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.
Bipolar Disorder & the Endocannabinoid System
The phrase “cannabis and mental health” conjures thoughts of anxiety, depression and schizophrenia. However, bipolar disorder is rarely considered from the perspective of the endocannabinoid system in mental health. Iranian researchers at Kerman University recently reviewed the beneficial and harmful aspects of endocannabinoids in this disease. First the bad news: There is an association between daily cannabis use and earlier onset of bipolar disorder (although interpreting cause-and-effect from these studies is rarely appropriate). And despite CBD’s potential anti-anxiety and anti-depressant effects, large doses of oral CBD has not prevented manic episodes in a few human trials. But there is good news too! Activating the CB2 receptor is promising on many levels. Bipolar disorder, like most neurological diseases, involves brain inflammation. The authors describe numerous molecular pathways through which CB2 attenuates inflammation and can protect neurons from harm. Moreover, we should note that psychiatric problems are often related to gut dysfunction, which cannabinoids can ameliorate. Green leafy vegetables, rich in β-caryophyllene, are one of the best dietary sources of chemicals that activate CB2. The Iranian scientists go on to describe how a breakdown product of endocannabinoids — called arachidonic acid — promotes abnormally high levels of inflammation in bipolar patients. The relationship between endocannabinoids and these inflammatory molecules is complex, but it provides a promising avenue for future research. There is reason to study compounds which differentially modulate cannabinoid receptors, blocking CB1 while activating CB2, in the treatment of bipolar disorder.
A study of middle-school drug prevention published a stunning statement in the journal Addictive Behaviors: Personally threatening children is not the best way to make kids fear cannabis. The study, performed by psychologists at Claremont University in California, is a redux of the Drug Abuse Resistance Education (DARE) program founded during Ronald Regan’s drug war. The authors’ stated goal was to ensure that kids who were apathetic towards cannabis could be made to fear the plant. So the researchers began with 538 middle-school students. They then picked a subgroup for further “education,” comprising 101 people who were resistant to the DARE redux, but who were ambivalent to cannabis and had never used before. The authors report — without chagrin — that personally threatening these pre-teens was not effective. It’s worth reiterating that — over 100 middle school students were deemed not sufficiently fearful of cannabis, and so were threatened to further scare them. The researchers also tried belittling the kids (“experts have found that [people like you] are very childish”). And, just as in the DARE programs of the past, it didn’t even work. This leads into one of the major criticisms that DARE has faced. When teens realize that the horror stories of “reefer madness” were exaggerated, they start to question whether other drug education is equally misinformed. Is binge drinking that bad? Is sharing needles really unsafe? Thus, poorly designed drug education ends up leading to more dangerous drug use. Because in reality, almost no other recreational drugs are as safe as cannabis. DARE programs and their successors like the study here undermine genuine harm-reduction efforts by giving people cause to disbelieve and disengage. But the examples of Switzerland and Portugal have shown that harm-reduction and decriminalization is the best way to reduce dangerous drug use. DARE — with an approach akin to abstinence-only sex education — has consistently drawn criticisms of this nature. Their hard-line view has led them to promoting fake news. They have encouraged children to act as informants, reporting parents to the police for drug use. DARE currently runs the keepin’ it REAL campaign, which appears equally ineffective.
Cannabis in Cancer Treatment
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.
Cannabis & Psychosis
The claim that cannabis causes or precipitates psychosis has long been a foundation for opposing cannabis. Yet with hundreds of millions of dollars invested and over a century of dedicated research, the argument remains weak. A brief article by UK researchers attempts to describe why. Population studies clearly demonstrate that cannabis use does not simply cause schizophrenia — there is little correlation between rates of cannabis use and schizophrenia in the population (these are called epidemiological studies). But there is consistently an association between cannabis use and the development of psychosis. Three common explanations are (1) cannabis might precipitate schizophrenia in vulnerable populations, (2) people use cannabis to self-medicate, even before a diagnosis of schizophrenia, and (3) certain genetic or environmental factors may promote both cannabis use and schizophrenia. Although the authors do not describe this directly, the first point is reminiscent of arguments from the anti-vaccination campaign — when epidemiological research indicated that vaccination does not correlate well with the rate of autism, the argument moved to “it can precipitate autism in vulnerable individuals,” a claim that is much harder to test. This, applied to cannabis, is essentially the argument of (1). The authors instead highlight how research methodology has precluded an ability to prove or disprove explanations (1) and (2). Research even sometimes suggests that schizophrenia predicts cannabis use, rather than the other way around. The high prevalence of tobacco use is another major confounding factor in cannabis research. Finally, the authors conclude their commentary by emphasizing demographic limitations. Women are often excluded from these studies — most inquiries into this topic have studied only men from western countries. This is a major problem that pervades medical research.
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.