Bob Kaufmann

The Entourage Effect

 

The entourage effect of cannabinoid activity was first described in 1998 when the biological activity of an endogenous cannabinoid (2-Arachidonoyl-glycerol) was increased by related, endogenous non-cannabiols (2-acyl-glycerols), which show no significant activity when used by themselves.1

In understandable English

A compound that can bind to a receptor site is called a ligand.   (A receptor site is a specific place on a receptor protein which is located in the outer membrane of a cell),   When the ligand binds to the receptor, it induces a certain activity to occur inside that cell.  The entourage effect occurs when the reaction inside the cell is changed because some other compound is present around or inside the cell.  

There are several known mechanisms by which the entourage effect occurs including:

  1. The compound binds to a receptor, not on the receptor site, but a different place on the receptor protein called the allosteric site. When it does this, it either increases or decreases the activity induced inside the cell.  Compounds that do this are called positive or negative allosteric ligands, respectively.  Some allosteric ligands bind to the allosteric site but don’t change the activity inside the cell.  These are called neutral allosteric ligands.  They can be significant clinically because they can block the ability of positive or negative allosteric ligands from binding and exerting their effect.2,3  To be an entourage effect and not just an additive effect, the entourage causing compound cannot bind to same receptor site to which the ligand binds. 
  2. The compound can bind to a completely different receptor protein on the surface of the cell and either increases or decreases the activity induced when a ligand binds to the receptor site.  4,5
  3. Some compounds can do both 1 and 2.

It is well established that CBD is an allosteric ligand of the CB1 receptor and modifies the effects of THC when it binds to CB1 in certain cells.3  However, CBD doesn’t do this on all cells, just certain ones.  We do not yet understand this fully.  This is an example of the mystery that still exists in the entourage effect.  However, the entourage effect of cannabinoids is not limited to THC and CBD but many, if not all, the other minor cannabinoids have been shown to have an entourage effect also.6 In addition, terpenes (compounds that cause smell and taste and are abundant in hemp products) have potent entourage effects with cannabinoids.  Even flavonoids (other smaller compounds occurring in hemp) may have some limited entourage effects.

The importance of the entourage effect is illustrated in a study conducted in a mouse model of inflammatory bowel disease (IBD).  In this study, the half the mice were treated with just cannabidiol (CBD) and the other half were treated with a CBD-enriched hemp oil (CBDHO).  The CBD treated mice had improvement in the motility of the bowel after treatment but no improvement in the inflammation of the bowel.  The CBDHO treated mice had the same improvement in motility but they also had complete resolution of the inflammation in the bowel. 7

Bottom line

The entourage effect is very important clinically and the use of CBD-enriched hemp oil that contains both 1) the other minor cannabinoids (usually including low levels of THC) and 2) terpenes is often better than just CBD by itself.8  However, hemp oil is a naturally occurring material and the concentrations of the various cannabinoids and terpenes can vary widely.9  To obtain consistent results using hemp oil, these variations should be minimized.  That’s why it is extremely important for people to obtain their hemp oil from manufacturers that continually test and maintain quality control of the consistency of their product and publish that information. 

 

(On a personal note: This discussion is a prime example of what a wise old medical school professor once said to me, “If you can think it could happen in medicine, it probably does.”)

References:

  1. Ben-Shabat, S, etal. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacology.1998;353(1):23–31
  2. Morales P, etal. Allosteric modulators of the CB1 cannabinoid receptor: a structural update review. Cannabis Canna Res 2016;1(1):22-30.
  3. Straiker A, et al. Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons. Mol Pharmacol.2018 Jul;94(1):743-748
  4. Ho W, etal. Entourage effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br J Pharm 2008;155:837-46.
  5. Petrocellis L, etal. Effect on cancer cell proliferation of palmitoylethanolamide, a fatty acid amide interaction with both the cannabinoid and vanilloid signaling systems. Fundamental & Clin Pharmacology 2002;16:297-302.
  6. Pagano E, et al. An orally active Cannabis extract with high content in cannabidiol attenuates chemically-induced intestinal inflammation and hypermotility in the mouse. Frontiers Pharmacology 2016;7:341.
  7. Ross R. Tuning the endocannbinoid system: allosteric modulators of the CB1 receptor. Br J Pharm 2007;152:565-66.
  8. Russo E. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharm 2011;163:1344-64.

 

 

 

Pain

The Disease

Pain is not a disease but a symptom felt by individuals who are experiencing something uncomfortable, either real or perceived.  The uncomfortableness may be due to a multiplicity of factors including:

  1. Stimulation of nerve fibers in the periphery due to injury, i.e., cuts, incisions, tears, etc. (Nocioceptic Pain)
  2. Damage to nerve fibers in the periphery, spinal cord, or brain. (Neuropathic Pain)
  3. Release of chemicals from inflammation that stimulate nerves as pain (Inflammatory Pain)
  4. The brain’s learned response that certain movements, stimulations, or situations lead to pain so one feels pain before damage is done. (A type of Neuropathic Pain called allodynia)
  5. The feeling of pain in an amputated limb. (A type of Neuropathic Pain called Phantom Pain)
  6. Pain caused from emotional, mental, or behavioral factors, i.e., headache, stomach ache, etc. (Psychogenic Pain)
  7. Pain secondary to cancer and or cancer therapy.
  8. Chronic Pain often involves a combination of several of the above.

 

Pain can be classified many ways and the above list should just be considered an example. In all cases of pain, the concept of perception is foremost.  Therefore, the feeling of pain is not just the stimulation of nerves but the brain’s perception of the stimulation.  This is so important because in stressful situations when someone is physically hurt, pain may not be perceived until the stress of the situation is resolved, i.e., injuries in sports or war.  In non-stressful situations, the amount of injury to produce the feeling of pain is often very similar from one individual to another, however, the perception of the intensity of the pain and the person’s ability to function with the pain can vary greatly.  CBD-enriched hemp oil has been shown to effect many of the physiologic and psychologic changes that occur with different types of pain.  With some types of pain in certain individuals, CBD-enriched hemp oil is adequate to control the pain perception and with other types of pain or individuals, it may only be helpful and require other medications to control the perception.  The following research explanations are generalized descriptions.  For more detailed analysis of the research on any particular time of pain, go to the disease list and find that particular subject, i.e, Pain-Neurologic, or Pain-Inflammatory, etc.

 

Research

Pain is a complex experience produced by a unique combination of nerve cells that integrates the cognitive-evaluative, sensory-discriminative, and motivational-affective components that are located in different sections of the brain.1 Clinically, the sensation of pain can be treated by reducing the sensory input as well as by manipulating affective-motivational and cognitive factors as well as blocking the local causes of the pain.1 If the anterior cingulate cortex (ACC), a specific area of the brain associated with pain processing, is disconnected from the rest of the brain, the patient will still be able to localize the pain, but the pain does not bother the patient.1 CBD has been shown in both animals and in humans (via MRI studies) to effectively do the same thing.1  Other studies have found that CBD works in the brain in a manner similar to that of morphine.2,3 In addition, CBD changes the way our brain reacts to expected pain by changing how we remember painful events and reducing the anxiety associated with learned pain.4,5  This data suggests that CBD is useful in pain management by disassociating the perception of pain from the stimulus of pain.

Disassociation is not the only mechanism by which CBD assists with pain management.  CBD blocks nocioceptive pain in rodents but not so much in humans, however, it does change the perception of nocioceptive pain in humans.6  CBD is anti-inflammatory which, as the inflammatory process lessens, the pain lessens.7-9  Diabetic neuropathic pain is prevented and reversed with CBD, probably due to its effect in preventing the release of inflammation cytokines in the spinal cord.10,11  Cannabinoids have been found to significantly reduce neuropathic pain and help with the pain-related morbidities of sleep and quality of their symptoms.12-14  Cannabinoids have been shown to be helpful adjuvants in patients with chronic pain and with cancer-associated pain, especially in those patients who are not controlled on usual pain medications or are having to increase their pain medications repetitively.15-19 However, when using products with significant amounts of THC, their effectiveness in reducing pain is often outweighed by their adverse side effects.16,20,21 

Bottom Line

Cannabinoids, including CBD, are helpful in some types of pain but not so helpful in others.  The side effects of THC limit the effectiveness in pain control of cannabinoids containing significant amounts of this compound.  Most studies of pain have been performed using cannabinoids with significant amounts of THC.  However, the limited studies of CBD and CBD-enriched hemp oil in pain have yielded encouraging results in both pain perception and the elimination of the stimuli of pain.   However, at this time the FDA has not approved CBD or CBD enriched hemp oil for the management of pain.

 

 

References:

  1. Fuchs P, etal. The anterior cingulate cortex and pain processing. Frontiers Integrative Neuroscience 2014; 8:35.
  2. Laun AS, etal. GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol. Acta Pharmacol Sin. 2018 Jun 25.
  3. Ruiz-Medina J, etal. GPR3 orphan receptor is involved in neuropathic pain after peripheral nerve injury and regulates morphine-induced antinociception. 2011 Jul-Aug;61(1-2):43-50.
  4. Bitencourt R, Takahashi R. Cannabidiol as a therapeutic alternative for post-traumatic stress disorder: From bench research to confirmation in human trials. Frontiers Neuroscience 2018; 12:502
  5. Jurkus R, etal. Cannabidiol regulation of learned fear: Implication for treating anxiety-related disorders. Frontiers Pharm 2016;7:454.
  6. Lötsch J, etal. Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings. Eur J Pain. 2018 Mar;22(3):471-484.
  7. Brunstein S. Cannabidiol (CBD) and its analogs: A review of their effects on inflammation. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.01.059
  8. Xiong W, etal. Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha-3 glycine receptors. Exp. Med. Vol. 209 No. 6 1121-1134
  9. Costa B, etal. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol; 2007; 5:556(1-3):75-83
  10. Toth C, etal. Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. Molecular Pain 2010; 6:16.
  11. Wang D, et al. Activated microglia in the spinal cord underlies diabetic neuropathic pain. Eur J Pharmacol. 2014 Apr 5;728:59-66.
  12. Lynch M, Campbell R. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharm 2011;72(5):735-44.
  13. Meng H, etal. Selective Cannabinoids for Chronic Neuropathic Pain: A Systematic Review and Meta-analysis. Anesth Analg. 2017 Nov;125(5):1638-1652.
  14. Serpell M. et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment Eur J Pain. 2014 Aug;18(7):999-1012
  15. Hoggart B, et al. A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain J Neurol. 2015 Jan;262(1):27-40.
  16. Kazantzis NP, etal. Opioid and cannabinoid synergy in a mouse neuropathic pain model. Br J Pharmacol 2016;173(16):2521-31.
  17. Darkovska-Serafimovska M, etal. Pharmacotherapeutic considerations for use of cannabinoids to relieve pain in patients with malignant diseases. J Pain Res 2018;11:837-47.
  18. Fallon M, etal. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo—controlled phase 3 studies. Br. J Pain 2017;11(3):119-33.
  19. Boychuk DG, etal. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. J Oral Facial Pain Headache 2015;29(1);7-14.
  20. Casey S, Vaughan C. Plant-based cannabinoids for he treatment of chronic neuropathic pain. Medicines 2018;5;67.
  21. Kahan M, etal. Prescribing smoked cannabis for chronic noncancer pain. Can Fam Physician 2014;60:1083-90.

Pain

Pain is not a disease but a perception to a real or perceived noxious stimulus.  Therefore, the management of pain involves 2 concepts:  Our perception to the stimulus and the elimination of the stimulus.  CBD-enriched hemp oil appears to have the potential to affect both.

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Asthma

The Disease

Asthma is a disease of the lungs that consists of 3 clinical aspects: 1) bronchoconstriction, 2) inflammation of the bronchi, and 3) excess mucus production.  The disease is usually characterized by a constant state of hyper-reflexivity of the bronchi to allergic components (allergens—usually pollen and/or animal dander).  When the patient breaths in these allergens, a cascade of events happens.  The allergens bind to allergy cells (mast cells) in the bronchi causes them to release histamine and inflammatory causing agents.  Initially, the patient will experience bronchoconstriction followed by inflammation and resulting swelling, excess mucus production, and a further increase in the sensitivity of the lung to any allergen or breathing problem.  Repeated exposure to the allergens causes the lungs to be in a consistent state of inflammation and, as a result, persistent problems with asthma symptoms.  Medical care of asthma consists of: 1) remedies to reverse the bronchoconstriction (i.e.,  albuterol, etc.), 2) remedies to prevent and/or treat the inflammation (i.e., inhaled steroids, montelukast, etc), and 3) remedies to decrease the allergic response to the allergens (allergy shots, Xolair, etc).  Inhaled steroids are the mainstay for persistent allergy treatment because, as they decrease the inflammation in the lungs, the excess mucus production and airway reactivity decrease and, as a result, the lung’s reaction to allergens decreases, also.

Research Findings

The inflammation of the lungs is caused by the release of inflammatory compounds from the allergy cells in the lung of patients with asthma.  CBD lowers the amount of these inflammatory causing compounds in the lungs in asthma  and raises the level of specific anti-inflammatory causing compounds.  It appears that CBD does not reverse the bronchoconstriction in asthma and should not be used for this purpose.  THC, the compound in marijuana that makes people high, does reverse bronchoconstriction somewhat if it smoked or vaped directly into the lung, however, this can actually cause or worsen an asthma attack in some individuals.  CBD does not worsen asthma and does not have to be smoked or vaped to decrease the inflammation in the lung.  It may be taken orally or under the tongue to have an effect.

Animal Studies

In rodent animal models of asthma, systemic administration of cannabidiol decreases the inflammation of the bronchial tubes and decreases mucus production by lowering 4 different interleukins (IL4, -5, -6, and -13) and TNF-alpha, compounds that are elevated in asthma and cause the inflammation.1,2  In addition, cannabidiol did not lower the levels of IL10 which is protective against bronchial inflammation and helps in decreasing the allergic response.2,3 In a guinea pig model of asthma, pulmonary administration of THC but not cannabidiol was found to reverse the bronchoconstriction associated with asthma.4

Human Studies

Similar the the guinea pig model, pulmonary administration of THC and not CBD was found to produce bronchodilatation in humans.5,6 However, the smoking of TCH or its inhalation using a mist produced bronchoconstriction in some cases.7  Using human bronchial epithelial cells, THC has an anti-inflammatory effect that is mediated through CB2 receptors and the bronchodilation effect is through CB1 receptors.8,9

Bottom line

CBD in animals decreases the inflammation associated with asthma and it may also do this in humans via the CB2 receptor pathway.  THC seems to be a bronchodilator but only if inhaled via smoking or misting, which causes bronchoconstriction in some individuals.   No controlled studies in humans have been performed using hemp oil.  However, at this time, neither CBD nor marijuana is recommended for the treatment of asthma by the FDA.

Bottom line

CBD decreases the inflammation associated with asthma in animals and apparently also in humans.  THC has some ability as a bronchodilator but only if inhaled via smoking or misting, which causes bronchoconstriction in some individuals.   No controlled studies in humans have been performed using hemp oil.  However, at this time, neither CBD nor marijuana is recommended for the treatment of asthma by the FDA.

 

References:

  1. Jan T, et al (2003). Attenuation of the ovalbumin-induced allergic airway response by cannabinoid treatment in A/J mice.  Toxicol Appl Pharmacol. 2003 Apr 1;188(1):24-35.
  2. Vuolo F, et al (2015). Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma.  Mediators of Inflamm.  2015 Vol. 2015: Article ID 538670, 5 pages
  3. Chung F (2001). Anti-inflammatory cytokines in asthma and allergy: interleukin-10, interleukin-12, interferon-gamma. Mediators Inflamm. 2001 Apr; 10(2): 51–59.
  4. Makwana R, et al (2015). The Effect of Phytocannabinoids on Airway Hyper-Responsiveness, Airway Inflamation, and Cough.  Pharm. & Exp. Thera. 2015 Apr; 353:169-180.
  5. Taskin D, et al (1975). Effects of smoked marijuana in experimentally induces asthma.  Am Rev Respir Dis. 1975 Sep;112(3):377-86.
  6. Gong H, et al. (1984). Acute and subacute bronchial effects of oral cannabinoids. Clin Pharmacol Ther. 1984 Jan;35(1):26-32.
  7. Taskin D, et al (1977). Bronchial effects of aerosolized delta 9-tetrahydrocannabinol in healthy and asthmatic subjects.  Am Rev Respir Dis. 1977 Jan;115(1):57-65.
  8. Grassin-Delyle S, et al (2014). Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors.  British Journal of Pharmacology (2014) 171 2767–2777
  9. Shang VC, et al (2016). Δ9-Tetrahydrocannabinol reverses TNFα-induced increase in airway epithelial cell permeability through CB2 Biochem Pharmacol. 2016 Nov 15;120:63-71.

Asthma

Asthma is usually characterized by a constant state of hyper-reflexivity of the bronchi to allergic components causing bronchoconstriction, inflammation of the bronchi, excess mucus production.  CBD decreases the inflammation in the lung produced by asthma which will also decrease mucus production and decrease airway reactivity giving it the potential to help alleviate the symptoms associated with asthma.

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  • Research summary of CBD treatment of Asthma.
  • “Bottom Line” implications and suggestions concerning CBD treatment of Asthma.

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