Marijuana (Cannabis)

Clinical Endocannabinoid Deficiency (CED)

The endocannabinoid system (ECS) is a naturally occurring neuroendocrine communication network that regulates many physiologic functions including gastrointestinal (GI) function, appetite and metabolism, pain, memory, movement, immunity, and inflammation.

When the ECS is poorly regulated these functions become impaired, leading to clinical symptoms that may manifest as Clinical Endocannabinoid Deficiency (CED) syndromes.

To understand CED it is critical to be familiar with the endocannabinoid system (ECS). Before proceeding, please read the section:

Endocannabinoid System (ECS)

 

Links to other Pertinent Educational Pages:

Links to ALL Marijuana Educational Pages

Marijuana (Cannabis) – Fibromyalgia

Cannabinoids:

Cannabinoids

Cannabidiol (CBD)

 

Terpenes:

Terpenes – An Overview

Terpenes: β-Caryophyllene

 

ECS-Related Compounds:

 Curcumin

Palmitoylethanoamide (PEA)

 

Key to Links:

Grey text – handout

Red text – another page on this website

Blue text – Journal publication

 

Clinical Endocannabinoid Deficiency (CED)

 

Function of the Endocannabinoid System (ECS)

The endocannabinoid system (ECS) regulates many physiologic functions ranging from the immune system to the nervous system and it affects sleep, appetite, mood, pain and other functions. The most understood functions of the ECS are related to regulation of the central nervous system (CNS) and immune function in the body. The ECS also plays a critical role in maintaining the skin and its barrier function. For example, dysregulation of the ECS has been implicated in various skin disorders like atopic dermatitis, itch, acne, hair growth/loss, and hyper/hypopigmentation.

 

Many pre-clinical animal and laboratory-based studies have shown that modifying the activity of the ECS affects many medical conditions including: mood, anxiety disorders, movement disorders, neuropathic (nerve) pain, epilepsy, multiple sclerosis, spinal cord injury, cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, insomnia, drug addiction, Alzheimer’s disease, and osteoporosis.  However, there is a lack of good quality human-based research to confirm the specifics of what these pre-clinical studies suggest.  It is been believed that some conditions including migraine headaches, fibromyalgia, and Irritable Bowel Syndrome (IBS) may be the result of an underlying endocannabinoid deficiency (see below), indicating they may be effectively treated with cannabinoid medications.

 

Clinical Endocannabinoid Deficiency (CED)

The ECS maintains an underlying endocannabinoid tone that reflects the levels of anandamide (AEA) and 2- arachidonoylglycerol (2-AG), the centrally acting endocannabinoids. This tone is balanced by their synthesis and breakdown as well as the relative density of cannabinoid receptors in the brain. When endocannabinoid function is decreased in Clinical Endocannabinoid Deficiency (CED), there is a lowered pain threshold along with disruption of digestion, mood, and sleep which are all regulated by the ECS. The CED theory also proposes that such deficiencies can be caused by genetic or congenital factors or they can be acquired due to injury or disease. As a  consequence, characteristic pathological syndromes occur with particular symptoms.

The best evidence for CED is present for migraine, fibromyalgia, and irritable bowel syndrome (IBS).  There are shared pathophysiological characteristics in these three conditions:

 

  • Each of these conditions must be clinically diagnosed based on subjective criteria because they all lack characteristic tissue pathology or objective laboratory findings.
  • Each of these conditions are diagnoses of exclusion that often require extensive negative diagnostic work-ups.
  • Each of these conditions are and often labeled psychosomatic in origin or worse, wastebasket diagnoses, at one time or another by skeptical clinicians
  • Each of these conditions are associated with hyperalgesia (excessive sensitivity to pain).
  • Each of these conditions are generally associated with anxiety and depression.
  • Comorbidity is often present in these three diagnoses. Primary headaches co-occur in up to 97% of fibromyalgia patients; up to 35% of chronic daily headache patients also fit clinical criteria of fibromyalgia; up to 32% of IBS patients also meet many criteria for fibromyalgia, while 32% of fibromyalgia patients also meet many criteria for IBS.
  • While some patients suffer from only one of these syndromes, there is increased lifetime risk for developing another or all three of these conditions.

 

Other disorders that may represent CED

Other disorders possibly related to CED include: neonatal failure to thrive, cystic fibrosis,  causalgia, brachial plexopathy, phantom limb pain, infantile colic, glaucoma, dysmenorrhea, hyperemesis gravidarum, repetitive miscarriages, post-traumatic stress disorder (PTSD), bipolar disorder and possibly many others.

 

Diet and the Endocannabinoid System

From an evolutionary perspective, the co-evolution of diet and human physiology explains how many phytochemicals and foods modulate the endocannabinoid system. Diet is likely a key player in the shaping of certain endocannabinoid genes. The mismatch between a high-calorie Western diet and genes that have adapted over generations of food restriction and hunting has lead to chronic metabolic disorders. Abnormal activation of the ECS with CB1 receptor overstimulation, and subsequent ECS downregulation may be the consequences of excessive consumption of foods rich in refined carbohydrates and fats.

 

On the other hand, a diet emphasizing vegetables and spices, typical of the Mediterranean diet, contains the appropriate amounts of CB2 receptor agonists and cannabimimetic elements necessary to counter CB1-mediated metabolic stress. The Mediterranean diet may restore the dysregulation of the ECS and reduce neuroinflammation, oxidative stress. Preclinical studies have shown that the neuroprotective, immunomodulatory and antioxidant benefits provided by the many cannabimimetic compounds of the Mediterranean diet offers a therapeutic approach to slow down the progression of many neurodegenerative diseases.

See: Mediterranean Diet and Neurodegenerative Diseases – The Neglected Role of Nutrition in the Modulation of the Endocannabinoid System – 2021

 

 

Clinical Endocannabinoid Deficiency (CED) – Treatment

Various approaches for treating CED-related conditions are possible.

See: Getting Started

 

Initial Management

It should be emphasized that the ECS operates as a homeostatic regulator that may require only a gentle pharmacological nudge, rather than a forceful shove by potent agonists. Thus, it is recommended to start treatment gently with curcumin due to its mild agonism of CB1 and with FAAH inhibitors (PEA or CBD) that will raise AEA levels. When using CBD, the use of additional synergistic constituents, including certain minor cannabinoids and terpenes is recommended.

 

If necessary, one may proceed to more potent CB1 agonists (Δ8-THC, Δ9-THC, Marinol, Nabilone). When progressing to a more potent CB1 agonist, low doses should be initiated to stimulate the ECS and yet avoid the development of tolerance. Δ8-THC, which is a less potent CB1 agonist compared to Δ9-THC, might be considered as an initial step in this progression but at this time there is inadequate research regarding its safety and effectiveness to allow for its recommendation.  Since Δ9-THC alone is often poorly tolerated by inexperienced patients, initial management should start with the introduction of a standardized whole cannabis extract that contains CBD and terpenes which offer synergistic benefits and may reduce side effects.

 

Multimodal Approach

Beyond drug interventions, evidence suggests that lifestyle approaches should be integrated into the treatment of CED.  Specifically, low-impact aerobic exercise has demonstrated beneficial effects on endocannabinoid function. Dietary supplementation with probiotics and prebiotics may help not just IBS symptoms but also the entire spectrum of CED conditions. Ultimately, a multimodal approach is most likely to be effective in treatment of CED.

 

Resources:

National Academy of Sciences

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

 

www.Healer.com

This website appears to be good resource for exploring medical marijuana.

 

References:  

 

Endocannabinoid System (ECS) – Basic Science

  1. The Discovery of the Endocannabinoid System – 2012
  2. Endocannabinoid signaling at the periphery – 50 years after THC – 2015
  3. A Personal Retrospective – Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs) – 2016
  4. Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review – 2015
  5. Cannabinoid Receptors – Nomenclature and Pharmacological Principles – 2013
  6. CB1 & CB2 Receptor Pharmacology – 2017
  7. GPR3 and GPR6, novel molecular targets for cannabidiol. – PubMed – NCBI – 2017
  8. The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents. – PubMed – NCBI – 2017
  9. Pharmacokinetics and pharmacodynamics of cannabinoids. – PubMed – NCBI
  10. Clinical Pharmacodynamics of Cannabinoids – 2004
  11. Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two. – 2017
  12. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. – PubMed – NCBI
  13. Pharmacology of Cannabinoids
  14. Cannabinoid receptor 2 – Potential role in immunomodulation and neuroinflammation Review – 2013
  15. Cannabinoid Receptors and the Endocannabinoid System – Signaling and Function in the Central Nervous System – 2018
  16. Crystal Structure of the Human Cannabinoid Receptor CB1 – 2017
  17. The_Endogenous_Cannabinoid_System_A_Budding_Source
  18. Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydrocannabinol and Cannabidiol on Human Cognition – 2017
  19. Evidence for THC versus CBD in cannabinoids – 2018
  20. Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review – 2015
  21. Cannabinoid Receptors – Nomenclature and Pharmacological Principles – 2013
  22. Care and Feeding of the Endocannabinoid System – A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System – 2014
  23. CB1 & CB2 Receptor Pharmacology – 2017
  24. Dissociation between morphine-induced spinal gliosis and analgesic tolerance by ultra-low-dose α2-adrenergic and cannabinoid CB1-receptor antagonists – 2018
  25. GPR3 and GPR6, novel molecular targets for cannabidiol. – PubMed – NCBI – 2017
  26. Role of the endocannabinoid system in diabetes and diabetic complications – 2016
  27. The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents. – PubMed – NCBI – 2017
  28. The Role of Endocannabinoids System in Fatty Liver Disease and Therapeutic Potentials – 2013
  29. Mediterranean Diet and Neurodegenerative Diseases – The Neglected Role of Nutrition in the Modulation of the Endocannabinoid System – 2021

 

 

ECS  – Endocannabinoid Deficiency Syndrome

  1. Clinical Endocannabinoid Deficiency (CECD): Can this Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions?-2004
  2. Endocannabinoids in Chronic Migraine – CSF Findings Suggest a System Failure – 2006
  3. Endocannabinoids in Chronic Migraine – CSF Findings Suggest a System Failure – 2006
  4. Clinical Endocannabinoid Deficiency Reconsidered- Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes – 2016

 

ECS – In Disease

  1. Role of the endocannabinoid system in diabetes and diabetic complications – 2016
  2. Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation – 2016
  3. The Role of Endocannabinoids System in Fatty Liver Disease and Therapeutic Potentials – 2013
  4. The endocannabinoid system in pain and inflammation – Its relevance to rheumatic disease – 2017
  5. The endocannabinoid system in pain and inflammation – Its relevance to rheumatic disease – 2018
  6. Endocannabinoid System: A Multi-Facet Therapeutic Target. – PubMed – NCBI
  7. Enhanced endocannabinoid tone as a potential target of pharmacotherapy. – PubMed – NCBI
  8. Targeting cannabinoid receptor CB2 in car
    diovascular disorders- promises and controversies – 2012
  9. Targeting Cannabinoid Signaling in the Immune System – “High”-ly Exciting Questions, Possibilities, and Challenges – 2017
  10. Care and Feeding of the Endocannabinoid System – A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System – 2014
  11. Targeting cannabinoid receptor CB2 in cardiovascular disorders- promises and controversies – 2012
  12. The Endocannabinoid System and Heart Disease – The Role of Cannabinoid Receptor Type 2 – 2019
  13. Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in gastroparesis – A sex- and subtype-dependent observation – 2021

 

ECS – Pain

  1. Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation – 2016
  2. Dissociation between morphine-induced spinal gliosis and analgesic tolerance by ultra-low-dose α2-adrenergic and cannabinoid CB1-receptor antagonists – 2018
  3. Impact of Efficacy at the m -Opioid Receptor on Antinociceptive Effects of Combinations of m -Opioid Receptor Agonists and Cannabinoid Receptor Agonists – 2015
  4. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain – 2009
  5. The Endocannabinoid System and Pain – 2009
  6. The endocannabinoid system in pain and inflammation – Its relevance to rheumatic disease – 2017
  7. The endocannabinoid system in pain and inflammation – Its relevance to rheumatic disease – 2018
  8. The Endocannabinoid System, Cannabinoids, and Pain – 2013
  9. Cannabinoid receptor 2 – Potential role in immunomodulation and neuroinflammation Review – 2013
  10. Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint
  11. Role of endocannabinoid system in dopamine signalling within the reward circuits affected by chronic pain – PubMed – 2019
  12. High Times for Painful Blues – The Endocannabinoid System in Pain-Depression Comorbidity – 2015
  13. Cannabinoid‐based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain – an updated review – 2021
  14. The endocannabinoid-alcohol crosstalk – recent advances on a bi-faceted target – 2018
  15. Molecular Understanding of the Activation of CB1 and Blockade of TRPV1 Receptors – Implications for Novel Treatment Strategies in Osteoarthritis – 2018
  16. Dual-Acting Compounds Targeting Endocannabinoid and Endovanilloid Systems—A Novel Treatment Option for Chronic Pain Management – 2016
  17. The Role of the Brain’s Endocannabinoid System in Pain and Its Modulation by Stress – 2015

 

ECS – Entourage Effect (Synergy)

  1. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  2. Cannabis and cannabis extracts – greater than the sum of their parts? – 2001
  3. Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Δ9-Tetrahydrocannabinol. – PubMed – NCBI – 2018
  4. Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydrocannabinol and Cannabidiol on Human Cognition – 2017
  5. Evidence for THC versus CBD in cannabinoids – 2018

 

ECS – Palmitoylethanolamide (PEA)

  1. Palmitoylethanolamide Modulates GPR55 Receptor Signaling in the Ventral Hippocampus to Regulate Mesolimbic Dopamine Activity, Social Interaction, and Memory Processing – 2017

  

ECS – Fatty Acid Amide Hydrolase (FAAH)

  1. Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders – 2009
  2. A Personal Retrospective – Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs) – 2016

 

ECS – Related

  1. Cannabis-conclusions – 2017 National Academy of Sciences
  2. Cannabis-chapter-highlights – 2017 National Academy of Sciences
  3. Cannabis-report-highlights – 2017 National Academy of Sciences
  4. Clinical Endocannabinoid Deficiency (CECD): Can this Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions?-2004
  5. Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation? – 2016
  6. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. – PubMed – NCBI
  7. Cannabinoids and Cytochrome P450 Interactions. – PubMed – NCBI Pharmacogenetics of Cannabinoids – 2018
  8. Adverse effects of medical can
    nabinoids – a systematic review – 2008
  9. Cannabimimetic effects modulated by cholinergic compounds. – PubMed – NCBI
  10. Antagonism of marihuana effects by indomethacin in humans. – PubMed – NCBI
  11. Pharmacokinetics and pharmacodynamics of cannabinoids. – PubMed – NCBI
  12. Clinical Pharmacodynamics of Cannabinoids – 2004
  13. Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two. – 2017
  14. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. – PubMed – NCBI
  15. Pharmacology of Cannabinoids
  16. Current-status-and-future-of-cannabis-research-Clin-Researcher-2015

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