Cannabinoids

Many Chronic Pain-Related Cannabis Studies Lack “High-Quality” Evidence

Cannabis-based medicines for chronic neuropathic pain in adults (Review)

In Summary:

In a recent Cochrane meta-analysis of studies investigating the use of medical cannabis for chronic neuropathic pain management, the authors determined that no results were what they could consider “high quality.” All data which related to degrees of pain relief, adverse events, and “Patient Global Impression of Change” were largely of very low or low quality, with some outcomes being of moderate quality. The meta-analysis concluded that no existing evidence backs up the use of cannabis for chronic neuropathic pain; however, the quality of evidence examined highlights the need for more controlled studies.  

Dr. Caplan and the #MDTake:

Depending on the system of organization one prefers, pain can be divided up into different subtypes. For one system, it’s three subtypes: neuropathic, nociceptive, and “other.” For another system, pain can be organized by timing (sharp, acute, chronic, breakthrough), location (bone, soft tissue, nerve, referred, phantom), or by the relative system (emotional, cancer, body.) This review discusses the subtype category of “neuropathic pain” as a means of grouping pain to study. The measures used to assess the pain are as subjective as the categories themselves. Clearly, compounding the two subjective divisions is unlikely to produce “high quality” data, but it is a misleading interpretation to take away that there is no good quality information to glean from the observations this review organizes, and also a misinterpretation to jump to an idea that cannabis is not helpful. Rather, given the statistical tools we currently use, and the subjective systems of understanding pain are not well-matched to translating the effects of cannabis on pain into this type of data.

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Benjamin Caplan, MDMany Chronic Pain-Related Cannabis Studies Lack “High-Quality” Evidence
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Spinal Cord Injury and Severe Traumatic Brain Injury Patients Use Cannabis to Manage Symptoms

Cannabis Use in Individuals with Spinal Cord Injury or Moderate to Severe Traumatic Brain Injury in Colorado

In Summary:

Spinal cord injury patients report that medical cannabis helped them alleviate many symptoms of their injury including spasticity, pain, sleep disruptions, stress, and anxiety. Traumatic brain injury patients list their reason for use as reducing stress/anxiety and improving sleep. Both groups of patients reported recreational use prior to and following injury for a variety of reasons.

Dr. Caplan and the #MDTake:

Healing from traumatic injuries is never solely a matter of local tissue changes. The injured tissues, and the experience of being injured create ripple effects which can disrupt multiple other organ systems, and the entire experience of normalcy. A chemical stress response is one of the most common (and often adaptive) responses to an injury, but the burden of stress, adapting to a new illness, and associated loss of normalcy and sleep can be disastrous to the process of healing. As anxiety and sleeplessness snowball into daily problems themselves, a kernel of injury sometimes amplifies to become a life-altering change.

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Benjamin Caplan, MDSpinal Cord Injury and Severe Traumatic Brain Injury Patients Use Cannabis to Manage Symptoms
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Informing Doctors and Patients on Cannabis Use for Pain

Paper Title: Cannabis and Pain: A Clinical Review

Although results from many bench-scientific and preclinical animal trials support the use of medical cannabis for pain management, there is not yet an equal body of evidence in human clinical trials. However, this is, in part, due to the fact that, despite millennia of accounts supporting the use of cannabis to treat a large number of medical concerns, in the shorter history of cannabis research, the number of controlled, double-blind, placebo studies are limited, and to some points of view, may not even be possible. Additionally, in an era where increasingly more patients request cannabis therapy from their clinicians, health professionals are catastrophically undereducated on the topic. Furthermore, given the status of the modern opioid crisis, there is a growing need for alternative pain management strategies: states with medical marijuana laws experience significantly fewer opioid-related deaths than states lacking them. Additional research could reduce these deaths further and provide viable alternatives for patients seeking pain management when other therapies have failed. 

Below are interesting clippings from this article, points that are either described eloquently or bring a welcome addition to the ongoing discussion:

Benjamin Caplan, MDInforming Doctors and Patients on Cannabis Use for Pain
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Study Finds “Insufficient Evidence” to Support the Use of Medical Cannabis for Pain Management

In Summary:

In a recent review of systematic reviews and controlled studies, researchers were unable to find sufficient evidence to support the clinical use of medical cannabis or the pharmaceutical formulations for gastrointestinal, cancer, or rheumatic pain, or weight loss in cancer of AIDS. Many data from previous studies were either statistically insignificant or were of low quality. However, the authors did find that existing literature sufficiently supported the treatment of neuropathic pain with cannabis. Additional controlled studies may shed more light on the use of cannabis for general pain management. Interestingly, while the authors do raise two important limitations of the studies that they highlight in the article (inadequate size of some studies and generally limited supply of traditional scientific studies from which to draw conclusions) they do not address some of the more fundamental concerns with the reporting.

Dr. Caplan and the #MDTake:

The limitations of studies in cannabis are numerous and an important consideration for researchers as they study cannabis, and equally essentially to consider for those of us reading the study product. To my personal count, there are at least 40 different types of biases that can skew data in a way that delivers information other than a precise description of actual events. This study, as many like it, presumptuously assumes that, if data doesn’t show a trend that so-mocked “anecdotal” data shows, then surely the anecdote must be incorrect. What if the reviews are simply not yet accurately recording what human iteration has discovered repeatedly for millennia?

The conclusion the review draws follows:

Conclusion: The public perception of the efficacy, tolerability, and safety of cannabis-based medicines in pain management and palliative medicine con- flicts with the findings of systematic reviews and prospective observational studies conducted according to the standards of evidence-based medicine.

BUT…

Is the right question for science to question the validity of the stories that individuals are telling, against an imperfect science of information collection, as well as the limited scope of statistical validity for understanding data? Or is the right task for science to question its own methods of assumptions in discovery and understanding?

On the one hand, we have millions of people calling the color of the ocean “blue.” On the other hand, we have data that tells us that water, in fact, has no color. Similarly, the anecdotes from cannabis consumers are telling a story that is starkly different from the currently available data.

For those interested in combing through a close inspection of the many ways that data can be misrepresented and misunderstood, check out https://first10em.com/bias/

and/or watch the video below:

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Benjamin Caplan, MDStudy Finds “Insufficient Evidence” to Support the Use of Medical Cannabis for Pain Management
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Dr Caplan’s response to Surgeon General advisory statement

Last week’s statement by the US Surgeon General

https://www.hhs.gov/surgeongeneral/reports-and-publications/addiction-and-substance-misuse/advisory-on-marijuana-use-and-developing-brain/index.html

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Benjamin Caplan, MDDr Caplan’s response to Surgeon General advisory statement
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Cannabinoid Receptors Play Important Roles in Anti-inflammation, Anti-depression, Immune modulation, and HIV support

Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation Review

Summary Info:

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.

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Benjamin Caplan, MDCannabinoid Receptors Play Important Roles in Anti-inflammation, Anti-depression, Immune modulation, and HIV support
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Hope for Cannabis as a Future Treatment for Tourette’s Syndrome

Single center experience with medical cannabis in Gilles de la Tourette syndrome

A small study on adult Tourette’s patients demonstrated a reduction in tics after treatment with medical cannabis. Treatment with cannabis resulted in a global impression of efficacy score of 3.85 out of 5, signifying an improvement of symptoms. However, many patients reported undesirable effects that resulted in their withdrawal from the trial. Cannabis holds potential for Tourette’s syndrome treatment, however, more work is required to better understand what is causing the positive effects and to flush out reproducible benefits while minimizing the undesirables.

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Benjamin Caplan, MDHope for Cannabis as a Future Treatment for Tourette’s Syndrome
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Vape-Gate 2019: Review of The Risks of vaping

Risks on the Production Side of the Market:

  • 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)

Individual Differences:

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:

1. Pneumonia (bacterial)

2. Aspiration Pneumonia

3. Idiopathic Acute Eosinophilic Pneumonia

4. Hypersensitivity Pneumonitis (extrinsic allergic alveolitis)

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.
  • Safe heating elements: chamber-based convection/conduction heating
  • Avoid direct contact with coils, and avoid combustion
  • Use fresh products from state-sponsored dispensaries or stores
  • Avoid products that are repeatedly reused (including vaporizer pens and vaporizer heating tools that stay full of organic material for more than a brief period of time
  • Prefer systems that include the opportunity to easily clean and replace individual used components
  • Use rubbing alcohol to clean any heating tools regularly

In Infographic form :


Sample Reference News Articles:

All about Vitamin E Acetate:

1.

https://www.nytimes.com/2019/08/31/health/vaping-marijuana-ecigarettes-sickness.html?smid=nytcore-ios-share

2.

3.

https://www.washingtonpost.com/health/2019/09/05/contaminant-found-vaping-products-linked-deadly-lung-illnesses-state-federal-labs-show/

4.

https://www.foxbusiness.com/healthcare/electronic-cigarettes-vapes-scott-gottlieb

5.

https://www.cnbc.com/2019/08/26/fake-juul-pods-fill-shelves-after-vaping-giant-pulled-fruity-flavors.html

6.

https://www.latimes.com/california/story/2019-08-25/knockoff-cannabis-products-headache-for-california-legal-weed

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Benjamin Caplan, MDVape-Gate 2019: Review of The Risks of vaping
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A case of an abnormal heart rhythm. Is cannabis to blame?

Article title: Atrioventricular Nodal Reentrant Tachycardia Triggered by Marijuana Use: A case report and review of the literature

Summary:

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.

Clinical Impressions:

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.

ECG showing AVNRT at the time of presentation.

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Benjamin Caplan, MDA case of an abnormal heart rhythm. Is cannabis to blame?
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Does Cannabis affect blood pressure, heart rate, brain blood flow?

Article title: Acute Cardiovascular Effects of Marijuana Use

The Review:

The authors of this systematic review combed through multiple previously published studies, looking at the short-term cardiovascular effects of THC on the body. The cardiovascular effects they covered included: changes in blood pressure, heart rate, and blood flow to the brain (cerebrovascular circulation).

This review showed that for blood pressure, the results were undecided, as some studied showed a drop in blood pressure, while others did not. For heart rate, the studies showed an increase after consuming marijuana, but quantity and duration were not mentioned. As for blood flow to the brain, only one study showed a potential decrease while the others found no change. The THC percentage of the products used (mainly inhaled ones) ranged from 1.2% to 17.5%.

Dr Caplan and the #MDTake:

This limited review aims to evaluate the effects of THC on blood pressure, heart rate and blood flow to the brain, but it has important limitations. In terms of how the changes were recorded in the studies and the relevant amounts (of what is changing) were not mentioned. For instance, while the study did show that THC may increase heart rate in the short term, it is not clear what the relevance is, what risk this may poses to consumers if any. Past literature has shown that heart muscle can respond to specific cannabinoids, both in the lab and in animals trails. Several case studies have reported individuals with grave reactions, although these concerns have yet to be replicated in a controlled manner, nor correlated with any specific circumstances or components of cannabis. Toward a goal of maximizing safety, caution is likely warranted for those consuming cannabis with known cardiac risk factors (including heart dysfunction, blood pressure concerns, rhythm abnormalities, and others) particularly with regard to the consumption of high THC products.

Clinical Impressions:

Clinically, there is a distinct trend of people who have found heart rate effects with their cannabis use, mostly increased heart rates at the beginning of use (both when first beginning to consume cannabis as well as early on during an episode of consumption.) There seems to be a tolerance to the heart rate effects because many report that this effect wanes over time. There are a clear group of patients for whom cannabis lowers blood pressure, but also groups for who it either has no effect or increases blood pressure. The long-term trend again seems that tolerance plays a role in bringing all extremes to the middle ground. Regarding blood flow, there seems to be a clear increase in local blood flow with topicals and, at least among CED Clinic patients, no observable relationship between cannabis use and blood flow, from a macroscopic perspective.

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Benjamin Caplan, MDDoes Cannabis affect blood pressure, heart rate, brain blood flow?
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