotherapy. Since then, research has demonstrated numerous possible applications of THC and cannabis in cancer patients, including painkilling, protecting the brain from toxic chemo, and even synergizing with the treatment itself. Doctors in California recently presented case reports from five cancer patients with night sweats, showing that these individuals could manage their symptoms by ingesting pure THC. Four of the five patients swallowed 5 mg of THC or less at bedtime. After one week, one patient stated, “This is the first time I haven’t been waking up all drenched.”
Combining CBD with Anti-Epileptic Drugs
Cannabidiol (CBD) is an astonishingly safe drug. Currently, the biggest safety concern is that at high doses it can alter the metabolism of other pharmaceuticals. That means CBD might amplify the toxicity of other drugs. This has come to a fore with epilepsy treatment, since overdosing anti-epileptic drugs (AEDs) is very dangerous. GW pharmaceuticals, the sole producer of pharmaceutical CBD available in the United States, recently published another study of how high doses of pure CBD (1500 mg/day) and AEDs might interact in adults. CBD tripled the exposure to the active metabolite of clobazam. It slightly increased (by ~25%) the exposure to an AED called stiripentol. And it did not appear to affect valproate levels. GW’s scientists also examined the converse: how do these three AEDs affect the body’s metabolism of CBD? Clobazam increased the levels of CBD and its metabolites by 30-50%. (CBD’s metabolites may confer anti-epileptic activity in and of themselves.) Stiripentol appeared to decrease the patients’ exposure to CBD by 20-30%, indicating stiripentol primed the body to metabolize CBD faster. And valproate didn’t seem to interact with CBD, at least not metabolically. These results are similar to previous research. It reaffirms that even very large doses of CBD can be used safely with anti-epileptic drugs. The study also provides support for using CBD as a first-line treatment, rather than a last resort: adding new medications to a CBD regimen had a minor or negligible effect on the breakdown of CBD. These data indicate that new drugs can be safely added to a CBD regimen. As with earlier research, CBD seems to most significantly affect clobazam, although the two drugs can be combined safely and effectively. There are still concerns regarding the interaction between CBD and valproate, which can potentially cause liver dysfunction — that wasn’t seen in this cohort, but liver enzymes should be closely monitored in any patients taking valproate and CBD together. Finally, it’s important to recognize that metabolism is not the only indicator of how drugs interact. This study looked at the rate of adverse events (side effects) in each treatment group. Since each group only consisted of 10-15 people, the results should be taken as concerns for future research to address, not definitive conclusions. About 10% of participants experienced rashes, which were severe enough for 6% of the patients to withdrawal from the study.
THC Better than CBD?
In clinical research, cannabis is often set up to fail. Federal restrictions privilege studying isolated molecules from cannabis over the plant itself. And even when cannabis research is done, scientists are often forced to use low-quality weed from the National Institute of Drug Abuse. Because of this, most of the useful medical data on cannabis comes from observational studies, where people consuming cannabis are asked about their experience. Researchers in Albuquerque recently analyzed an app-based survey of over 3,000 cannabis users. They found that higher THC levels predicted better symptom relief for most problems (including anxiety and depression, but not all kinds of pain). CBD levels were not related to symptom relief, on average. This format for research, however, is likely biased. THC provides an immediate and obvious effect, whereas CBD may confer its effects with more subtlety. We don’t know how people found the app, or even that the app developers gave all the data to the researchers, so these results might not be representative of the medical marijuana community in general. The scientists are forthcoming about limitations of the study. However, they only report the correlation between cannabinoids and symptom relief for three conditions, not all 27 conditions surveyed. And because the data are owned by the app developer, we cannot interpret the results beyond what the authors have chosen to present. Despite these caveats, the study highlights a significant medical value of THC.
This is Your Brain on Drugs
According to a recent study by University of Pensylvannia scientists, there were
small or limited associations between [adolescent] cannabis use and structural brain measures. But even calling the effect small is aggrandizing harms. Their data didn’t support the notion that teens using cannabis causes any changes in the developing brain. The report goes on to say that
Detailed studies of vulnerability to structural brain alterations and … long-term risk are clearly indicated, which is directly refuted by their own data. A few days earlier, another study from the University of Colorado Boulder found that a few brain regions are larger in adult cannabis user, though this wasn’t associated with different cognitive abilities.
Loss of Cannabinoid Receptors in Adenomyosis
Adenomyosis is a menstrual complication that causes heavier bleeding and pain during a woman’s period. About one in five women suffer from it. As with most female diseases, it is poorly studied and consequently hard to treat. The endocannabinoid system (ECS) is known to be involved in reproductive tissues, and it is dysregulated in pathologies like endometriosis, so it makes sense to consider the ECS in this condition. A recent publication by Chinese scientists suggests that adenomyosis is associated with lower levels of cannabinoid receptors in uterine tissue. The researchers took tissue samples from 45 middle-aged women suffering from adenomyosis, as well as healthy controls. The two primary cannabinoid receptors, CB1 and CB2, were expressed at significantly lower levels in the group of women suffering from adeonmyosis. This alone doesn’t tell us whether the ECS is protective or harmful: Is the loss of cannabinoid activity contributing to the disorder? Or is the body suppressing the ECS to protect itself? We would need new experiments to answer these questions. But there’s reason to believe that the loss of CB1 would cause problems. CB1 levels normally fluctuate throughout the menstrual cycle, yet there was no discernible variation for women who had been diagnosed with adenomyosis. And the lower expression of CB2 could lead to greater inflammation and pain.
Injecting Uncertainty into Science
Preclinical studies are supposed to provide precise, controllable, and translational models for human diseases. But the manipulations that researchers use — like injecting a precise dose of THC into a rat — may sometimes miss important points. What if smoking and injection have different effects? How might this bias results? University of Florida researchers asked just that question, studying the effects of injected vs. smoked THC in rats. Injecting low doses of THC impaired memory. But female rats’ memory were slightly improved by cannabis smoke. Male rats showed no differences when exposed to the smoke. The researchers also did an exploratory analysis of their data (which means that after they tested their hypothesis, they sifted through the data to find more trends). They found that the males who had the worst memory to begin with were aided by THC, at least using this model of memory. (The model may actually be testing the rats’ ability to focus.) Why is there a sex difference? It could be caused by a difference in two neurotransmitter systems (GABA and CB1) in males and females. Note: these results shouldn’t be interpreted to mean that smoking cannabis will improve women’s memory. We are simply highlighting an important factor in preclinical research. These results partially contradict a quick hit from last week.
Anandamide Modulates Panic
Does Legalization Cause Underage Use?
A few researchers have tried to answer this question, with mixed results. Alex Stevens at the University of Kent reanalyzed the data from a 2015 paper which claimed that liberal cannabis policies increase teen use. The data included a multi-year survey of over 170,000 people in 38 different countries. Such a large data set has many variables that can be analyzed. The analysis by Stevens only involves a few changes: it includes participants who did not list their number of siblings; it includes missing data from Sweden; it accounts for gender differences in cannabis use that may not be the same in every country. These methodological changes allow Stevens to analyze roughly 57,000 more participants than in the original study. Using these methods, the data do not support the notion that more liberal cannabis laws promotes teen use. This is not absolute proof that decriminalization, medical laws, or outright legalization will not affect teen use. But such fears are not well substantiated. Moreover, the converse — criminalizing drug use — is abjectly harmful for drug users.