Quick Hits

Welcome to Quick Hits! This is a new feature on Project CBD, where we collect some of the most interesting and informative tidbits of research into cannabis over the past week.

Injecting Uncertainty into Science

Posted: March 11, 2019
A rat smoking weed

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

Posted: March 11, 2019
Rainbow Boa Snake
Panic, as a mental health disorder, results from overactive stress hormones, hypersensitivity to certain neurotransmitters, and a desensitization to the parasympathetic system — which is supposed to quell the fight-or-flight reaction after a threat has disappeared. New research from Brazilian scientsts in São Paulo examined how endocannabinoids, specifically anandamide, plays a role in panic-like reactions in mice. Injecting various doses of anandamide into a brain region called the dorsomedial hypothalamus, they found that moderate doses suppress panic, but high doses have no effect. This is called a “biphasic” or “U-shaped” dose response. The moderate dose of anandamide activated CB1 to reduce panic-like behavior. But at high doses, anandamide also began to activate the ion channel TRPV1, which counteracted anandamide’s anxiolytic effect. THC also has a biphasic effect on anxiety, possibly through the same two receptors. How did the researchers get the mice to panic? They put the mice in front of a predators — the South American rainbow boa snake.

Does Legalization Cause Underage Use?

Posted: March 4, 2019

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.

TRPV1 Protects Neurons in Multiple Sclerosis

Posted: March 2, 2019
Most everyone has had the experience of biting into a spicy pepper and feeling heat permeate their mouth. This feeling comes from the activation of TRPV (pronounced trip-vee) receptors. These are ion channels that sense stimuli like heat, pressure, light, acidity, herbs, and toxins. TRPV receptors exist on many kinds of cells — from taste buds to neurons. A recent article by a team of Italian scientists in Frontiers in Neurology examined the role of TRPV1 in multiple sclerosis, a neurodegenerative disease for which cannabis extracts are used in many countries. Activating TRPV1, even with potent toxins like resiniferatoxin, reduced the release of inflammatory chemicals by immune cells in the brain, thus reducing harms in a cellular model of multiple sclerosis. The scientists also examined 132 patients with MS, finding that mutations in the TRPV1 receptor was associated with neuroinflammation. Oddly enough, activating TRPV1 is usually associated with pain and inflammation (think pepper spray or a spider bite). It may be that activation of this receptor leads to long-term desensitization, which is why the researchers found a protective effect. Plant cannabinoids like THC, CBD, and CBC (cannabichromene) both activate and desensitize many TRP channels.

Cannabis & Pediatric IBD

Posted: March 2, 2019
Drawing of child with stomach ache
Cannabis is used by many individuals with inflammatory bowel disorder (IBD), which includes conditions like Crohn’s disease and ulcerative colitis. IBD is not uncommon among people younger than 18, and about one in three of these individuals use cannabis to manage symptoms such as nausea, pain, and fatigue. Three authors review clinical and preclinical data regarding the use of cannabis and cannabinoids for IBD. They highlight that cannabis has shown better results than CBD alone, although the data are fairly limited with poor controls in both cases. Unfortunately, the authors appear caught up in THC-phobia, insinuating that no THC exposure is acceptable: “[C]annabis use needs to be actively discouraged in children with IBD.” This statement seems to be at odds with the data they review. Although hyped-up medical claims about CBD should be discouraged, THC fear-mongering is also inappropriate. Both THC and CBD have robust safety profiles, much more so than many pediatric medications. (Note, an interview with a professor at the University of Michigan reviewing the same data in the adult population is freely available here.)

Results Pending

Posted: March 2, 2019
Black widow on leaf
Scientists from the Netherlands recently published the protocol for an upcoming study examining how CBD might be helpful in treating specific phobias. The endocannabinoid system is required for eliminating fearful memories, or at least making them palatable. But why have they only published their methods? It’s part of an ongoing movement to make science more accurate. Many statistical methods assume that the researchers plan all of their data analysis before looking at any of the data. Otherwise they might try to explain trends in the data, even spurious ones, based on their own biases. (This is called HARK-ing, or hypothesizing after results are known.) The researchers make their study more reliable by publishing their methods in advance.

What Do Vets Know About CBD?

Posted: February 27, 2019

A number of surveys have asked doctors what they know about cannabis and how comfortable they feel talking with patients about it. A similar survey was recently conducted about CBD and dogs among over 2000 veterinarians in the United States. Less than half of vets were comfortable talking to clients about CBD for pets. Among this group, vets were most comfortable recommending CBD for pain management, anxiety, and seizures in dogs. Young vets were much less likely to talk with clients about CBD or cannabis. Among those who had experience treating pets with CBD, the vast majority (~80%) did not feel that state veterinary organizations provide enough guidance on how to abide by state or federal laws. A similar proportion believed that from a moral and medical perspective, CBD should be allowed for pets. Only 16% of them supported the schedule 1 status of cannabis, and even fewer thought that CBD should remain a schedule 1 drug.

Low Dose THC Can Improve Cognition

Posted: February 26, 2019
Improved brain function

THC and other cannabinoids are known to induce neurogenesis — the creation of new neurons — in the brain. There are reasons to believe that this can positively influence diseases like dementia or traumatic brain injury, as well as the ability to learn. Malaysian researchers recently probed the question, does THC improve cognition by inducing neurogenesis? Yes, but only at the right dose. When they applied a dose 6-7 times lower than is commonly used to study THC’s effect on memory, the rats learned from their environment more rapidly and showed signs of neurogenesis in a brain region called the hippocampus. The improvements were even greater after chronic treatment. Unfortunately, these sorts of animal studies are hard to interpret because of the number of factors involved. The results of experiments on THC and cognition may change if the animal is stressed in its learning environment, if mice are used rather than rats, if the dose is given at a different time, etc.

Ketamine Functions Through CB1

Posted: February 24, 2019
Ketamine

Ketamine is a dissociative anaesthetic that has shown some promise for treating severe depression. Historically, it has been used as a tranquilizer in veterinary medicine and as a recreational club drug. Low doses of ketamine prevent pain. Brazilian scientists recently provided evidence that this painkilling effect is partly mediated by the endocannabinoid system: When the scientists blocked the CB1 receptor, ketamine did not prevent pain. And when anandamide levels were boosted, the analgesic effect was potentiated. Previous research by this group showed that ketamine causes endocannabinoids to be released in certain parts of the brain. It will be interesting to see if the antidepressant effect of ketamine is also mediated by endocannabinoids — the primary action of ketamine is to inhibit a glutamate receptor called NMDA, which is intimately involved in long term potentiation (LTP). Cannabinoids also appear to influence depression by regulating LTP.

Lupus and ABHD6

Posted: February 24, 2019

Systemic lupus erythomatosus, often simply called lupus, is a severe autoimmune disorder where the immune system attacks the nucleus of cells – their genetic control center. Problems can be expressed anywhere in the body, though rashes in the skin, joints, and vital organs are most common. Treatment of lupus generally requires intense immunosuppresive drugs, often targeting inflammatory molecules called interferons. But these drugs make a person more susceptible to other diseases. Mutations in the gene encoding ABHD6, which breaks down the endocannabinoid 2-AG, are associated with lupus. Indian researchers probed this connection, suggesting that overactivity of ABHD6 limits the body’s ability to quell its overactive response to interferons. Normally 2-AG will activate CB2 receptors on immune cells, which seems to provide a tonic inhibition of interferon release.