Research: Cannabis Entourage Effect 4.0

Liquid Life Research: Cannabis CBD THC Terpenes and the Entourage Effect

Introductions and image by @SuperFunker.

1) Russo (2016) reviewed research with a focus on addressing Clinical Endocannabinoid Deficiency through Cannabis therapy. He explained the importance of a well functioning Endocannabinoid System and the potential of Cannabis to restart/balance associated functionality. Russo identified numerous treatment-resistant ailments that may respond to Cannabis-based medicines: migraine, fibromyalgia, irritable bowel syndrome, Huntington’s disease, Parkinson’s disease, post-traumatic stress disorder and depression. Although isolated cannabinoids have been found to provide some relief, these pure extracts demonstrate limited utility. Instead, Russo indicated that a whole-plant therapeutic protocol and the associated Entourage Effect is a superior therapeutic strategy.

Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes.

Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.

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2) Again, Russo (2018) conducted a broad review of Cannabis research and diseases that may be ameliorated with Cannabis medicines. The primary focus of this paper is neurological conditions, specifically:

  • Intractable epilepsy
  • Brain tumors
  • Parkinson’s disease
  • Alzheimer’s disease
  • Traumatic brain injury
  • Chronic traumatic encephalopathy

Additionally, Russo provided an updated list of other brain-related ailments that have been treated with Cannabis:

  • Multiple sclerosis
  • Epilepsy
  • Chronic pain
  • Schizophrenia
  • Sleep disturbance, glaucoma
  • Tourette’s syndrome
  • Dementia
  • Post-traumatic stress disorder
  • Social anxiety

He then provided a specific list of Alzheimer’s symptoms that have been mitigated with Cannabis:

  • Agitation
  • Anxiety
  • Psychosis
  • Insomnia
  • Anorexia
  • Aggression
  • Depression
  • Pain
  • Memory loss
  • Neurodegeneration
  • Aβ plaque formation

A common theme: superior medical outcomes are typically observed as a result of the Entourage Effect which is induced by broad-spectrum Cannabis extracts.

Cannabis Therapeutics and the Future of Neurology.

Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.

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3) In this manuscript, Russo (2019) describes medical possibilities of Cannabis and the associated complexity of its phytochemical makeup, suggesting that Cannabis strains be referred to as chemical varieties (chemovars). Ultimately, Russo leads you to the general conclusion that full-spectrum formulas induce an Entourage Effect that results in greater potency/effectiveness, a broader dosage range and fewer side-effects. In contrast, isolates have limited utility. Russo encourages further exploration of Cannabis synergy and suggests selective breeding. However, he resists clinical attempts to “reinvent the phytocannabinoid wheel.” Instead, Russo opts for a more natural expression of genetics, because “The plant does it better.”

The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain,” No Gain.

The topic of Cannabis curries controversy in every sphere of influence, whether politics, pharmacology, applied therapeutics or even botanical taxonomy. Debate as to the speciation of Cannabis, or a lack thereof, has swirled for more than 250 years. Because all Cannabis types are eminently capable of cross-breeding to produce fertile progeny, it is unlikely that any clear winner will emerge between the “lumpers” vs. “splitters” in this taxonomical debate. This is compounded by the profusion of Cannabis varieties available through the black market and even the developing legal market. While labeled “strains” in common parlance, this term is acceptable with respect to bacteria and viruses, but not among Plantae. Given that such factors as plant height and leaflet width do not distinguish one Cannabis plant from another and similar difficulties in defining terms in Cannabis, the only reasonable solution is to characterize them by their biochemical/pharmacological characteristics. Thus, it is best to refer to Cannabis types as chemical varieties, or “chemovars.” The current wave of excitement in Cannabis commerce has translated into a flurry of research on alternative sources, particularly yeasts, and complex systems for laboratory production have emerged, but these presuppose that single compounds are a desirable goal. Rather, the case for Cannabis synergy via the “entourage effect” is currently sufficiently strong as to suggest that one molecule is unlikely to match the therapeutic and even industrial potential of Cannabis itself as a phytochemical factory. The astounding plasticity of the Cannabis genome additionally obviates the need for genetic modification techniques.

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