Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation Review
Previous research and characterization of cannabinoid receptors (CBs) have consistently demonstrated the therapeutic potential for many medical conditions. CB1, the receptor responsible for the intoxicating (and other psychoactive) effects of cannabis, has demonstrated the ability to modulate concentrations of certain other neurotransmitters, giving it the capability of acting as an antidepressant. Additionally, mice lacking CB1 receptors exhibited increased neurodegeneration, increased susceptibility for autoimmune encephalomyelitis, and inferior recovery to some traumatic nerve injuries. The CB2 receptor is generally attributed to support for modulating the immune system and calming some of the body’s natural, core inflammatory signaling systems. Activation of the receptor has been found to associate with neuroinflammatory conditions in the brain, and in appropriate circumstances, can result in the programming of cell death among some immune cells. This effect points toward a role in communication, inflammation and autoimmune diseases. Furthermore, evidence points to CB2 holding significant potential in HIV therapy. Binding partners of CB2 inhibit the HIV-1 infection and help to diminish HIV replication. Historically, these staggering findings have escaped traditional modern medical understanding. Further investigation into the therapeutic potential of cannabis, with respect to the treatment of inflammation, depression, autoimmune diseases, and HIV is at a minimum, clearly warranted for a more comprehensive understanding of effective medical therapy.
Dr Caplan and the #MDTake:
The main points here no longer seem to be investigational trends, but just pillars of Cannabis Medicine that are embarrassingly new, and poorly recognized by the modern medical establishment. While the bulk of consumers, including patients, may not engage with the science on a molecular basis, by iterative or intuitive science, individuals are diligently discovering what forms of cannabis serve their personal interests more effectively. This is, through a scientific lens, a trial-and-error adventure through products, which have various ratios of cannabinoid-receptor activation or inhibition, that ultimately achieves a similar result, which is a clinical relief for a particular ailment. Does the fact that the process does not begin with a clear understanding of the involved receptors and receptor modulators really matter? If one of the primary objectives of Medicine is to treat and/or ease suffering, and the products are built upon a bedrock of chemical safety (misuse, inappropriate, or misinformed production of products notwithstanding), it should not matter that people discover it by happy accident, or through more direct achievement.
Bacteria: Within facilities that lack appropriate oversight, any bacteria present during the manufacturing of a vaped product can be a source of risk for the consumer.
Fungus: Similarly, fungus can be a normal part of ambient air and life on earth, particularly around plants and soil. If production facilities do not have state-of-the-science monitoring or control mechanisms to limit mold, fungus can accumulate during the manufacturing process and can be transmitted to consumers.
Particles: Nicotine- or cannabis-containing products that are not produced in regulated facilities (home-grown and/or street-sold real or counterfeit products) may contain dangerous solvents, including solutions that contain lipid content that does not belong inside human lungs. Equally concerning, even in states with strict regulatory oversight over cannabis, the regulations may not cover particulate matter which may come into the consumer’s body from the containers that store tested cannabis products. For example, labs across the US have identified particles of vapor cartridge construction materials that become airborne during the heating process of vaporization. There is currently no testing standard for such circumstances. More, the sheer volume of particles emitted by a tool producing vapor is unregulated. With respect to its effects on the lungs, it is likely that there are meaningful differences (and potential risk differences) between a vaporizer which produces a small cloud of particles compared with one that produces a large, dense cloud.
Nicotine/E-liquids: Many nicotine vaporizers contain flavoring, coloring, preservative liquids that can be irritating to the lungs and breathing architecture. Non-nicotine liquid mixers can include sugary substances which promote dangerous growth of bacteria, inside the lungs.
Supervision: Street or home-produced products lack quality control measures to ensure that they are made safely, and/or contain safe ingredients, and are being delivered inside safe devices. In contrast, most FDA-overseen nicotine products and state-overseen cannabis production facilities limit many risk factors for currently-known threats to health
Risks on the Consumer Side of the Market:
Bacteria: Once purchased, products exposed to everyday life can acquire potentially dangerous bacteria after they are produced and sold. When used with poor maintenance practices, or by a consumer with hygiene practices that may add additional risk, bacterial infections can arise.
Fungus: Like bacteria exposure and potential infections, mold/fungus can accumulate after a vaping product is purchased. Good maintenance/cleansing practices help to prevent this risk, and appropriate hygiene around the consumption of vaping products typically minimizes this concern.
Particulate Matter: When using and re-using vaporizer tools (pens, vaporizer ovens, edibles), foreign particulate matter may break-off from cartridges, or may accidentally enter into products that were previously free of these contaminants. Many of the popular vaporizer cartridges, for example, seem to come from three facilities in China and are sold, worldwide, because of the attractive low price-point. Across the US, lab evidence has discovered evidence of small particles of the cartridges themselves (plastics, metals, other materials.) These particles can cause irritation to, or have toxic local effects on, the lungs. These reactions can certainly stimulate an inflammatory response which is sometimes equally uncomfortable as the offending irritation.
Coughing: Vaporizing a product which causes the user to cough excessively can risk the accidental aspiration of bacteria or particles from the mouth. These particles, if small enough, can cause inflammation or infection in the lungs.
Nicotine: In addition to the well-documented increased risk of cancer from the consumption of nicotine, this chemical is an irritant to the tissues with which it interacts, causing arterial wall constriction and thickening. It increases blood pressure and heart rate, promotes increased inflammation and suppresses normal immune system function. More, it also artificially elevates dopamine, norepinephrine, and acetylcholine, with poorly understood consequences that are unlikely to be healthy for the lungs.
Maintenance: Vaporizing old or poorly-kept products may ignore the very real effects of deterioration of materials which may pose health concerns. A product which is not well-maintained or regularly cleaned may contain infectious particles, irritating particles, toxic elements which may also be found in a pocket or storage container (insecticides, animal poisons, other chemicals which may preserve or protect during production or travel)
Between the production and the consumer sides of the vaporization arena, individual differences and outside influences can have a tremendous impact on the experience of vapor. Someone with a history of lung disease may tolerate a very different product than someone without such a history. Similarly, someone with a weakened immune system may have a more difficult time healing from an average exposure (to an irritant or an infectious particle) than someone with different circumstances. These are not likely to explain a large incidence of illnesses, but in addition to the concerns above, they may help explain a smaller portion.
Some of the Medical Illnesses Potentially Associated with Vaping:
Typically this is related to the components of e-cigarettes: nicotine, propylene glycol/glycerol, ethylene glycol, any of >7000 flavorings, metals including tin, lead, nickel, chromium, manganese, and arsenic (have all been found in e-cigarette liquids), also nitrosamines common to tobacco, carbonyl compounds, volatile organic compounds, and phenolic compounds.
General Recommendations for Safer Consumption:
Use state-supervised companies, including dispensaries for cannabis-related vaporizer materials, and reputable nicotine suppliers
Convection vaporizer ovens that involve safe heating materials (ceramic, glass, quartz) are preferable to vaporizer cartridges.
Any means of detaching product from direct contact with a heat source is preferable. For example, stainless-steel containers that hold product, and are then placed into a heating chamber, is likely to be safer than placing product directly against heat.
Article title: Atrioventricular Nodal Reentrant Tachycardia Triggered by Marijuana Use: A case report and review of the literature
The effect of cannabis on the heart is not yet well-understood. This report highlights a case of one 40-year-old patient who had, an hour after smoking cannabis, a specific type of cardiac rhythm abnormality (arrhythmia) called atrioventricular nodal reentrant tachycardia (AVNRT). There is a physical component of this abnormality, an errant track where aberrant rhythms re-enter the heart and can cause rapid heartbeats (tachycardia.) In the discussion, the authors suggest that cannabis use, at higher doses, may stimulate the parasympathetic system, which happens to be involved in electrical current tracks in our heart. The authors further hypothesize that in susceptible people, as in this case, cannabis may affect this electrical pathway in the heart, and may disrupt a stable rhythm.
Dr Caplan and the #MDTake:
Abnormal heart rhythm disorders can be life-concerning conditions, however, there have only been 17 or so reported cases (see Table 1) of life-threatening cases in the medical literature. As it is exceedingly rare, it can be difficult to determine if cannabis is implicated or not.
Including rare, serious heart conditions, relatively benign circumstances, and conditions related to structural heart disease, arrhythmias are a relatively uncommon condition. Nevertheless, CED Clinic has seen many patients who have atrial fibrillation, a smaller but significant number of patients who have stable low or elevated heart rates, and a rare few with irregularly irregular abnormalities. Some patients have embraced cannabis while anticoagulated (helpful to reduce the risks of potentially dangerous clots), and some who are engaging with cannabis have been treated surgically. The approach to cannabis that most seem to prefer is a slow, gradually increasing dosage routine, where one can become accustomed to low doses, prior to advancing to something which may be more therapeutic, while minimizing the potential cardiac impact. Fortunately, to date, we have observed no grave repercussions that seemed caused, correlated or attributable to cannabis.
Article Title: A meta-opinion: cannabinoids delivered to oral mucosa by a spray for systemic absorption are rather ingested into gastro-intestinal tract: the influences of fed/fasting states.
Sativex® spray is made of a 1:1 ratio of THC and CBD. It is marketed for use in the treatment of spasticity in patients with Multiple Sclerosis and is absorbed into the bloodstream through the oral mucosa. This absorption has the benefit of rapid absorption, as it avoids the slow process of digestion which is the typical path of absorption for edibles. This meta-opinion (expert opinion) review argues that Sativex is actually washed down by our saliva and digested through our gastrointestinal tract very much like edibles, and NOT merely absorbed in the mouth via oral mucosa, as the producers suggest. The authors reviewed several research studies which have found that the concentrations of THC and CBD in the body, following administration of Sativex differed if a patient had a meal or not beforehand. This would suggest that Sativex is indeed absorbed in the gastrointestinal tract, rather than merely through the oral mucosa.
How this matters to consumers:
Toward a goal of reproducible dosing and effects, consumers would do well to understand the effects of various methods of absorption. Specifically, it is helpful to know that the effect of Sativex may be delayed if it follows a meal.
Forget CBD; flavonoids found in cannabis have been found to be 30 times more effective painkillers than aspirin, targeting inflammation at the source and making them great alternatives for pain killers. If produced on a larger scale, they could help get away from the opioid crisis.
Title:Preferences for Medical Marijuana over Prescription Medications Among Persons Living with Chronic Conditions: Alternative, Complementary, and Tapering Uses
In a survey of 30 patients using medical cannabis for a range of diseases including rheumatoid arthritis, cancer, hepatitis C, PTSD, among others, patients reported an array of benefits they have reaped from cannabis use. Patients successfully used cannabis in several ways: as an alternative to prescription medication, complementarily with prescription medicine, and to gradually replace use of prescription medication.
Benefits described by participants included the effects of cannabis lasting longer than that of opioids, lower risk of addiction, fewer side-effects. Patients also saw their sleep, anxiety, appetite, and adverse reactions improve with the use of medical cannabis. Larger, more controlled studies may suggest cannabis more affirmatively as an alternative or complementary therapy with prescription medications.
Title: Novel approaches in clinical development of cannabinoid drugs
A pamphlet has recently been published that highlights new approaches in the clinical development of cannabinoid-based therapies. The pamphlet begins with a look into how current cannabinoids affect patients based on gender, stress, physiological variations, and also delves into how cannabis works on the body in general.
A novel therapy that features an oral version of tetrahydrocannabinol (THC) and a synthetic activator of cannabinoid-receptor-1 (CB1) is explored in this piece and frames it to be a promising future therapy. The pharmacological properties of these two novel therapies were optimized during development after various analysis techniques, forming medications that the authors hope to see in future clinical trials.
Although the authors remain hopeful that their cannabis-based therapies will reach clinical trials soon, trials featuring cannabinoids are difficult to test in a formal setting because of a dire lack of funding. The federal government still lists cannabis as a Schedule I substance, under the Controlled Substances Act, meaning that the federal government does not support the idea that cannabis has any medical use. Considering the legal status of cannabis, only privately-funded studies are able to take place, and unfortunately, that leaves cannabis research in an area of complete bias and prohibitively underfunded. Considering the massive literature supporting a myriad of novel therapeutic benefits, this is a costly reality to the health and well-being of millions.
Scientists found that blocking CB1 receptors and CB2-receptors in young zebrafish resulted in morphological deficits, reductions in heart rate, and non-inflated swim bladders. These findings indicate that the endocannabinoid system is pivotal to the development of the locomotor system in zebrafish, and that disturbances to the endocannabinoid system in early life may have detrimental effects.
The translation of these effects to humans is obviously not direct, but it is important for science to learn about safety and expected effects, to examine how chemistry interacts in petri dishes, how basic organic/animal functions are impacted in a living thing, and when the time is appropriate, to then assess any effects in humans