Quick Hits

Welcome to Project CBD Quick Hits, where we collect some of the most interesting and informative tidbits of research into cannabis over the past week.

CBD and Organ Transplant

Posted: May 8, 2019

With CBD becoming more mainstream, doctors are on the lookout for how this powerful chemical affects human health. But a typical adult in the U.S. takes at least one pharmaceutical, and CBD’s interaction with other medications can be significant, especially given how easily one can overdose on common drugs. A new potential interaction has been highlighted by scientists at the University of Cincinnati, in Ohio. They report a woman using an extremely high dose of pure CBD for epilepsy — between 2-3 grams per day. She was also taking tacrolimus, a common immunosuppresive drug, to treat a kidney disorder. When combining these two treatments, tacrolimus levels in the blood rose by three-fold — dangerous result. Because the addition of CBD helped control the seizures, her doctors helped her adjust the dose of these two drugs. This is commonly what happens with drug-drug interactions — there is an important need to monitor drug levels, but the interaction can be managed without ill effect for many patients.

Tacrolimus is a mainstay medication for organ transplant, so this possible interaction could be important for patients who need an organ transplant. Moreover, there has been some research on the potential to use CBD in transplant patients. Both THC and CBD tend to tone down immune activity and they have recently been suggested for treating graft-versus host disease, a potentially deadly reaction to organ transplants. How relevant is a cannabinoid-drug interaction like this to the average person? It depends greatly on the dose of CBD. In this case, there are probably two proteins that CBD interferes with to increase drug exposure — it inhibits CYP3A4, an enzyme that breaks down more than half of all pharmaceuticals, and it can inhibit P-gp, a protein which pumps chemicals out of certain cells. But this woman was using multiple grams of CBD per day. If she got this from good quality cannabis flower (say, a flower that’s 20% CBD by weight), she would have to eat half an ounce each day.That’s not the normal dose that people take, even those using cannabis for epilepsy. When unpurified cannabis extracts are used, the common doses are 10-100 times lower. THC and other plant compounds appear responsible for this greater potency, and the consequent lesser risk of drug-drug interactions. In other words, THC seems to make CBD a safer more effective medicine.

Dosing Pure CBD

Posted: May 8, 2019

CBD is clearly a useful medicine in the treatment of some types of epilepsy, yet patients are faced with dilemmas when they must decide which product to use, how to incorporate it with other medications, and how to begin dosing. Isolate CBD products have the advantage of being standardized, although they suffer from numerous limitations. There is plentiful evidence that orally ingesting high doses of pure CBD reduces pediatric seizures. Kids are first given a single dose of 5 mg CBD per kg of body weight (written 5 mg/kg CBD) per day. Then the dose is cautiously raised by around 5-10 mg/kg each week and the administration is spread out across two or three doses a day. All the while, the patient’s doctor will be looking out for new side effects and changes in the metabolism of other drugs. Some patients find sufficient relief at 20 mg/kg CBD, whereas other take up to 50 mg/kg per day.

A recent article published in CNS Drugs reaffirms this general protocol. Patients in this study were given between 10-40 mg/kg CBD, split into two doses a day, for six days. A bidirectional drug-drug interaction was reported between CBD and clobazam (a benzodiazepine anti-epileptic drug), which has been seen previously. Patients using clobazam had about 2.5-3 fold higher exposure to the highest dose of CBD, and this 40 mg/kg dose of CBD also elevated clobazam levels. Consistent with other reports, CBD and clobazam can be used safely together, but the dose of both drugs should be lower than normal. One 16-year-old on the 40 mg/kg dose had temporarily abnormal liver function (measured by alanine aminotransferase levels), which resolved on its own. This dangerous side effect occurred in one other study of CBD, likely due to an interaction between cannabidiol and valproate. The authors here do not report whether this patient was using valproate as well. Unfortunately, there is a severe conflict of interest among the study’s authors. A single company provided the CBD solution, funded the study, and wrote the results: Insys.

Insys is best known for bribing doctors and illegally marketing fentanyl; it is one of the groups most responsible for the modern opioid epidemic. In early May, top Insys executives were criminally convicted for their role in tens of thousands of overdose deaths. But this lethal criminality somehow not a disqualifying factor in the pharmaceutical world: the DEA gave a green light to Insys for marketing a THC isolate at the start of 2018. They now have clinical trials investigating CBD for epilepsy and numerous drugs for treating opioid addiction, a sick irony.

THC Makes Oxycodone Safer

Posted: May 8, 2019

Many prohibitionist arguments are being flipped on their heads. CBD’s anti-anxiety effects have replaced much of the reefer madness mentality. Rather than causing lung cancer, marijuana appears to have anti-cancer activity, if anything. And in spite of the gateway theory, whereby casual cannabis use supposedly escalates to heroin, we find that cannabis helps to treat pain and reduce opiate use. An animal study out of the Scripps Research Institute reaffirms that THC generally reduces the addictiveness of opioids. In simple words, when animals (including humans) are given THC, they have less interest in seeking opioids, alcohol, and other drugs. They respond less intensely to cues or triggers that remind them of past addictions. Although everyone has a unique response to cannabinoids, this is the average effect.

The recent Scripps study looked specifically at self-administration, which is the gold standard animal model in addiction research. Not only were the rats uninterested in oxycodone after getting THC, but THC potentiated the painkilling effect. So while THC made oxycodone less addictive, it also made it a more effective pain treatment. Oxycodone is one of the opiates most responsible for modern opioid addiction.

Preclinical work is only a first step in medicine, and before we jump to conclusions let’s not overlook animal studies where THC potentiates opioids’ addictivness or cannabinoids interfere with the painkilling. But the beneficial effects are seen in human research. People using cannabis are much more likely to decrease or stop opioid use (different surveys suggest that between 30-60% of opioid-users are able to entirely switch to cannabis)

Placebo Genetics

Posted: May 6, 2019
Placebo effect cannabinoid receptors

Throughout history, cannabis has been described as a treatment for hundreds of different conditions. If scientists find it hard to believe cannabis can do so much, they may chalk up the results as just a placebo. But the placebo effect is powerful. It accounts for roughly half of the efficacy of opioids and antidepressants. And, ironically, the placebo effect actually functions in part through the endocannabinoid system. The belief that an empty capsule will help an ailment causes your brain to release anandamide, which can kill pain, reduce headaches, and much more.

Not everyone gets the same benefit from placebos, and it tends to run in families, suggesting genetic mutations can alter placebo sensitivity. Researchers at the University of Maryland and the NIH recently highlighted the importance of endocannabinoid genes in the placebo effect. A variant of the FAAH enzyme, which breaks down anandamide, was associated with greater placebo response. The alternative version of this gene is associated with greater rates of addiction and a notably higher pain tolerance. Mutations in FAAH may also relate to obesity, thanks to other chemicals that FAAH regulates. The researchers looked at two other mutations – one in the mu opioid receptor and another in COMT, an enzyme that metabolizes serotonin, dopamine, and many illegal drugs. These mutations interacted with each other to modulate how well people would respond to a placebo.

“Into the Weeds”

Posted: May 6, 2019

A major benefit of legalization is regulation (at least in theory). Cannabis in a legal market can be held to safety standards such as the absence of dangerous pesticides. While autonomous community-enforced regulation can exist without government intervention, this does not happen at the global scale which the cannabis industry has reached today. So how well are governments doing with their pesticides regulations? Bay area journalist Nate Seltenrich recently dug into this issue.

Normally pesticide policy is regulated by the EPA. But the EPA is a federal agency and it has refused to offer guidance for pesticides on cannabis, so each state has reinvented the wheel while guessing at safe levels of pesticides. California and Oregon have compiled different lists of pesticides and their acceptable limits, while further north in Washington, no pesticide testing is required at all. Canada, meanwhile, has a zero-tolerance policy.

Uncertainty has arisen because of the tobacco lobby, which managed to avoid researching any implications of smoking pesticides: “EPA does not assess intermediate or long-term risks [of pesticides] to smokers because of the severity of health effects linked to use of tobacco products themselves”, according to the Government accountability office. So while testing for pesticides drives the cost of legal weed up, it’s hard to know it this even ensures safety.

And that is only considering human health — heavy, systematic use of pesticides has an enormous environmental cost. Seltenrich highlights a few pesticides allowed by California that should arguably be banned entirely: the “possible carcinogen” bifenthrin, and two neurotoxic organophosphates called diazenon and acephate. The latter is also considered a possible carcinogen and possible endocrine disruptor. The Golden State, which is currently considering labeling cannabis a developmental toxin, would do well to ensure that true developmental toxins are not sprayed on cannabis. In fact, the California Depatment of Pesticide regulations published an article on the dangers of pregnant mothers being exposed to organophosphates in cannabis. Unfortunately for consumers, smoked cannabis seems to carry pesticides into the body very well. A publication from chemist Jeffrey Raber, indicated that upwards of 60% of pesticides could be inhaled when smoking a pipe.

But the situation is not solved easily. California is an agricultural region and pesticides can drift from other farms onto cannabis; the extraction process concentrates most pesticides along with cannabinoids leading to failed test results on seemingly good products. Federal legalization would likely standardize U.S. regulations — we hope that states, as laboratories of democracy, will have found a reasonable solution by that time.

Project CBD has been engaged with California’s pesticide regulations in the past. The current issue we are most concerned with is the allowance of neonicotinoids on cannabis (there are three, imidacloprid, thiamethoxam, and acetamiprid). All three of these have been banned in France, and two are banned in mainland Europe because of their toxicity to pollinators and their ability to contaminate groundwater. Imidacloprid is one of the most common pesticides used worldwide. It’s been found at high levels in CA water supplies, and the safety data — on which limits have been based — used a species that’s particularly insensitive to imidacloprid toxicity. This is striking to us, since the original draft regulations banned all three (see page 52).

THC & CBD for Dementia

Posted: May 1, 2019

A pilot study recently demonstrated that cannabis extracts can be safely used to ameliorate symptoms of severe dementia. Swiss researchers at Geneva University Hospitals decided to use cannabinoids to help ten patients with severe dementia. They took a 2:1 extract of CBD and THC, titrating patients up to about 20 mg CBD and 10 mg THC per day. The oil extract was infused into cake to make it more palatable to the seniors, and the dose was split across three meals a day. Two months into treatment, half the seniors had eliminated other drug use, including morphine, benzodiazepines, and antipsychotics. This reduction in pharmaceutical use, along with the direct activity of the cannabinoids, dramatically reduced behavioral problems and the rigidity that accompanies dementia. Patients were monitored for up to five months, and the beneficial effects appeared to persist unabated. Previous research hasn’t always shown beneficial effects of THC in dementia, so why was this group different? Well, other studies tried to use pure THC (in the form of Marinol, for example). Pure THC is not particularly pleasant, and generally patients can only tolerate low doses. But as part of a less refined cannabis extract, a higher dose of THC could be taken without ill effect. The reaction of the patients’ families was “astonishingly positive,” according to the authors. Although this was only a small pilot study, comprising ten individuals, it suggests that cannabis can be used safely and effectively in people with severe dementia.

FAAH Mutation & Pain Insensitivity

Posted: May 1, 2019

There are curious cases of people who feel no pain or have extreme resistance to discomfort. These individuals are often studied by researchers who hope to develop better methods of pain management. One such woman was discovered after she recovered from a highly painful wrist surgery using Tylenol alone. As researchers at the University College of London found out, she had a history of this sort of endurance, and it appeared to have been passed on to her son. With her consent, they ran genetic tests, identifying two mutation in genes related to FAAH. FAAH is the primary enzyme tasked with metabolizing anandamide (an endocannabinoid) and two anti-inflammatory molecules called OEA and PEA. The pain-resistant woman had higher levels of all three of these chemicals in her blood, which the doctors suspected may be responsible for her uncanny comfort in the face of pain. Interestingly, chemical inhibitors of FAAH have not been successful in clinical trials. Limited by tolerance, differences between rat FAAH and human FAAH, and unrelated off-target effects, the drugs designed to ease suffering by blocking FAAH have not worked well enough in humans. So it is surprising that two mutations might have such a powerful effect. This case study may help pharmacologists learn a new way to target FAAH that is more effective for controlling pain and less likely to cause tolerance. But there is a lot left to understand before we get there. One of the two mutations occurred in what is called a pseudogene — a genetic mimic of FAAH that doesn’t function properly. Pseudogene doppelgangers are usually important in regulating their authentic counterparts. Could better medicines be created by targeting the genetic regulation of FAAH, rather than influencing it directly? And what about FAAH-2, a functional copy that exists in humans but not rats? Given the previous failures with pharmaceutical FAAH inhibitors, this research may be slow to develop.

"Why Insurance Should Pay for Medical Cannabis"

Posted: April 29, 2019

As CBD and recreational cannabis have gained considerable momentum, important aspects of medical marijuana are falling by the wayside. The magnified focus on economic incentives and tax revenue has overshadowed the significance of cannabis as medicine. Just as with insulin and other life-saving medications, a hyper-vigilance towards profit leads to price gouging and undermines patients’ access to medicine. To ensure patient access, insurance companies need to cover the medical use of cannabis, as Drs. David Casarett and Donald Abrams recently emphasized in the American Journal of Bioethics. They first highlight that two active components of cannabis (THC and CBD) are approved by the FDA in various formulations and are covered in those cases. There are specific medical indications for which cannabis has good quality evidence: nausea, chronic and neuropathic pain, some seizure disorders, and quality of life in cancer patients. While much remains to be learned in order to optimize cannabis therapeutics, its utility in medicine is not in question. Moreover, a 2014 court ruling in New Mexico demanded that an insurer must cover medical cannabis for employees. So there is a precedent for insurance companies to provide coverage in compliance with state laws. As a matter of fact, insurance companies could be playing a leading role in the integration of cannabis into medicine. The glacially slow movement of both medical education and formal laws means that insurers can have an immediate impact in promoting access to medical cannabis. And as the authors of the article point out, insurers actually benefit from the increased use of cannabis, which is associated with lower use of opioids, benzodiazepines, anti-psychotics, and other pharmaceuticals. This benefits insurance companies directly by reducing their need to pay for other medications. The profit incentive in medical insurance is an enormous issue that could, for example, be relieved by a Single Payer program. But regardless of federal law, insurers can have a positive impact on the health care system immediately by simply covering the medicinal use of cannabis.

Cannabinoid Limits for Driving

Posted: April 28, 2019

In 2017, Michigan’s government founded a commission to recommend policy on cannabis and driving, specifically how to set THC limits. Two years later, in March 2019, they released their conclusion: “[T]he Commission finds there is no scientifically supported threshold of ∆9-THC bodily content that would be indicative of impaired driving” (emphasis added). They instead suggest the use of impairment test, although they recognize that these were designed for recognizing alcohol impairment, which is not the same as THC intoxication. Why can’t a simple breathalizer be used for cannabis, as is done for alcohol? There are two major issues. First, unlike alcohol, cannabinoids aren’t detectable in your breath — either blood or saliva samples are necessary. Second, blood concentration of THC doesn’t indicate the amount of THC in the brain or the user’s intoxication. It is currently unknown how to relate blood levels of THC to intoxication, thanks to factors like tolerance, the build-up of THC in the fat, and the different profiles of edibles, vaping, and sublingual administration. Federal policy is zero-tolerance: it’s illegal to drive with any amount of THC in the blood. But the Michigan Supreme Court ruled in 2013 that the zero-tolerance policy does not apply to cannabis used legally under state law — being “under the influence” is necessary for prosecution. But exactly what constitutes “under-the-influence” with respect to cannabis is still unclear. The Commission indicates that smoking THC-rich cannabis right before driving seems to increase crash risk by 20-35%. Accidents are less likely to be fatal when one of the drivers has THC in his or her bloodstream. Although this risk is relatively small, THC appears to seriously amplify the impairment from alcohol. The crash rate and risk of death among cross-faded drivers is much higher than drunk drivers.

CB2 Reduces Dopamine Release

Posted: April 28, 2019

Cannabinoids play a diverse role in addiction. They confer some of the euphoric feelings of many drugs, but also help eliminate memories that trigger cravings. The also regulate dopamine in a part of the brain called the ventral tegmental area (VTA). Normally, dopamine release in the VTA helps orient animals, including humans, to new kinds of stimuli. But the flood of dopamine feels good and consequently reinforces behavior, which can arouse pathological drug-seeking, gambling, eating, and other addictions. The role of the CB2 receptor as a regulator of dopamine was recently examined by an international collaboration of Chinese and U.S. researchers. Activating CB2 with a synthetic cannabinoid reduced excitatory signals that promote dopamine release in the VTA, but not inhibitory signals. CB2 did not just decrease the signals sent to the VTA; researchers isolated individual neurons and showed that CB2 activation also reduced their intrinsic excitability by opening an ion-channel. These results indicate that chemicals which activate CB2 may have anti-addictive properties – a feature possessed by a number of compounds in cannabis.