Future Medicine

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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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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Arthritis Sufferers Lead the Way for Advancing Cannabis as Pain Medicine

A Weedmaps News piece, looking earnestly at cannabis and arthritis. As the title suggests, arthritis sufferers are, indeed, leading the way for advancing cannabis as pain medicine.

“We know cannabis is a powerful anti-inflammatory agent that functions differently from other drugs like Tylenol, Ibuprofen, steroids, or the biological options that work on the immune system and can present severe side-effects,” Caplan told Weedmaps News. “We don’t see that w/ cannabis”

“There is still not enough of what modern medicine calls the gold standard- randomized trials or review trials that collect multiple studies – but anecdote is not meaningless,” Caplan said.

“Stories we hear from individuals are very meaningful and worthwhile,” Caplan said. “We live in a scientific culture that thinks we should discount anecdotes and only pay attention to the highest quality data, which I think is misleading and not fair.”

Benjamin Caplan, MDArthritis Sufferers Lead the Way for Advancing Cannabis as Pain Medicine
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Cannabis Use for Medicinal Purposes is No New Phenomenon

Article Title:

Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history

In Summary:

Although medical cannabis has only lately become more popularized, its use dates back to as early as 3,000-10,000 B.C. According to evidence in ancient texts and glyphs, Cannabis sativa was used to treat fatigue, rheumatism, and malaria, as well as numerous other common maladies. Around 60 B.C., Assyrian clay tablets and Egyptian Ebers Papyrus document ancient Egyptian women using C. sativa for pain management and to improve their mood. More recently, nineteenth-century English doctors prescribed cannabis to reduce pain, inflammation, nausea, and seizures, and to soothe difficulties of menstruation. In a shock to the human historical trend, both England and the United States moved to prohibit its use in the 1930s, creating steep barriers for its therapeutic use, and an enduring smokescreen for the memory of its historical continuity.

Dr. Caplan and the #MDTake:

The history of cannabis use is often shocking to modern consumers, who have grown up hearing the biased views of the 20th-century leaders. A testament to the powerful reach of political propaganda, even medical schools adopted the rhetoric of the age, without second-guessing. Fortunately, the march of oral history and social spread of cannabis use perpetuated a very different, much less menacing tale. Now, it is time for the sophistication of modern medicine to catch up and lift cannabis understanding and consumption to modern medical standards.

History of Cannabis YouTube playlist: bit.ly/CEDCannabisHistory

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Benjamin Caplan, MDCannabis Use for Medicinal Purposes is No New Phenomenon
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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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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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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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Info about Traveling & Cannabis

Here is a nice summary of information for US medical cannabis patients with respect to traveling while on a cannabis regimen (what to think about, including plane/trains/automobiles, helpful tips, which states have reciprocity, and/or access to medical cannabis options, etc)

https://www.safeaccessnow.org/travel

Benjamin Caplan, MDInfo about Traveling & Cannabis
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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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