Cannabis and Human Immunocompetence

Although I’m not a medical physician, nor do I assert that any of the following information will treat, cure or prevent any disease, I am driven by a wealth of personal experience successfully applying cannabis through two years of immuno-suppressive chemotherapy, as well as four years in the cannabis industry, and six years of higher education and laboratory research in molecular biology and medicinal chemistry. It’s my sincere and humble hope this article may offer critical insight for those seeking to positively influence their health and wellness through holistic, informed self-medication with cannabis.???

Abstract

Despite anecdotal evidence suggesting phytocannabinoids interact with the human immune system, the precise mechanisms of these interactions remain largely unknown. Even so, numerous publications have reported remarkable concentrations of endocannabinoid receptors and related proteins in various immune tissues, thus implicating the system as an integral part of immunological function.

Recent clinical research offers further evidence to support endocannabinoids and related endogenous fatty acid derivatives as potent regulators of immune activity. However, the ultimate effect of these molecules binding to their associated receptors is highly contingent upon the particular type of immune cell being studied. Furthermore, specific combinations of endocannabinoids and fatty acid derivatives are demonstrated to induce distinct downstream effects. Distilling general assertions to their overall impact on human immunocompetence has remained difficult. As asserted in prior comprehensive reviews, the variable and bi-directional nature of endocannabinoids on immune activity suggests they are vital to maintaining immunological homeostasis within the human body.

The nascent field of affective immunology has established compelling links between human behavior, emotional affect, inflammation, and immunocompetence. Monoamine neurotransmitters conventionally implicated in the development of affective mood disorders are also demonstratively essential as regulators of immune activity. This purported cross-talk between the central nervous and immune systems is suggested to be mediated by inflammatory markers, such as cytokines and endogenous fatty acid derivatives, thus implicating these compounds as key players in a network of small molecule messengers responsible for signaling numerous organ systems during a coordinated immune response.

Phytocannabinoids are widely reported to reduce inflammation, emotional stress, pain, and insomnia while improving digestive health and appetite, all of which are direct contributors to human immunocompetence. Recent insight into the ‘entourage effect’ attributes the efficacy of phytocannabinoid therapies to multiple exogenous plant compounds working in concert, suggesting that specific combinations are required to induce particular physiological responses, and that phytocannabinoids and terpenes serve to regulate one another in a manner similar to endocannabinoids and fatty acid derivatives. Given their ability to affect numerous organ systems and factors contingent to homeostatic immune function, phytocannabinoid therapies have immense clinical potential for the treatment of immunological and inflammatory diseases, mood disorders, and beyond.

Introduction

Prevailing medical opinion generally agrees that available information regarding the effect of cannabis on human immunocompetence is insufficient to draw over reaching conclusions. Despite this complexity, numerous immune cells are able to biosynthesize, uptake and degrade endocannabinoids, and are induced to proliferate, migrate, or become apoptotic in response to their presence and/or particular extracellular stimuli. Most notably, endocannabinoid receptor agonists promote growth and proliferation of multiple hematopoietic stem cell lines that give rise to progenitor cells of the human immune system, and therefore may offer alternative treatment options for patients with compromised immunity, such as those undergoing radiation, chemotherapy, allogeneic bone marrow transplants, or diagnosed with severe forms of aplastic anemia. These findings form the basis of credence for investigation of pharmaceutical cannabinoid preparations in the treatment of autoimmune diseases and immunodeficiency syndromes, with specific combinations of phytocannabinoids and terpenes showing immense clinical promise.

The Human Immune System

Prior to exploration of cannabis and immunocompetence, it is first relevant to review the physiological structure of the immune system itself. The immune system is composed of a wide diversity of cells distributed throughout various tissues of the human body that work in concert to assure homeostasis: the state of equilibrium achieved when interdependent physiological processes function in a balanced and stable manner. Killing cancerous tissue, fighting invading pathogens such as bacteria, fungi, or viruses, healing wounds, and clearing cellular waste and debris, represent only a fraction of the responsibilities the immune system undertakes to assure sustained vitality for the human body.1,2

In fact, the immune system is so vital for human health that multiple organ groups are dedicated to the generation, storage, maintenance, and deployment of immune cells. The bone marrow, spleen, liver, intestines, skin, and lungs work in concert with the circulatory and lymphatic systems to form a complex network of vessels, capillaries, and lymph nodes connecting the immune system with the deepest reaches of the human body. This vast network of organs, tissues and cells may be classified into two major branches pursuant to the particular role they play in coordinating and executing an immune response.2,3

Innate Immunity

The first of these two branches is ever-vigilant, always present, and primarily concerned with non-specific defense of mucosal and epithelial tissues found in the skin, lungs, and intestines. The Innate Immune System is embedded into every surface that shares an interface with the outside world, and acts as the first line of defence against foriegn pathogens. Phagocytic cells such as neutrophils, monocytes, macrophages, and dendritic cells work in concert with natural killer cells, mast cells, and a host of other white blood cells, to patrol vulnerable tissues and fight invaders. Once a threat is located, these cells act quickly to engulf and destroy the pathogen in question before sending signals to other cells via messenger proteins, such as cytokines and/or complement system proteins. These signals work in a synergistic manner to induce a coordinated immune response, and send crucial information further downstream for cells, tissues, and organs in the secondary branch of the immune system.2,3

Adaptive Immunity

Known as the Acquired or Adaptive Immune System, the second branch of immunity is responsible for receiving and interpreting information generated by innate immune activity. Specialized cells, referred to as B Lymphocytes, analyze fragments of invading microbes presented by dendritic cells and macrophages, and interpret information from cytokines and complement system proteins. This molecular information from the innate immune system is crucial to mobilizing a targeted, adaptive immune response. Once the particular pathogen is identified, mature B cells within lymph nodes produce customized antibodies: small proteins with the ability to seek out, immobilize, and sequester their target pathogen. Further activation of a variety of T cells allows the adaptive immune system to easily travel throughout the body, locate hostile invaders, bombard their targets with toxins, and finally neutralize the potential threat. Following this initial cascade of adaptive immune activity, information from antibodies is eventually stored within memory B cells to facilitate immune responses and reduce the time required to eliminate future infections of the same pathogen.2,3

The Endocannabinoid System

Interestingly, the endocannabinoid system is in fact far more ancient than humankind itself. With its structure and function largely conserved through eons of animal evolution, this system has long been a critical component of vertebrate life on earth.4?The discovery of endocannabinoids in the early 1990’s sent ripples through the global medical community. Further research revealed endocannabinoid receptors were the most widely distributed receptor class yet to be discovered. The near ubiquitous presence of receptors throughout human tissues implicated the endocannabinoid system as a critical component of multiple cognitive and physiological processes. It was eventually demonstrated endocannabinoids were integral to memory, neurogenesis, appetite, energy balance, metabolism, thermoregulation, homeostasis, sleep, exercise, motivation, analgesia, reproduction, autonomic nervous responses, sympathetic nervous responses, synaptic depression, social behavior, motor function, microcirculation, immunity, and stress responses, to name only a few.5–10

Receptors and Ligands

We now know of two endocannabinoid receptor types, designated CB1 and CB2, with the former located within mammalian nervous, reproductive, and immune tissues, and the latter found in peripheral tissues, but particularly prevalent in the immune system. Both receptors may be activated or inhibited by binding to one or multiple signaling compounds that serve to regulate the spectrum of aforementioned functions of our endocannabinoid system.11?These signaling molecules are primarily endocannabinoids: a large family of fatty compounds, also known as lipids, that transmit information by binding to endocannabinoid receptors.

N-arachidonoyl ethanolamide, more commonly known as anandamide (AEA), was the first endocannabinoid to ever be discovered. A mere three years later, a second endocannabinoid, 2-arachidonoylglycerol (2-AG), was identified in high concentrations in brain tissue and serum.12?It was eventually determined AEA binds to CB1 and CB2 receptors but exhibits a particularly high affinity for CB1 of the brain, while 2-AG has comparable binding affinity for both receptors yet induces a more profound and effective receptor response.7

More recently discovered endocannabinoids include virodhamine,13?noladin ether,14?n-arachidonoyl glycine (NAGly),15?and 2-arachidonoyl lysophosphatidic acid (2A-LPA).16?When considered as a whole, the aforementioned compounds represent a summary of currently known ’core’ endocannabinoids which share a common precursor: arachidonic acid, responsible for the inflammatory "arachidonic acid cascade" response.17,18?Accordingly, ’core’ endocannabinoids share marked structural similarities and demonstrate similar physiological effects.19–21

Unlike monoamine neurotransmitters and other primary messengers, endocannabinoids are neither precedently generated nor stored prior to their release. Rather, all endocannabinoids are locally biosynthesized on demand from lipid precursors inherent to the cytoplasmic membrane of each cell. A diverse family of enzymes are responsible for endocannabinoid biosynthesis and degradation. Although endocannabinoids may be generated by virtually any tissue of the human body, the particular types of enzymes localized in that tissue ultimately determines the physiological effect and subsequent metabolic degradation to which the endocannabinoid is subject.6,9

Non-endocannabinoid Lipid Derivatives

While not strictly considered endocannabinoids themselves, a number of endogenous fatty acid and lipid derivatives are reported to exhibit a range of effects on the endocannabinoid system without directly interacting with endocannabinoid receptors. These derivatives primarily belong to one of two lipid families: acylethanolamides, which includes compounds such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), and lysophospholipids, such as lysophosphatidylinositol (LPI),22?sphingosine-1-phosphate (S1P), lysophosphatidic acid (LPA), sphingosylphosphorylcholine (SPC), and lysophosphatidylcholine (LPC).23–25

The first family of lipids, the acylethanolamide derivatives, have recently been the focus of a plethora of new research due to their promising application as clinical targets. Administration of PEA alone has exhibited analgesic and anti-inflammatory activity, and is currently being investigated as a possible therapeutic agent in the treatment of various types of chronic pain.24,26–29?OEA has also demonstrated potent anti-oxidant and anti-inflammatory properties, and is currently being applied as a neuroprotective supplement in the treatment of alcohol abuse. Further research on OEA suggests the compound is able to alter microbiota composition, thus supporting its use as a digestive supplement for mediation of a variety of intestinal diseases.30–32

Both PEA and OEA potentiate the effect of AEA through a purported ’entourage effect’: a phenomenon asserting particular combinations of medicinal compounds work synergistically to produce a specific clinical effect that may not otherwise be possible via administration of any individual compound alone.33?Despite recent strides in research, the mechanisms of this effect have yet to be fully elucidated and are still subject to much speculation. Notably, other derivatives such as 2-linoleyl glycerol, 2-palmitoyl glycerol, and 2-oleoylglycerol were initially hypothesized to potentiate the activity of 2-AG, but were later proven by a recent publication to act as functional antagonists that diminish the endocannabinoid effect.34–36?Rather than interact directly with endocannabinoid receptors, fatty acid amides bind to G-protein coupled receptors, such as the novel cannabinoid receptors GPR55, GPR18, GPR119, and GPR35.18,31

The second family of lipids, the lysophospholipid derivatives, are also known to regulate a myriad of cellular functions, including proliferation, survival, migration, chemotaxis, cytoskeletal architecture, cell-to-cell contacts and adhesion, Ca2+ homoeostasis, and Ca2+ dependent functions.24?Similar to other fatty acid derivatives, lysophospholipids have no affinity for endocannabinoid receptors, and instead influence the system through related G-protein coupled pathways.23?Lysophospholipid signaling has been implicated in the development and regulation of cardiovascular, immune, and nervous system diseases, as well as inflammation, arteriosclerosis and cancer.24,37–41

When considered as a whole, these two families of lipid derivatives and their associated G-protein coupled receptors form a complex cross-regulatory network of signaling pathways that reaches far beyond endocannabinoids and their receptors alone. "It is now clear that, in addition to the classic CB1 and CB2 receptors, cannabinoid-related agents interact with a spectrum of macromolecular targets, including: other receptors; ion channels; transporters; enzymes and; protein- and non-protein cellular structures. Evidence for cannabinoid modulation of these targets has already been the subject of excellent reviews??(Kreitzer and Stella, 2009; De Petrocellis and Di Marzo, 2010; Pertwee, 2010)."18

Endocannabinoids and the Immune System

Endocannabinoid Receptor Distribution in Immune Cells

Immune cells abundantly express both CB1 and CB2 receptors, but predominantly display CB2 with a prevalence of 10 to 100 times more receptors relative to CB1. Expression of endocannabinoid receptors is common to cells of both the innate and adaptive immune systems, with the degree of receptor expression ranked from highest to lowest by the following list: B cells, natural killer cells, monocytes, polymorphonuclear neutrophils, CD8 lymphocytes (killer T cells), CD4 lymphocytes (helper T cells).

CB1 and CB2 receptor activation is demonstrated to have complex downstream effects on a multitude of signaling pathways involved in immune function. CB2 receptors and endocannabinoids are known to mediate the mitogen activated protein kinase (MAPK) pathway, ultimately inducing a cascade of events that culminates in transcription of DNA from specific genes, and translation of the particular proteins they encode. Immune cells also have specific mechanisms for endocannabinoid transportation and metabolism.42–45?A wealth of biochemical evidence suggests that macrophages and leukocytes engage in intracellular endocannabinoid biosynthesis, uptake, and degradation. When cultured in vitro, basophils and macrophages also exhibit the capacity to biosynthesize both endocannabinoids and their associated fatty acid derivatives.

Endocannabinoids and Immune System Activity

Endocannabinoids are demonstratively responsible for regulating the proliferation and apoptosis of both T and B lymphocytes, modulating macrophage responses, inflammatory cytokine production, as well as immune cell activation and chemotaxis. Other immune cells have been observed to regulate the activity of enzymes generating or metabolizing endocannabinoids in direct response to particular stimuli. Specifically, human peripheral lymphocytes increase intracellular concentrations of AEA, and down regulate associated enzymes for AEA metabolism upon exposure to endotoxins from gram-negative bacteria. Furthermore, macrophages and platelets are demonstrated to contain 2-AG, and markedly increase intracellular levels of the endocannabinoid in direct response to the same endotoxin.43,46

Additionally, endocannabinoids are implicated in the migration and activation of B lymphocytes, dendritic cells, and mast cells. As reviewed in prior sections, dendritic and B cell activity is crucially important to bridge innate and acquired immune activity, and properly mount an effectively coordinated immune response. CB2 receptor stimulation may be associated with B cell proliferation and mobilization during immune responses. However, the mechanism of purported B cell activation is currently unexplored. Endocannabinoids may exhibit a direct effect on B cells, or the mechanism could be mediated by activation of other immune cells, such as macrophages and T cells typically required for B lymphocyte activation.43,46

Activation of CB2 receptors is critical in mediating inflammatory responses, and is demonstratively effective in treatments for inflammatory diseases and injuries of the liver, heart, brain, gastrointestinal tract, and kidneys. Endocannabinoids are also proven to inhibit release of inflammatory cytokines in macrophages, further supporting the rationale for application of endocannabinoids as clinical anti-inflammatory agents. Their effects on T lymphocytes are very similar, with both AEA and PEA inhibiting the production of inflammatory cytokines currently implicated in the development of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and autoimmune hepatitis.46?Furthermore, CB2 agonists are found to reduce cytotoxin production and increase recruitment and proliferation of a variety of immune cells.

Taken together, these findings suggest CB2 selective compounds may reduce inflammation via increased proliferation and recruitment of immune cells in addition to reduction of biochemical inflammation markers such as cytokines.47?Simultaneously, endocannabinoids are found to decrease histamine release and increase levels of beneficial cytokines integral to humoral immunity: immune activity associated with the detection and production of macromolecules such as antibodies, complement system proteins, cytokines, and antimicrobial peptides.43?More recently, endocannabinoids have been implicated in lowering the likelihood of death from COVID-19 infection, purportedly due to their hypotensive and anti-inflammatory properties.48

Most notably, endocannabinoids are found to induce growth and proliferation of hemato-poietic cell lines, the immature stem cells of the bone marrow and lymph nodes that ultimately proliferate and mature into a wide variety of cells of the immune and circulatory systems. AEA is specifically reported to profoundly increase stem cell proliferation across multiple cell lines, thus suggesting that endocannabinoids play a central part in early cell development and immune support.49,50?AEA and 2-AG are also known to inhibit or arrest growth and induce apoptosis (programmed cell death) in cancerous, injured, or malignant tissues. Since these cancerous cells characteristically over-express CB receptors, the effects of cell death are limited to unhealthy tissues and do not otherwise affect healthy cells, further supporting the endocannabinoid system’s role in tumor suppression and possible application during clinical cancer treatment.51

Although findings such as these offer compelling support for the proposed role of endocannabinoids as local immunomodulators, their overall effect on immune activity is difficult to ascertain. For example, CB1 and CB2 receptors negatively regulate adenylyl cyclase activity, and thus inhibit the cAMP/Protein kinaseA (PKA) pathway, suggesting that endocannabinoid receptor stimulation could antagonize the early events of immune cell activation and result in immunosuppression. In fact, AEA demonstrates a profound immunosuppressive effect on human T and B lymphocyte proliferation in a rapid dose-dependent fashion, with upwards of fourty percent inhibition of the in vitro culture observed within four hours following endocannabinoid administration.

Several other in vitro and in vivo studies have reported inhibition of antibody formation following activation of CB1 and CB2 receptors on particular B and T lymphocytes. Cannabinoids are also known to suppress the actions of B cells, T cells and NK cells, as well as macrophages. However, "the net effect is to reduce resistance to infection (for reviews see Cabral and Dove Pettit, 1998; Klein et al., 1998; Porter and Felder, 2001).52–54?This could be a negative consequence of CB2 receptor ligand therapy. Nevertheless, mice deficient in the CB2 receptor appear to be healthy (Buckley et al., 2000),55?which points towards the potential use of specific CB2 receptor ligands as anti-inflammatory agents, especially in diseases such as Alzheimer’s disease and multiple sclerosis, where overactive microglia are believed to promote neuronal damage (reviewed by Neuroinflammation Working Group, 2000).47

Endocannabinoids and Immunocompetence: Summary

Overall, it can confidently be asserted that endocannabinoids exhibit complex regulatory effects on the human immune system, and far more data is needed to form a comprehensive picture of the synergistic action of fatty acid derivatives, endocannabinoids, and their associated enzymes and receptors, on immune activity. Notwithstanding the multitude of further research precluding a complete understanding, available data reasonably supports the hypothesis that endocannabinoid signaling in immune tissue is critical for immune function, and may provide a tonic control of immune cell activation.

Considering its potential to both stimulate and inhibit immune activity, its highly likely the endocannabinoid system plays a key role in the maintenance of homeostatic immune function by limiting spontaneous, overly-robust immune responses, such as those observed in inflammatory and autoimmune diseases.56?The physiological role of the endocannabinoid system and the associated G-protein coupled receptors mediated by non-endocannabinoid lipid derivatives presents a plethora of particularly attractive targets for investigation as therapeutic agents in clinical treatments.

Phytocannabinoids, Terpenes, and Terpenoids

Cannabis and hemp have been revered for their medicinal properties for millenia. Their role in ayurvedic and chinese healing practices has asserted an undeniable anthropological significance and historically proven efficacy. More modern cannabis pioneers have laid the groundwork for our current understanding of phytocannabinoids, the exogenous cannabinoid compounds native to cannabis, hemp, and a limited number of other plant species.57

Besides a vast selection of phytocannabinoids, cannabis and hemp are also rich in volatile oils common to nearly all plant species. Known as terpenes, these fragrant oils are produced by a wide variety of organisms, from conifers and herbs to algae and insects. The near ubiquitous presence of terpenes in nature is eclipsed only by their utility in our daily lives as cosmetics and perfumes, household cleaning supplies, industrial solvents, and numerous botanical medicines. Terpenes are typically branched hydrocarbon molecules often containing polyunsaturated rings, and may be modified by functional groups to form the closely related terpenoids.58

The structure of every terpene, terpenoid, and phytocannabinoid is rooted in the various possible geometric combinations of an individual subunit, known most essentially as isoprene. This subunit is enzymatically cross-linked during biosynthesis within the trichomes of the cannabis plant to form a variety of terpene sub-classes, with each class delineated by the number of subunits inherent to its molecular structure. The vast number of possible geometric combinations of isoprene subunits has given rise to an immense variety of molecules that have played an essential role in the development of our global ecology and the direction of our evolutionary biology.58

Cannabis and hemp are particularly remarkable with regard to the sheer breadth of their terpene and cannabinoid expression. While other plants generally express small subsets of molecules throughout their lifetime, extensive natural and artificial selection of cannabis and hemp has produced a plethora of unique chemical profiles.57Although the chemotype of available cultivars varies considerably, cannabis and hemp may still be classified into several discrete groups based on predominant ratios of major molecular constituents.58–60?Most varieties will contain either tetrahydrocannabinolic acid (THCa), cannabidiolic acid (CBDa), or cannabigerolic acid (CBGa) as their primary cannabinoid, in combination with a terpene profile typically dominated by either limonene, beta-myrcene, terpinolene, or beta-caryophyllene.61

Less common phytocannabinoids, terpenes, and terpenoids are referred to as ’minors’, and include compounds such as cannabinol (CBN), cannabicyclolic acid (CBLa), cannabichromenic acid (CBCa), cannabigiverolic acid (CBGVa), cannabidivarinic acid (CBDVa), tetrahydrocannabiverinolic acid (THCVa), alpha- and beta-pinene, beta-caryophyllene oxide, alpha-bisabolol, geraniol, guaiol, eucalyptol, humulene, linalool, nerolidol, ocimene, and terpinene.

Pharmacological Effects of Phytocannabinoids

Given that phytocannabinoids demonstrate similar affinities for the same primary endocannabinoid receptors, their pharmacological effects may somewhat be inferred from endocannabinoid activity. Indeed, research demonstrates phytocannabinoids exhibit neuroprotective and neuro-regenerative effects in a manner similar to endocannabinoids and associated lipid derivatives,62?and are also found to interact with G-protein coupled receptors.63

In addition, phytocannabinoids are observed to support immune function and in some cases exhibit direct and measurable effects on immune activity. A modest association has been reported between frequent cannabis use and increased total and differential white blood cell counts.64?In addition, exogenous plant cannabinoids have demonstrated anti-cancer activity,18?antibiotic activity,65?and anti-inflammatory activity.66?However, co-administration of opiates and cannabis in addicts is reported to induce T-cell immunosuppression through a purported "disturbance in cytokine balance, in particular, interleukin-17 (IL-17)/interleukin-10 (IL-10) production."67–69

Particular phytocannabinoids, such as d9-Tetrahydrocannabivarin (THCV), and even some terpeniods, such as beta caryophyllene oxide, are purportedly able to influence sugar metabolism, insulin resistance, satiation, and hunger, thus offering new putative therapies for the treatment of diabetes and obesity.70,71?Cannabis has also demonstrated a clinical significant response in placebo controlled studies of patients with Crohn’s Disease.72–74

Possibly their most widely regarded and longest known property, phytocannabinoids are associated with reliable impacts on emotional affect and mental health. In new research released earlier this year, smoked cannabis was investigated for effects on cognitive performance and emotional affect in a study group of ninety one healthy young adults. One hour after administration, friendliness and elation were markedly increased in test subjects, especially those in the high THC subgroup, while fatigue decreased. Overall, cannabis was found to exhibit significant positive effects on mood for up to twenty four hours follow administration, while sustaining little to no cognitive impairment.75?Interestingly, particular phytocannabinoids have demonstrated activity at 5HT serotonin receptor sites implicated in a host of neurological and psychological diseases, and are currently being investigated for their anxiolytic, anti-depressive, focus and mood enhancing effects.76–78

The Entourage Effect

In contrast to current pharmaceutical cannabinoid formulations such as Dronabinol, Marinol, and Epidolex which contain single cannabinoid preparations, plant derived therapies may contain diverse mixtures of hundreds of compounds, including phytocannabinoids, terpenes, terpenoids, and flavinoids. The chemical composition of each cannabis cultivar is highly dependent upon a variety of genotypic and phenotypic factors.58–60,79?However, distinct cannabinoid and terpene profiles often characterize particular cultivars in a relatively stable manner.80?In fact, chemical composition is highly predictive of taxonomic affiliation and geographic origin amongst cannabis cultivars studied.81?This predictability enables specific cultivars to be sought out for their purported chemotypical profiles and associated subjective effects.82

Patients are observed to distinguish between cultivars based on olfactory input alone with precision, and particular aromas are shown to be linked to their perception of potency, effect, quality, and price.82?A recent analysis of over 800 cannabis cultivars explored the relationship between flavor, chemical composition, and subjective effects as reported by cannabis users. The study revealed strong correlations between reported medical benefits, flavor profiles, and chemical composition, suggesting the aforementioned variables are closely related and likely interdependent.83?This phenomenon is broadly attributed to the entourage effect, a phrase coined by Dr. Mechoulam asserting the medicinal efficacy of cannabis and hemp is rooted in the collective action of many molecules working in concert, rather than a single cannabinoid, terpene, endocannabinoid, or fatty acid derivative acting alone.33

Recent strides in research by Dr. David Meiri and his team have substantially narrowed the broad claims previously made by the entourage effect. Starting with an initial subset of cultivars implicated to improve particular patient outcomes, the Meiri group applied refined techniques in deductive reasoning to remove selected terpenes and cannabinoids from phytocannabinoid extracts of subject cultivars until only essential contributors to therapeutic effect remained. Medical physicians in the near future may be able to specify particular cannabinoid and terpene combinations to treat individual maladities with extreme precision and efficacy. In combination with other research efforts, it will not be long before highly targeted formulations of cannabinoids and terpenes are released for the treatment of specific cancers, autoimmune diseases, inflammatory diseases, and beyond.35,36

Affective Immunology

Emerging research in the nascent field of affective immunology seeks to investigate the link between human behavior, emotional responses, and immune function established by a growing body of medical evidence.84,85Pioneers in this field assert the immune system is highly dynamic in its nature and exhibits a plasticity akin to the central nervous system, such that both systems continually receive input from their environment and modulate highly structured responses contingent to perceived stimuli.

The Pathophysiology of Mood

Although transient emotional states do not always directly correlate with immune function, as both ‘negative’ and ‘positive’ feelings can be associated with increased white blood cell counts,86,87?overall mood, personality, and behavior can strongly correlate with particular white blood cell levels of the innate immune system.88?Specifically, basophilic granulocyte and thrombocyte cell counts significantly differed between mood groups studied, with cell counts “highest in the hedonic group and lowest in the anhedonic group,”88?suggesting a direct link between emotional affect and immune activity.

Considerable experimental and clinical evidence has reported patients suffering from mental disorders are more susceptible to immune diseases, and patients suffering from immune diseases have a demonstrated increase in incidence of emotional disorders.85,89–97?Furthermore, depression, anxiety, bipolar affective, obsessive compulsive, and autism spectrum disorder are correlated with increased instance of inflammatory, autoimmune, endocrine, cardiovascular, and metabolic disease.98,99

A large majority of mood disorders are attributed to deficiencies in specific monoamine neurotransmitters or associated receptors.100?Interestingly, particular phytocannabinoids, such as CBG and CBD, have demonstrated activity at 5HT serotonin receptor sites, and are currently being investigated for their anxiolytic and mood enhancing effects.76,77?Additionally, administration of CBD alone was proven moderately helpful in alleviating symptoms of schizophrenia, social anxiety disorder, and comorbidities of ASD, and ADHD.78

Serotonin and Immunomodulation

Many immune cells are also well documented to be directly regulated by the monoamine neurotransmitter serotonin via associated 5-HT receptors located within the immune cellular membrane.98,101–103?Thrombocytes in particular are observed to contain serotonin lodged within their structure but lack tryptophan hydroxylase, the enzyme that would enable the cell to biosynthesize its own serotonin, affirming the monoamine must be derived from an extracellular source.104

The majority of serotonin within the human body is reportedly biosynthesized in the intestines before being taken up by transporters and stored within granules on platelets circulating in the bloodstream.103?Upon activation, these platelet granules release their contents and initiate a cascade of immune activity. The inherent relationship between mood, immune activity, and gut health is further demonstrated by recent clinical evidence that has correlated irritable bowel syndrome with particular personality traits, such as tendency towards anger, depression, anxiety, neuroticism, and hypersensitivity to pain.105

Compellingly, serotonin is also believed to serve a vital role in the purported cross-talk between the brain and immune system.98,106?Recent findings indicate serotonin signaling within the central nervous system can be modulated by pro-inflammatory cytokines released by the immune system, suggesting that release of the monoamine “is an integrated physiological and behavioral response to inflammatory events and pathogens. From this perspective, altered 5-HT/immune conversations are likely to contribute to risk for neurobehavioral disorders historically linked to compromised 5-HT function or ameliorated by 5-HT targeted medications, including depression and anxiety disorders, obsessive-compulsive disorder (OCD), and autism.”98,107

The Gut-Brain Axis

A representative majority of the human immune system is located within the gut, primarily associated with mucousal tissues of the intestinal epithelium. Clinical research has established a strong link between mental health states with positive affect, healthy gut microbiota, and diets rich in tyrosine and tryptophan (precursors to the monoamine neurotransmitters dopamine and serotonin, respectively).32,100,108

Emerging data over the past two decades has revealed the gut is in fact an integral part of a complex communication network between the central nervous, immune, and digestive systems known as the gut-brain axis.109,110?In further support for this proposed axis, probiotics have shown to positively influence emotional affect. Conversely, imbalances or "alterations in gut microbiota composition may be associated with pathogenesis of various neurological disorders, including stress, autism, depression, Parkinson’s disease, and Alzheimer’s disease."111–114

More recently, bioactive lipids were also proposed to assist in cross-talk between the nervous and immune systems.115?Accumulating evidence suggests a bidirectional relationship exists “between the immune and nervous systems, whereby inflammatory mediators [like bioactive lipids or cytokines] can directly modulate emotions that, in turn, can strongly influence immune responses, thus affecting health.”115–117?When considered as a whole, these findings strongly support an intimately interdependent relationship between mental, digestive, neurological, and emotional health, inflammation, and human immunocompetence.

Concluding Remarks

Remarkable concentrations of endocannabinoid receptors, ligands, and related fatty acid derivatives found throughout the human immune, central nervous, and digestive tissues are clear evidence of an intimate and complex multi-directional communication link between the aforementioned (and likely additional unlisted) organ systems, mediated by small-molecule messengers such as lysophospholipids, endocannabinoids, monoamine neurotransmitters, cytokines, and fatty acid amides, a collective phenomenon herein affectionately dubbed the ’Small-Molecule Mediated Multi-Organ Coordination System,’ or by the acronym SMMOCS.

The synergistic action enabled by SMMOCS is demonstratively inherent to human health and homeostasis, and likely serves to network these various systems to form an integrated awareness of virtually the entire organism. This awareness may then subsequently manifest via subconscious behavioral impulses, persistent emotional states, or a variety of psycho-physiological pathologies. It is reasonable to speculate that the subtle perception of various possible combinations of small-molecule messengers enabled by the entourage effect allows for highly refined observation and precise tonic control of physiological state changes across these organ systems.

The interconnected nature of SMMOCS and its inherent relationship to cognitive function, appetite, metabolism, sleep, anxiety, depression, autism spectrum disorder, bipolar disorder, analgesia, neurological disease, various cancers, immunological disease, inflammatory disease, behavior, motor function, digestive function, microcirculation, and emotional affect, offers an incredible diversity of pharmacological opportunities. The development of custom formulated phytocannabinoid preparations made specifically for a wide spectrum of refractory mental and physical health disorders may possibly bring relief to billions of combined patients globally.

It is highly suggestible that diligent efforts in selective breeding of cannabis and hemp, in combination with precise and repeatable methods in extraction, isolation, characterization, and derivation of phytocannabinoids, terpenes, terpenoids, endocannabinoids, and other related small-molecule messengers and receptors, will eventually elucidate the vastly complex and thus far incomplete relationship between SMMOCS and human immunocompetence.

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-ABOUT THE AUTHOR-

Wayne J M Karim is a medicinal chemist and cannabis specialist with training in total chemical synthesis, analytical chemistry, molecular biology, and microbiology. Wayne completed his studies for Bachelor’s of Science in Biology at the University of California Riverside, and his studies for Master’s of Science in Medicinal Chemistry at the University of San Francisco.

Following his employment as Director of Extraction for the world’s first medical cannabis company, Tikun Olam, Wayne founded Cweed LLC where he currently serves as Chief Scientific Officer. Cweed LLC currently provides professional consulting services to the global cannabis and hemp industries, while also supporting numerous cooperative research ventures in the sector to further improve quality, safety and sustainability.?