CB2

Cannabinoids Further Demonstrate Therapeutic Potential in Interactions with Adrenaline and Serotonin Systems

Regulation of noradrenergic and serotonergic systems by cannabinoids: relevance to cannabinoid-induced effects

In Summary:

Among many system-wide interactive effects, the noradrenergic and serotonergic hormone/signaling systems are responsible for pain, mood, arousal, wakefulness, learning, anxiety, and feelings of reward. A recent review dives deeper into the interactions between cannabinoids and these two systems: cannabinoids play roles in exciting, inhibiting, and regulating the nerve activity and feedback of both the noradrenergic and serotonergic systems. This data further underscores the therapeutic potential of cannabis for conditions such as depression, chronic pain, and insomnia, all of which are mediated, at least in part, by these systems. Further research may uncover more specific therapies targeted toward the noradrenergic and serotonergic systems and their interactions with cannabinoids.

Dr. Caplan and the #MDTake:

It would be shocking to imagine that, in addition to the usual fruits and vegetables on display at supermarkets, all of a sudden, there was a new category of healthy food. Similarly, the recognition that cannabinoids play a central role in animal physiology is embarrassingly recent. Surveying a sea of illnesses that have become increasingly common, over the last hundred years, before which cannabis was a common household product, also begs the question about a relationship between the circumstances. Might some of the common maladies of modern medicine be attributable to a cannabinoid deficiency syndrome?

A Schematic overview for regulation of NA/LC and 5-HT/DRN cells by the CB1 receptor
Neurochemical Evidence for cannabinoid-induced effects
Electrophysiological evidence for acute effects of cannabinoids on neuronal activity
Neurochemical evidence for cannabinoid-induced effects in the locus coeruleus
Functional evidence fo cannabinoid-induced effects
Electrophysiological evidence for acute effects of cannabinoids

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Benjamin Caplan, MDCannabinoids Further Demonstrate Therapeutic Potential in Interactions with Adrenaline and Serotonin Systems
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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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New Developments of Cannabinoid-Based Drugs

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.


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Benjamin Caplan, MDNew Developments of Cannabinoid-Based Drugs
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The Effect of Chronic Cannabis Use on Volumetric Alterations in Brain Regions

Title: Neuroanatomical alterations in people with high and low cannabis dependence

A recent article has been published revealing some volumetric alterations in specific brain regions in people who report dependence on cannabis. Magnetic resonance imaging revealed that the volume of certain regions, including the hippocampus, the cerebellum, and the caudate, in cannabis dependent users, were all reduced in size, relative to recreational cannabis users who did not use cannabis chronically. Future research will likely focus on the effects of the structural alterations on patients’ reward, stress, and addiction-relevant circuitry to examine the possible relevance of cannabis dependance on those circuits. 

There are certainly possibilities that suggest this volume difference could be of concern, but there are also a great number of explanations (more than likely) whereby this is related to another variable that we have not yet fully appreciated.

Currently, cannabis use is thought to have a little-to-no risk of addiction (beyond any “normal” product of medical value, such as coffee or eyeglasses), because it does not act directly on the reward circuit. Opioids have a high risk of addiction, and therefore a concerning safety profile, in part because of the direct effect of the opioid system on the reward pathway of the central and peripheral nervous systems. While the endocannabinoid system has been observed to act directly up the reward circuit, it does so in subtle, soft ways, making it an ideal adjunct therapy for opioids to help with pain management. Current research provides inconsistent results and appropriately emphasizes a need for more testing to validate the possibility of cannabis as a recommended pain medication. 

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Benjamin Caplan, MDThe Effect of Chronic Cannabis Use on Volumetric Alterations in Brain Regions
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CB1 and CB2 receptors play differential roles in early zebrafish locomotor development

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

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Benjamin Caplan, MDCB1 and CB2 receptors play differential roles in early zebrafish locomotor development
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Video: The Endocannabinoid System

A simplified overview of the human side of the human-cannabis interaction system!

Built from the growing mountain of literature inside the CED Foundation Medical Cannabis Archive

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Benjamin Caplan, MDVideo: The Endocannabinoid System
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Hangovers Resulting from Drinking Negatively Impact Everyday Memory

Alcohol Hangover Has Detrimental Impact Upon Both Executive Function and Prospective Memory

A recent study revealed that alcohol hangovers negatively impact everyday memory, specifically executive function (EF) and prospective memory (PM). EF and PM are cognitive functions that underpin everyday memory; things such as remembering an appointment or where you placed your keys. Participants of the study who suffered from hangovers were able to recall significantly fewer items from memory tasks than their peers. The findings of this study may prove useful when looking into how alcohol and cannabis interact with patients.

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Benjamin Caplan, MDHangovers Resulting from Drinking Negatively Impact Everyday Memory
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Genes in the Endocannabinoid and Opioid Systems may Provide Biomarkers of Obesity

Title: Preclinical and Clinical Evidence for a Distinct Regulation of Mu Opioid and Type 1 Cannabinoid Receptor Genes Expression in Obesity

Researchers have recently found that alterations of the type 1 cannabinoid receptor gene (CNR1) and mu opioid receptor gene (OPRM1)  contribute to the development of obesity. This phenomenon was shown in rat models who were given a high-fat diet and humans currently dealing with obesity. Due to the possibility of the up-regulation of CNR1 and OPRM1 providing a mechanism for developing the obesity phenotype, those two genes could serve as biomarkers for obesity. Fortunately, the up-regulation of CNR1 and OPRM1 is reversible and may also provide a target for combatting obesity and encouraging weight loss in obese individuals. 

Highlighted here are the interactions of the endocannabinoid and opioid systems. Contradictory evidence concerning the interaction of the two systems has come out in recent years making it difficult to come to any conclusions. The endocannabinoid system has been thought to provide a safe and effective method for combatting the opioid crisis. Opioids are highly addictive and dangerous, but they are an efficient way to minimize pain which has kept them in mainstream medicine. Opioids have led to countless overdoses in recent decades causing researchers to search for a more ethical option for pain relief. Cannabis has a much better safety profile, poses no risk of overdose, and offers a welcome change of pace to traditional choices. Conclusive research is still needed to confirm, and reconfirm the details.

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Benjamin Caplan, MDGenes in the Endocannabinoid and Opioid Systems may Provide Biomarkers of Obesity
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Cannabinoids Treat Chronic Gastrointestinal Disorders

Title: Nabilone administration in refractory chronic diarrhea- a case series

A new study reveals the efficacy of treating chronic gastrointestinal disorders with cannabinoids, such as Nabilone. Researchers followed case studies in which patients were given nabilone which greatly reduced symptoms of chronic diarrhea and weight gain, over a period of three months.

The cannabinoid treatment also reduced the abdominal pain felt by patients and improved their overall quality of life. Considering the favorable safety profile of cannabinoids and the effectiveness demonstrated in the patients, cannabinoids were deemed an appropriate and clinically beneficial method for the treatment of chronic gastrointestinal disorders, such as chronic diarrhea. 

Highlighted by this article are the many symptoms cannabis used to treat before the prohibition of cannabis and the scheduling of the medication under the Controlled Substances Act. Cannabis has been used in eastern medicine, for thousands of years, and used to be a prevalent medication in the late 19th and early 20th centuries, and has just recently been re-recognized as an option to treat anorexia associated with human immunodeficiency virus (HIV), nausea and vomiting due to chemotherapy, and various sleep disorders. Cannabis was once a well-recognized medication, but it has been mercilessly slandered by politicians. The rise and fall of cannabis have largely been politically driven pushes, and the plant and its effects deserve further study to examine the scope and efficacy of its therapeutic benefits. 

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Benjamin Caplan, MDCannabinoids Treat Chronic Gastrointestinal Disorders
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A Report on the Psychiatric Effects of Cannabis Demonstrates the Progress and the Gaps in Cannabis Knowledge

Psychiatric effects of cannabis 

A report published by the British Journal of Psychiatry in 2001 demonstrates the progress the medical community has made but also what gaps still need to be filled in when utilizing cannabis. This report found that excess consumption of cannabis leads to feelings of panic and anxiety and that 15% of those willing to respond to a survey experienced acute psychotic symptoms. It was also found that cannabis dependence can occur, as well as withdrawal, which can last for close to a week.  This article was a review that synthesized relevant studies but also claimed that the casual conclusions of these papers were difficult to find or replicate. 

This paper is interesting given its age considering it put out what was current data but then ended by stating the casual conclusions of each paper may not stand. 18 years later, some of the data has stood, and some have not. Users can gain a tolerance to cannabis but many are looking to mitigate it. The author uses the word dependence when discussing cannabis which is a word that holds weight and is up for debate. Intoxicating cannabinoids, like THC, affect the reward center, but non-altering cannabinoids, such as CBD, tend to work more noticeably outside of the brain, although all have mixed effects in both regions. Cannabinoids are not all the same, apply quite differently to various ailments, and have divergent effects. Blanketing an entire crop with a misinformed warning label seems irresponsible and unduly harsh. Users or those looking into cannabis-based medicine are encouraged to do their research. 

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Benjamin Caplan, MDA Report on the Psychiatric Effects of Cannabis Demonstrates the Progress and the Gaps in Cannabis Knowledge
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