To what extent is research on cannabis in pregnancy complicated by tobacco? That is the question doctors at the Washington University in St. Louis sought to answer with a study published in 2016. Since women who smoke marijuana are more likely to smoke tobacco, a known teratogen (fetal toxin), research on cannabis in pregnancy might yield false positive results. To answer this question the doctors reanalyzed data from 31 different studies – every publication on cannabis and pregnancy that met a few basic criteria, like measuring low birth weight and preterm birth, as well as distinguishing polydrug-using mothers from cannabis-only mothers. Their conclusion was strong: «the association between maternal marijuana use and adverse pregnancy outcomes may be attributable to concomitant tobacco use and other confounding factors and not marijuana alone.» This may be surprising to those who have seen many studies suggesting cannabis reduces birth weight. But nearly every such study admits that they couldn’t exclude the effects of tobacco, alcohol, and other factors. So study after study ends up biased by the same problem. When these reports are aggregated in a meta-analysis, however, there is enough data to disentangle the effects of tobacco and cannabis. This unintuitive situation is called Simpson’s paradox: many small experiments show one result (i.e. cannabis is associated with low birth weight), but pooling data exposes underlying factors (i.e. tobacco use). Once these extra factors are controlled, the association between cannabis use and low birth weight vanishes. These results, of course, don’t prove that cannabis absolutely can’t be harmful in pregnancy. But they indicate that, on it’s own, cannabis use has at most a very small effect, and that public health messages should be tailored towards women using tobacco and alcohol. Potential negative effects on long-term development couldn’t be assayed and should be studied in the future. But a lack of certainty is not an excuse to dredge up a nightmarish vision of children irreparably harmed from cannabis.
"Why Pregnant Women May Justifiably Choose to Use Cannabis"
“What about the children?” is a mantra that has been used to propel prohibition with misplaced fear. Scientists and politicians increasingly warn about the dangers of using cannabis during pregnancy. There’s only one issue: data doesn’t back them up. But a lack of evidence has never stopped the tides of prohibition. Unable to demonstrate that cannabis is actually harmful, public officials nevertheless warn that women are now more likely to report using cannabis during pregnancy (which partly reflects greater comfort talking to doctors, not greater use). But as doctors recently highlighted in a letter to the Journal of the American Medical Association, the “data we do have on cannabis does not show definitive harm.” Clinical trials are for all practical purposes illegal, and most publications on cannabis “conform to the unproven idea that cannabis deserves its dangerous designation.” Meanwhile, California is considering a policy that would designate cannabis a developmental toxin. There are legitimate concerns, such as the higher rates of alcohol use associated with cannabis. But we need to dispel the haunting specter that cannabis is harming the youth, not enshrine it in law.
Cannabinoids in Pregnancy
A new study from researchers at San Diego State University examined the interaction between cannabinoids and alcohol on the fetus. The scientists used pregnant rats to avoid the ethical implications of exposing babies to drugs. Fetal alcohol exposure impaired coordination and motor control of the rats, which lasted throughout adolescence. But CP-55,940 — a synthetic cannabinoid much more powerful than THC — did not affect motor control. It slightly reduced weight a week after birth, but this returned to normal by the rats’ adolescence. In combination with booze, however, the cannabinoid amplified alcohol’s toxicity. Research on cannabis and pregnancy has consistently demonstrated this interaction: Cannabis and THC are not intrinsically harmful to the fetus. But in the presence of fetal growth factors, combined with inflammation from alcohol or nicotine, cannabinoids become cytotoxic. This appears similar to the way cannabinoids are non-toxic in most settings but can encourage cell death in cancer cells (which are inflamed and proliferative, just like fetal cells exposed to alcohol). How do these sorts of results extend to research in humans? It will lead to false positives in research on the teratogenicity of cannabis. If women who consume cannabis and also drink or smoke cigarettes are not excluded from studies, then the synergy between cannabis and alcohol will be misinterpreted as a toxic effect of cannabis. Nearly all human research on cannabis in pregnancy is fatally flawed by ignoring this factor.
There is little evidence to show a directly harmful effect of cannabis in pregnancy. However, cannabinoids consistently amplify the toxic effects of nicotine and alcohol on the fetus. Preclinical research suggests one possible reason: activating the CB2 receptor with anandamide can decrease the expression of a transporter gene in the placenta. This gene encodes a protein which pumps a variety of chemicals out of the placenta, so its inhibition allows toxins to accumulate. It is also common in cancers where it protects the cancer from chemo. Other studies have suggested that cannabinoids may synergize with chemotherapies by interacting with this same chemical transporter. Previous research has highlighted that anandamide, in particular, may worsen fetal alcohol syndrome.
Hypoxic ischemia is a complication that can occur during birth wherein the baby can’t get enough oxygen, often causing some degree of brain damage. A number of treatments, including cannabidiol, can limit the extent of damage according to preclinical research. A study from a team of Spanish scientists explores the molecular mechanism for CBD’s protective effect. Previous research has shown that cannabinoid and serotonin receptors (CB2 and 5-HT1A, respectively) are required for CBD to reduce damage. This new paper suggests that the two receptors bind to each other — forming what is called a dimer — in response to oxygen deprivation. Normally, CB2 and 5-HT1A each signal through an inhibitory protein called Gi/o; after hypoxia, the signaling of Gi/o has a cytoprotective effect, preventing cellular damage. By dimerizing, the two receptors increase the likelihood of being mutually activated or inhibited. Applying agonists of both the CB2 and 5-HT1A receptors had an additive protective effect. On the other hand, blocking one receptor inhibited the other, an effect called cross-antagonism.
Why do Seniors Use Cannabis?
Legalization has led to lower rates of cannabis use among teens, while middle-aged and elderly adults are adopting extracts for the aches of aging. Scientists led by Julie Bobitt at the University of Illinois have surveyed older adults in Colorado, trying to understand why seniors use cannabis and the barriers they encounter. Nearly 90% of people over 61 cite pain as a major motivation for cannabis use. Older adults want more education on medical cannabis. They are confused about dosing, as well as the litany of different products available on the market. Many, having lived through the drug wars of Nixon and Regan, are anxious to talk with friends or even their doctors about cannabis. But when they do consult their primary care physicians, the doctors often decline to give information on cannabis or – worse yet – are wrong. One oncologist is quoted saying “there’s very little research done in regards to [cannabis and] cancer,” seemingly unaware that THC was approved by the FDA for managing certain cancer symptoms 34 years ago. A number of people reported their doctors refused to provide a medical card, forcing them to the recreational market. The lack of medical insurance, along with the need to visit multiple doctors, creates a large financial burden. Seniors emphatically emphasized their desire to delineate medical and recreational cannabis. They were excited to report that cannabis improved pain management and reduced their need for other pharmaceuticals (like opioids and benzodiazepines), many of which have heavier cognitive burdens than even a high dose of THC. Their medical beliefs about cannabis are largely predicated on dramatic personal experience. When asked about cannabis’s negative effects, seniors described the stigma more than specific side effects, and highlighted that alcohol is much more harmful, despite its broad acceptance. The last common theme cited by these aging baby boomers is the stigma. They fear the disapproval of family, friends, and physicians. Some seem to resolve their cognitive dissonance by dichotomizing youth and elderly use: “The kids can get their hands on it, their little brains aren’t ready for it.” This brings the report full circle: educating people on the current science will dispel the myths that engender the stigma.
CBD Treatment & Liver Impairment
Dosing cannabinoids is a conundrum. Anything between 5-500 mg CBD may considered a “reasonable” dose in different contexts. Finding an optimal dose is even more difficult for people with liver or kidney diseases, as these are the major organs that clear chemicals from the blood. So the makers of Epidiolex, an FDA-approved CBD pharmaceutical, studied how patients with liver impairment should be dosed. CBD can still be used safely, according to the article published in the Journal of Clinical Pharmacology, but the dose needs to be lower than in healthy individuals. The researchers asked thirty people to swallow 200 mg CBD then measured the cumulative exposure to CBD and its metabolites. Poor liver function cause a significant increase in CBD exposure. It was 2.5 times larger for those with moderate liver dysfunction, and over 5 times larger in those with severe impairment. The exposure to one of CBD’s active metabolites, 7-OH-CBD, was also inversely correlated with participant’s liver health. There were no serious adverse events in this small study, implying people with liver impairments can safely use CBD, though they should start with a lower dose and titrate more slowly. Liver capability did not influence the time it took for CBD to get through the gut: CBD’s concentration in the bloodstream peaked 2-3 hours after ingestion. (All participants ate two hours before ingesting CBD.) The researchers controled and tested for sex differences (none were apparent), but all participants were white. This is not uncommon, especially in small pilot studies such as these, but it’s a deep-rooted problem. The cumulative nature of research means that such choices build up and bias medicine.
Cannabis Mitigates Alcohol Toxicity
Heavy or even moderate drinking causes maladaptions in humans, ranging from cardiovascular disease to cirrhosis. Underlying many of these ill effects is alcohol’s ability to amplify inflammation. But the immune system is immensely complex, and “inflammation” is a catch-all term that accounts for most degenerative and age-related disease, so it is important to distinguish the specific molecules promoting inflammation. Interleukins are a class of proteins that orchestrate the movement of immune cells – most, but not all, increase inflammation. Researchers at the University of Colorado Boulder investigated interleukin levels of people with an alcohol use disorder. Drinking was associated with increases in interleukin 6, but the association was ameliorated in cannabis users. This protection seems particularly important, since interleukin 6 is also associated with the intensity of cravings for alcohol. Cannabis users had lower levels of another interleukin (1β) as well. These two compounds are also implicated in traumatic brain injury, and play a role in brain function and synaptic plasticity. Such pathways undoubtedly influence the effects long-term cannabis and alcohol use. Unfortunately, the authors make questionable statistical choices: “Given the exploratory nature of this work, we did not correct for multiple tests.” It is all the more important to make this correction in exploratory research or, better yet, not use the phrase statistically significant when the statistics are inappropriate. It will be necessary for future research to replicate this protective effect of cannabis in heavy drinkers.
THC with Antipsychotics
A new study from researchers at Yale University suggests that an antipsychotic called haloperidol decreases the psychoactive effects of THC. Reading between the lines in research, it’s always important to check the dose administered. These scientists gave participants an i.v. injection of THC (0.0286 mg THC per kg bodyweight, to be exact). For an average adult in the U.S. that means injecting about 2 mg of THC. It’s hard to compare this to human use, since each route of administration is unique: injection leads to qualitatively different effects than smoking, and no one is injecting THC as a recreational drug. The authors see the results as evidence that THC“s «psychotomimetic» effects are mediated by dopamine, though only a third of participants responded sufficiently to THC for the antipsychotic to have an effect. When the premise is THC-induced psychosis, the experiment involves injecting THC, and people who aren’t psychotic enough are excluded from the analysis, the experiment can’t say much about human experience.
Cannabis Degrades in Storage
One of the many political hurdles that cannabis researchers face is the supply chain – for decades the National Institute on Drug Abuse (NIDA) has been the sole producer of “research grade” cannabis. Most cannabis supplied by the U.S. government has less than 10% THC and it may have been stored for more than a yearr – which makes it very different from what is sold in most dispensaries. This low quality cannabis is more likely to give negative results, accounting for one of many factors that stymies research on the medical benefits of cannabis. A new paper from Italian scientists looks at how cannabis degrades in different storage conditions. They fit the rate of THC’s conversion to cannabinol (CBN) with a simple mathematical model (called first order kinetics). The model for CBD degradation was more complicated. Measuring THC and CBN levels allows the initial THC concentration and storage time to be predicted with the equations in the paper. Only freezing cannabis at -20 °C, not simple refrigeration, prevented significant breakdown over 4 years. Sadly, the authors hope that their model can facilitate the enforcement of drug laws. Racist drug laws create a large fraction of the U.S.’s population of 2.3 million prisoners. Drug charges account for at least 400,000 of these inmates, a quarter of whom have not even been convicted, and over a million arrests.