The interactions between plant cannabinoids and a drug-metabolizing enzyme called carboxylesterase 1 (CES1) was recently published in Drug Metabolism and Distribution. Researchers at the Universities of Michigan and Florida showed that THC, CBD, and cannabinol (CBN) all inhibit CES1. CES1 is important for activating or inactivating drugs that regulate blood pressure, as well as the ADD drug Ritalin. The concentrations at which the cannabinoids inhibit CES1 are large, but the interaction with high-dose CBD could be problematic. Large doses of CBD (hundreds or thousands of miligrams) are sometimes necessary, especially when CBD is used as an isolate. According to this study, THC and CBN are more potent inhibitors of CES1 than CBD, but they are used at much lower doses. Thus it is unlikely that THC or CBN will cause problematic interactions with CES1, though THC could conceivably inhibit CES1 at the peak of a high in heavy cannabis users. THC’s metabolites were also assayed, but they did not strongly affect CES1. Finally, there was some evidence that taking THC or CBN half an hour before the other drugs led to a greater interaction than taking both at the same time, but this didn’t seem to be the case with CBD. (This could be an artifact of the experimental method, or could suggest the mechanism of inhibition.) There’s a significant question that the researchers didn’t answer: What about chronic cannabis consumption? Often times the body adapts to the drugs it encounters; if CBD is inhibiting the CES1 enzyme, the liver may produce more of the enzyme to maintain balance. Currently there is no data to answer this question. The potential for cannabinoid-drug interactions shouldn’t be used to dredge up fears about cannabis, but it highlights another class of drugs that should be monitored when taking large doses of CBD.
Cannabis May Effectively Treat Crohn's
When doctors actively work with cannabis users to optimize medical treatment, patients with conditions like Crohn’s disease may finally find a safe and effective treatment. Medical researchers based in Ohio recently surveyed the prevalence of symptoms of Crohn’s disease in cannabis users and non-users. The rate of problems were 40-70% lower in cannabis users. Two thirds as many cannabis users had active symptoms like abdominal abscesses. And cannabis users were almost three times less likely to require TPN, an intravenous nutrient. According to the medics, «our study suggests that cannabis use may mitigate several of the … complications of Crohn’s disease among hospital inpatients.» One reason this report is so exciting is that the cannabis users were not receiving systematic guidance. The effect size is already large, but the potential for treating Crohn’s with cannabis will improve even more as doctors gain education and are able to assist patients in optimizing their cannabis regimen. It’s noteworthy that this survey didn’t specifically examine CBD, which has shown promise for ameliorating Crohn’s and other autoimmune disorders. A few other limitations should be mentioned. The survey doesn’t assess the cannabis dose, frequency of use, or chemical profile. Crohn’s is more prevalent in women, but only a third of the respondents were female, so the study may overemphasize atypical patients. And finally, association does not prove causation — there could be something common to this group of cannabis users that drives the association other than the herb itself.
Last week we wrote about a study on CBD and cancer. The authors suggested that CBD was fighting cancer cells by blocking a receptor called GPR55. A study published this year in Biomedical Pharmacotherapies presented similar results with a very different interpretation. The article showed that by activating GPR55, chemical analogs of CBD were able to protect insulin-producing cells in the pancreas. The authors see this in terms of its implications for type II diabetes. But the cell line used for the experiment is derived from a cancerous tumor! So this research could also be interpreted to mean that activating GPR55 protects cancer cells from stress. This underscores why preclinical research is only a first step in developing medicines. Dramatically different conclusions can be derived from similar results. That said, one study shouldn’t be seen as “right” or “wrong.” Both papers add to the understanding of how GPR55 regulates human diseases.
CBD in Addiction Treament
The endocannabinoid system is fundamental to addiction, but not in obvious ways. All sorts of cannabinoids appear to have anti-addictive properties: CBD, THCV, Rimonabant, THC. But Rimonabant acts by blocking the CB1 receptor, THC activates it, and CBD primarily functions in other ways. (This paradox is similar to other conditions, like Parkinson’s and obesity.) A review published by Australian researchers sheds light on various facets of addiction, as well as some of the neurological mechanisms by which CBD can limit addictive behaviors. CBD modulates serotonin directly and the endogenous cannabinoid and opioid systems indirectly. This appears to have a significant impact on how drug users recall their experience, diminishing the intensity of cravings and limiting the actual neurological effects of chronic addiction. The researchers review the role of cannabinoids in addiction, then discuss specific studies on various drugs. CBD shows promise in reducing alcohol and tobacco use, while THC appears to more effectively reduce the consumption of opioids. Individuals have reported that THC helps to get off of cocaine, but cannabinoids are less effective in animal models. All animal models of addiction are somewhat suspect, since community plays a huge role in the severity and consequences of addiction. The scientists even discuss the use of CBD to “treat” cannabis addiction, but these studies — a relic of decades of prohibition — rarely involve users who are trying to quit. (Several studies have looked at treating cannabis addiction with CBD, cannabis extracts, and even 240 mg of isolate THC.)
THC and Chronic Kidney Disease
The kidneys are a workhorse of the body, filtering nutrients from toxins. Oily cannabinoids like THC and CBD slip out of the kidneys’ filtration system, but they stop to interact with cannabinoid receptors that regulate kidney function. Researchers in British Columbia review information about cannabis use in patients with chronic kidney disease (CKD). THC appears to help manage pain, and smoking cannabis seems more powerful than taking a tinctures with equal parts CBD and THC. Cannabinoids (particularly CBDA and THCA) ameliorate nausea, but this hasn’t been demonstrated in CKD patients, specifically. And topical endocannabinoids (AEA and PEA) limited severe itching, called uremia-induced pruritus, completely eliminating the uncomfortable feeling in almost 40% of people. Unbalanced cannabinoid tone appears to play a role in chronic kidney disease, with CB1 receptors overactivated and CB2 receptors dificient. (A similar imbalance occurs in obesity and type II diabetes.) Can cannabis actually treat this underlying pathology? THCV is a minor cannabinoid that is present in large concentrations in rare cannabis strains. It gently blocks CB1 while activating CB2, and could be helpful for CKD and other conditions. But the system works in tricky ways — when THCV and CBD combine they may get in each other’s way, limiting the medical benefits. Hopefully doctors will pay attention to the possible role of cannabis in patients with kidney diseases.
Combining CBD with Cancer Treatment
Scientists in at Western New England University in Springfield, Massachusetts, briefly review 10 studies that shed light on how CBD might interact with cancer treatments. Half of these studies examine how CBD can affect the metabolism and distribution of anticancer drugs, a topic Project CBD has been discussing for years. As the authors describe, large doses or regular use of CBD can both increase and decrease the levels of different drug-metabolizing enzymes called CYPs, which will alter the effectiveness of a pharmaceutical. At even higher doses, CBD can also modify the expression of certain proteins produced by cancers to resist chemo. In mice, CBD prevents or reduces neuropathy caused by the chemotherapy paclitaxel. (The condition where even mild stimulus causes pain is called allodynia.) The New England scientists also highlight a few papers in which CBD synergizes with chemotherapy, improving the survival from glioblastoma (a severe brain cancer) and multiple myeloma (a type of bone cancer). These interactions make clear that CBD can influence cancer treatment, but they don’t shed much light on how many people might be helped (or hurt), and how to identify those groups of people. Yet THC is already approved for treating wasting syndrome in cancer patients. Despite the schedule 1 status of cannabis, it behooves the medical community to set up trials that take advantage of the already-existent group of people using cannabis while treating cancer. There are some legitimate concerns and many compelling possibilities.
Cannabinoids in Brain Cancer
Sometimes, science fails to see the tree for the forest. Statistical significance and double-blind trials are important, but so is human experience. Case studies are meaningful. Case studies often portend future discovery. So the case study of two Brazilian brain cancer patients who successfully combined CBD with their cancer treatment should not be dismissed. In their report, Paula Dall’Stella and other doctors in São Paulo describe the typical treatment plan for patients with glioblastoma. Patients who did not respond to the first treatment were given a drug cocktail called PCV along with CBD to reduce nausea. The authors highlight that “it is not possible to cure high-grade glioma patients … the aim of treatment is not only to prolong life, but also to prevent the deterioration of … quality of life.” These patients were still alive at the time the study was published, living longer than the median (15 months) after the diagnosis of glioblastoma. Both were able to play sports without excessive fatigue. These results don’t guarantee that everyone will find benefit from CBD, but it demonstrates that some people benefit significantly.
CB2 in Breast Cancer
Breast cancers are often classified by the receptors they express. The three most common breast cancer receptors respond to estrogen, progesterone, or epidermal growth factor. The latter include HER2-positive breast cancers. Identifying these receptors facilitates treatment. A study led by scientists in Spain indicates that the endocannabinoid system plays an important role in the treatment of HER2-positive cancer. In fact, the cannabinoid receptor CB2 binds to HER2 — forming what is called a dimer — and this dimerization is associated with poor treatment outcome. When THC binds to the CB2 receptor, it breaks up this dimer. The researchers show, step by step, how this can kill the breast cancer cells. First THC binds to CB2, which splits apart the HER2-CB2 complex, as well as other HER2 complexes. This switches the secondary messengers — called G-proteins — that the receptors use to send signals into the cell. The cell starts to cut up its own HER2 receptors with a protein called c-CBL, which has an anti-tumor effect. Receptor dimers are increasingly being considered as targets for treating cancer, pain, schizophrenia, and numerous other conditions.
CBD in Lung Cancer
Doctors in the UK recently reported the case of an elderly man who’s lung cancer responded to CBD. The man — being 81 years old — decided against chemotherapy or radiation, which would worsen his quality of life without much hope for extending it. Four months after a CT scan, the tumor cross section had shrunk to nearly one tenth of its initial size! The doctors — obviously surprised — found out that the patient had begun using a CBD oil 2-3 months earlier. He took 1.32 mg CBD twice a day for a week, then 6 mg CBD twice a day until the CT scan. He eventually stopped taking CBD oil because it caused mild nausea and had a bad taste. Please note: Project CBD does not endorse opting out of conventional treatment for the sake of using cannabinoids. Combining cannabinoids with cancer treatment seems very promising, but to try experimental therapy while refusing established treatments is dangerous.
Orphan Receptors in Cancer
An “orphan receptor” is the term for a receptor in the body whose natural activator is not known. GPR55 is a G-protein coupled orphan receptor that interacts with the other cannabinoid system. CBD appears to inhibit GPR55, while endocannabinoids may activate it. Researchers in the UK and Italy collaborated on a study of GPR55 in pancreatic cancer. Activating GPR55 increased the proliferation and metastasis of cancer cells, while inhibiting GPR55 with CBD or another molecule slowed tumor progression. Mice treated with CBD and the chemo gemcitabine survived nearly three times longer than the mice that didn’t receive CBD. Since CBD affects many different proteins, it’s hard to be sure that GPR55 is the main reason for CBD’s protective activity. The scientists emphasize that CBD and gemcitabine — which are both approved for use in humans — should be tested in clinical trials. Previous research has shown that activating GPR55 stimulates the immune system, opposing the anti-inflammatory immuno-modulating effect of the CB2 cannabinoid receptor.