Adverse Effects

Pre-clinical Evidence for Analgesic Effects of Cannabis Doesn’t Match Human Trial Results

Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings

In Summary:

Pre-clinical animal models of pain provide a wealth of data supporting the pain-relief capabilities of cannabis; however, reproducing this data in human clinical trials has proved difficult. Data from the animal pre-clinical trials point to cannabinoids reducing stress responses and pain-evoked stress, desensitizing pain receptors, and increased pain sensitivity in animals that lack cannabinoid receptors. However, human trials present conflicting results: several studies have shown dose-dependent relationships, and in the current review this was experienced by many participants, wherein lower and medium doses provided pain relief, but higher doses triggered increased sensitivity to pain. Controlled studies may show a lack of impressive pain relief effects, personal reports of pain relief associated with cannabis use are nearly universal in retrospective reports. This suggests that there may be an important effect on well-being or mood, rather merely sensory pain. Furthermore, the relieving effects of cannabis appear to impact men and women differently.

Dr. Caplan and the #MDTake:

Additionally, much of pain relief is subjective, in both sensation, description, and inside the study environment. The description of pain varies from person to person, and researchers may be asking the wrong questions to the right people or the right questions to the wrong people. In fact, a growing perspective is that this mismatch may be more common and more pronounced than previously recognized. The makeup of pain is also quite complicated. For instance, a limb might hurt, but if there is swelling or tenderness nearby, those may amplify the discomfort. How can we take the full picture into account in the form of helpful data points? What of the emotional or psychological impacts of pain? Is it even possible that such things can be fully understood, let alone measured reliably? Assuming that emotional phenomenon or stress/suffering can be conveyed to research scientists, how can we ever hope to compare one person’s experience to another’s? For example, one would imagine that frustration associated with the pain experienced by a venerable world war veteran, who has previously endured tremendous and complex pains and associated psychological trauma may be quite different from someone who has never experienced a particular pain before.

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Benjamin Caplan, MDPre-clinical Evidence for Analgesic Effects of Cannabis Doesn’t Match Human Trial Results
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Could Inhaled Cannabis Be More Effective to Relieve Pain than Oral Cannabinoids?

Cannabis for Chronic Pain: Challenges and Considerations

In Summary:

Comparisons between the use of inhaled cannabis plant versus pharmaceutical-grade oral cannabinoids demonstrate an advantage of inhalation over oral delivery. Conditions for which inhalation has provided superior over oral consumption include:

HIV, diabetic neuropathy, post-herpetic neuralgia, complex regional pain syndrome, spinal cord injury, traumatic neuropathic pain, multiple sclerosis, and cervical disk disease.

An important note: patients consuming cannabinoids orally are more likely to withdraw from studies due to negative side effects and lack of efficacy. Also, edible cannabis may compete, amplify, or have effects delayed, when interacting with other ingested foods and drinks, A major advantage of inhalation is the opportunity for patients to titrate, or easily test varying dosages at home, with reasonably rapid feedback. On the other hand, dosage adjustments for oral food-borne cannabinoids are much more complex, and cannabis in the form of oral pharmaceutical-products may require a doctor visit and a new prescription.

Dr. Caplan and the #MDTake:

In the clinic, there seems to be a great divide in the population, a group of patients who simply adore the edibles (often in low-dose candies, low-dose chocolate, or titrated tinctures), and a group who use inhalation, almost exclusively. There are also some who are discovering topicals (salves, patches, lotions). There is a growing number of patients who use each of these methods with intention, related to their timing of onset and their duration of action, but this requires education, practice, and a degree of sophistication in use that is relatively new to the industry.

As with most consumption, medicinal or not, it seems common for individuals to find a method that they enjoy and stick to it. Interestingly, in recent years, the US cannabis industry has evolved in a wild growth phase. As it has embraced a dynamic landscape, with increasing competition from all sides, including new stores and product offerings popping up all the time, there seems to be a growing openness, in consumers, to trying new products and exploring new offerings. Coincidentally, this openness to change and the unfamiliar happens to mirror one of the core neurobiological functions of cannabis in the brain, as seen across the neuropsychiatric and neuroimaging cannabis literature.

How exciting to imagine a future medicine that may help consumers to be more open to change?

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Benjamin Caplan, MDCould Inhaled Cannabis Be More Effective to Relieve Pain than Oral Cannabinoids?
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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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Adolescent Cannabis Use Linked to Sleep Disturbances

Sleep Disturbances, Psychosocial Difficulties and Health Risk Behavior

Summary info:

A Dutch study investigated sleep disturbances in adolescents. Sleep disruption was linked to cannabis use, psychosocial difficulties, health risk behavior, and increased suicidality. Additionally, gender disparity in results suggests that girls may be more susceptible to sleep disturbances than boys , a result consistent with past recognition of some gender discrepancies in cannabis activity. These results highlight the importance of discouraging haphazard cannabis use, during adolescence, and the need for further gender-focused research surrounding sleep habits and cannabis use.

Dr Caplan, CED Foundation, and the #MDTake:

There are a few important issues that converge in this review. Generally, the question of adolescents’ use, (as an alternative way of describing the question of effects on a developing brain.) Also, this paper raises valuable questions about how cannabis may be interacting with sleep hygiene, for better or for worse. Psychosocial impact and risky behaviors are very complex topics to engage, even with a fairly large population sample of (n=16,781.) There are lots of intercorrelated topics assessed, analyzed, and discussed in the review, and it is all-too-easy to want to find causal patterns that are not apparent, again for better or worse, unless one chooses to construe the results or interpretation with causation in mind. Realistically, it is very likely to find overlap in a population of adolescents who have psychosocial difficulties, engage in risky behaviors, have increased risk of suicidality, and consume cannabis. To point to one of the components, arbitrarily, as the primary cause of the others is to unnecessarily and unjustly oversimplify a complex set of circumstances. The essential tenet, different genders seem to react differently with cannabis, is an excellent take-away, and also that we have much more still to learn.

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Benjamin Caplan, MDAdolescent Cannabis Use Linked to Sleep Disturbances
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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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Reducing Cannabis Use Equally Effective as Abstinence in Treating Cannabis Use Disorder

Reduction in Cannabis Use and Functional Status in Physical Health, Mental Health, and Cognition

In a survey of 111 cannabis use disorder (CUD) patients with abstinent, low use, or heavy use of cannabis, similar benefits were experienced by patients who reduced their use to zero or low use. Both groups exhibited significantly better outcomes than the heavy use group with respect to overall health, appetite, and depression. According to the study, CUD patients “who used cannabis at a low level did not differ from the abstinent individuals in any of the functional outcome measures.” With a relatively small subject population, it is challenging to know if this is applicable to broader audiences, but regardless, It is likely to open up some new treatment option for CUD patients.

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Benjamin Caplan, MDReducing Cannabis Use Equally Effective as Abstinence in Treating Cannabis Use Disorder
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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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Exciting New Cannabis Compound with Great Therapeutic Potential

Functionalized 6-(Piperidin-1-yl)-8,9-Diphenyl Purines as Peripherally Restricted Inverse Agonists of the CB1 Receptor

Summary information:

A recent study has developed a synthetic compound that can act as an inverse agonist (a reverse activator) of cannabinoid receptor 1 (CB1.) Considering how prevalent these receptors are in the body, this may serve as a useful treatment for a great many concerns that involve this receptor, and/or for altering the effects of other cannabinoid therapies. The developed compounds are orally bioavailable and peripherally selective for CB1, meaning they can be taken by mouth and can still have action in the periphery of the body, as opposed to simply at the brain’s receptors. The selectivity and therapeutic benefits of these novel compounds present a promising development for the potential treatment of metabolic syndrome, diabetes, liver diseases, and gastrointestinal disorders, to name but a few.

Dr Caplan’s Input:

We have CB1 receptors from head-to-toe, through every organ, and just about everywhere in the body. This article highlights a few interesting points. While we have compounds which can activate a target cannabinoid receptor, the action in this review is actually stimulating an opposite impact (activating the opposite action, or an “inverse agonist” effect.) Also, the concept of targeting central (at the brain) vs peripheral (everywhere else) has not been well-addressed yet in Cannabis Medicine. If we can separate the two targets easily, the options for applications of cannabinoid therapies multiplies, as does the opportunity to eliminate undesirable effects.

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Benjamin Caplan, MDExciting New Cannabis Compound with Great Therapeutic Potential
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