Cannabis Science

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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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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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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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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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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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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