One broad effect of CBD and THC is the stimulation of neurogenesis — the production and integration of new neurons in the brain. This effect has been proposed as the basis underlying many of cannabis’ medical uses. Researchers in Barcelona, Spain, recently studied how CBD would affect addiction and learning in mice when neurogenesis was artificially prevented. They show that CBD reduces these mice’s desire to self-administer cocaine, but only when neurogenesis is allowed. Similarly, CBD’s beneficial effects on memory appeared to require neurogenesis. The anxyolytic effects of CBD, however, occured even when CBD was prevented from stimulating the creation of new neurons. The mechanism by which CBD promotes the growth of new neurons is still unclear. It’s important to mention that the researchers use temozolomide — a chemotherapy for glioblastoma — in order to prevent neurogenesis. It’s possible that this toxin prevents CBD’s effects on addiction and memory through a different mechanism, though the authors try to control for the other toxicities of temozolomide.
Markers of Endometrial Cancer
Recent research has indicated a role for endocannabinoids in endometriosis and related diseases. A study published in Frontiers in Oncology sought to determine whether endometrial cancer could be predicted by someone’s levels of the two canonical cannabinoid receptors (CB1 and CB2) and three related fatty acids (anandamide, OEA, and PEA). The researchers found a tendency for increased endocannabinoid levels among cancer patients. But there was little change in CB2 expression and a decrease in CB1 levels. The higher levels of anandamide and PEA in blood plasma could be one biomarker of endometrial cancer that doesn’t require an invasive biopsy, the researchers suggest. Unfortunately, the scientists don’t mention the timing of their blood collection. The endocannabinoid system makes up one part of the body’s natural clock — the circadian rhythm. Simple activities like singing or running can significantly change endocannabinoid levels in the plasma. Although this new research is promising and worth following up, it may be difficult to standardize measurements to find the proper “baseline” level of anandamide and PEA for a cancer diagnostic.
Caryophyllene Reduces Alcohol Consumption
Terpenoids — the volatile compounds that give many plants their smell — appear to confer some of the medical effects of cannabis. Caryophyllene (BCP) and its derivative caryophyllene oxide (BCPO) are particularly significant terpenoids found in many green leafy vegetables. They activate the CB2 receptor, which, according to a recent study, prevents some of the harmful effects of drinking alcohol. The researchers gave varying dietary concentrations of BCP and BCPO to mice consuming alcohol. A high dose of BCP reduced some effects of alcohol. A much lower dose of BCPO reduced both the amount of alcohol the mice would drink as well as some of the addictive and behavioral effects of alcohol.
CBD and Brain Tumors
Although cannabinoids have shown promise for epilepsy in general, Epidiolex is only approved for two kinds of childhood epilepsy. But this may be more a reflection of the FDA’s drug approval process than of the conditions for which CBD helps. (It is much quicker and cheaper to get approval for an untreated disease.) CBD appears to work well for many kinds of epilepsy. A study from the University of Alabama’s CBD program looked at the use of CBD for seizures in patients with brain tumors. The report described three male patients, between 17 and 40 years old, who developed seizures due to brain tumors. One patient’s seizures were reduced by over 50%, though he was taking an extremely high dose of 50 mg/kg/day CBD. A second patient, taking 20 mg/kg CBD per day was seizure-free for a month, a major decrease from 5 seizures every two weeks at the start of the study. This patient died during the study, seemingly unrelated to CBD. A third patient had a slight increase in the number of seizures, and he stopped CBD treatment due to side effects. Despite the increase in the total number of seizures, the researchers reported that the severity of his seizures were reduced during CBD treatment.
Pancreatitis in Cannabis Users
Pancreatitis is a severe and potentially life-threatening inflammation of the pancreas. Doctors at the Cleveland Clinic Foundation recently examined how cannabis users faired through pancreatitis compared to the general population. They surveyed records of 2.8 million acute pancreatitis patients over 10 years, and the results were dramatic. People with cannabinoids in their bloodstream were 3-4x less likely to die in the hospital. On average, they stayed in the hospital for about one fewer day and saved the hospital around $5,000 on additional interventions. Those using cannabis were also less likely to have a heart attack or to need mechanical ventilation. This highlights the importance of the public health benefits of cannabis use. Interestingly, preclinical research seems to indicate that THC would be harmful in pancreatic inflammation, and some case reports have linked pancreatitis to cannabis use. But we’ve seen a similar paradox with obesity. It could be that using cannabis chronically downregulates CB1 activity in the pancreas. Or maybe the anti-inflammatory effect of CB2 is more significant. The effect may also be partly due to demographic differences, as the authors highlight. Cannabis users are different from the general population not only because of their use. In this study, they were also 10 years younger and more often male. The lower mortality could be due to these differences, so the researchers re-weighted their data with a statistical method to match the demographics of the cannabis users and the population. This adjusted model attributed a smaller effect to cannabis, but most benefits remained statistically significant. (The numbers above are from this adjusted model.) The authors hypothesize that (1) lower weight and age among cannabis users could explain lower mortality, or (2) the anti-inflammatory effect of cannabis may protect people from inflammation in pancreatitis.
CB1 & Mammalian Memory
How do cannabinoids affect memory and learning? It seems like a simple question, but scientists study its answer in complex ways. The kind of memory in question, the species tested, the animals’ age and sex, and so on, all affect the answer. So, scientists at Kings College in London compiled 195 articles on cannabinoids and memory for review. They first separate spatial and non-spatial memory, as these appear to be different kinds of cognition. Unsurprisingly, CB1 receptor agonists, like THC, anandamide, and numerous synthetic cannabinoids impaired non-spatial memory. (They had no effect on spatial memory.) But when they separated the analysis by the efficacy of the drug (roughly meaning the maximal effect it can have) and the species, the story changed. In rodents THC, which has a lower efficacy than other cannabinoids, did not show a consistent effect on memory, although synthetic cannabinoids and anandamide did. Additionally, studies that applied cannabinoids chronically over time saw a tolerance to the memory-impairment — that is, humans and other animal tend to acclimate to CB1 activation over time. This doesn’t disprove human experience — and the researchers did see an effect of THC acutely in humans — rather it highlights differences between species. The authors don’t speculate about what causes species differences, but we will. One important feature of the endocannabinoid system is the presence of unique FAAH enzymes in rodents and humans. Another species difference is that higher levels of the neurotransmitter adenosine in some animals can diminish cannabinoids’ influence over memory. Despite the sometimes-amnesic effect of activating CB1, the researchers note that simply inhibiting the receptor doesn’t appear to improve memory. There are many complications layered onto the London scientists’ data. For example, cannabinoids specifically suppress fear-memories, but many experimental settings are traumatic for the animals involved. This can switch the effect of cannabinoids. Aforementioned species differences, and the biphasic effect gets in the way of a typical interpretation of the linear dose response. Although not too important for the average medical or recreational user, this study consolidates a significant and useful set of data for future research on cannabinoids and memory.
Legalization is a Misnomer
The movement to legalize cannabis used to be centered on the catastrophic impact of the drug war. Now the conversation has shifted to the medical utility of cannabis and the excitement of filling state coffers with tax revenue. But without dedicated attention to those most harmed by police enforcement of drug laws, their situation might not improve. A new study published in the Journal of the American Medical Association highlights how the youth have been left behind because legalization often does not reduce penalties for underage possession. Legalization efforts need to include stipulations for decriminalizing — or entirely depenalizing — youth possession of cannabis. Researchers at Eastern Virginia Medical school examined the arrest rate of youths and adults in states that have either decriminalized or legalized cannabis over 16 years. Legalizing adult use of cannabis has not reduced the arrest rate of minors for nonviolent possession. Decriminalizing cannabis, however, with it’s emphasis on stemming the imprisonment of drug users, is effective. Alaska, Colorado, and Washington have all kept criminal penalties for youth possession despite legalizing cannabis for adults. A brief editorial accompanied the JAMA article to further describe how much damage cannabis arrests continue to cause. They highlight that, between 18 and 20 years old, people are not protected by adult-use laws, nor by juvenile court. This group — too young to get high, but old enough for war — is especially vulnerable to forever being stigmatized with a felony charge for cannabis use. “This scenario seems perverse, especially in view of the well-established research finding that decriminalization has no measurable association with the prevalence or intensity of cannabis use at any age.” The editorial goes on to describe why full depenalization for cannabis possession is necessary: racial and socioeconomic disparities are great enough that an unpayable civil fine lands many people in jail anyway. In South Australia, more people are being arrested for not paying a cannabis fine than used to be arrested for possession.
CBD and THC Synergize in Epilepsy
Although great strides have been made in epilepsy treatment, a third of patients still do not find effective methods for preventing seizures. Cannabinoids, particularly CBD, have taken the limelight with their dramatic life-saving effects in some cases of intractable epilepsy. But cannabis is not the same as FDA-approved Epidiolex, an extract of isolated CBD. A recent study from scientists in Montreal highlight the this difference, demonstrating synergy between the anti-seizure activity of THC and CBD. Although epilepsy is known to result from neuronal hyperactivity, it’s underlying causes can be diverse. The researchers used two models of seizures (one chemical, another genetic) in zebrafish. High doses of either THC or CBD reduced the apparent seizures, but also caused side effects in healthy fish. By combining the two cannabinoids, the dose could be lowered. Seizures were reduced in the genetic model of epilepsy, but the behavior of regular fish remained normal. Although the 1:1 dose was synergistic, ratios with more CBD than THC (5:1 and 10:1) did not demonstrate much synergy. Being a fish study, of course, it doesn’t necessarily translate directly to humans. But there is quite a bit of evidence piling up that THC, CBD, and other components of cannabis synergize in such a way that a lower dose with fewer side effects can be used.
Seizures on Synthetic Cannabinoids
Synthetic cannabinoids are a dangerous group of designer drugs that bind tightly to cannabinoid receptors. They were initially used as tools in science — since THC and cannabis were nearly impossible for researchers to access. There are many dozens of related synthetic cannabinoids. Scientists in Australia and New Zealand recently examined how one, called CUMYL-4CN-BINACA, causes seizures. This synthetic cannabinoid binds with high potency to the CB1 receptor — about 10-20x higher than THC. Unlike THC, CUMYL-4CN-BINACA is a full agonist at CB1, meaning the effect upon binding is much stronger than THC’s effect. Read more about that here. The effect is so strong that it dysregulates neurotransmission, which causes seizures and a drop in body temperature. The scientists planned to try a range of doses, but at the fourth dose the animals’ body temperature dropped by 7 ℃ (12.6 ℉). The seizures and hypothermia could be partly blocked by giving the CB1 inhibitor, Rimonabant. (But Rimonabant also seemed to cause seizures at a high dose.) The cannabinoid CUMYL-4CN-BINACA was first described in a 2014 patent, and appears to have caused a handful of deaths in the EU and Turkey since 2016.
Cannabis for Fibromyalgia
Fibromyalgia is one of many poorly-understood pain conditions that occurs mostly in women. Israeli researchers recently published an observational study of 367 people using cannabis for fibromyalgia, and the results were promising! At the outset, nearly all patients reported severe pain (between 8-10 on a scale from 0-10). After 6 months of cannabis treatment, most people’s pain had decreased to 5. A number of quality of life measures were also much improved, along with sleep, appetite, and sexual activity. Around 20% of people who were taking opioids or benzodiazepines reduced or entirely eliminated their need for these pharmaceuticals. The patients were enrolled in the Israeli medical cannabis program, and their products came from one of 14 standardized strains. The typical daily dose was 1 gram of cannabis that had 15% THC and 4% CBD. The researchers explain that not everyone responded equally well. Those over 60 years old and patients apprehensive about cannabis responded worse to treatment, whereas people with spasticity as an additional complication and those who had used cannabis in the past responded better. From this data, it appears that cannabis can be as effective as other medications used for fibromyalgia (e.g. amitriptyline) — it deserves attention as a possible treatment. But there were some problems and limitations. About 30% of people dropped out of the study, which often inflates the good results. There were some mild side effects, like dizziness, dry mouth, and GI discomfort, although these occurred at low rates, even for studies on cannabis. Additionally, patients were only included in the study if they had failed other pain treatments for at least a year. The worse condition of this population could make treatment more difficult, or can cause false positive results due to regression to the mean.