conflicts of interest in making this presentation. ✗ The research referenced in this talk is largely pre- clinical. ✗ This talk is NOT about marijuana. ✗ Cannabis is a Schedule I Drug on the Federal level and is illegal for chiropractors to recommend it and for physicians to prescribe it. Check your State and Local Statutes.
(2021). A critical review of the definition of ‘wellbeing’ for doctors and their patients in a post Covid-19 era. The International Journal of Social Psychiatry, 67(8), 984–991. https://doi.org/10.1177/00207640211032259 The Overarching Theme
Wellbeing The endocannabinoid system (ECS) is a complex network of receptors, signaling molecules (endocannabinoids), and enzymes found throughout the body. Nazarenus, C. (2020). Medical Cannabis Handbook: For Healthcare Professionals.Springer Publishing Company. ✗ It plays a crucial role in maintaining homeostasis, or balance, in various physiological and cognitive processes.
refers to interventions aimed Harm reduction refers to interventions aimed at reducing the negative effects of health at reducing the negative effects of health behaviors without necessarily extinguishing behaviors without necessarily extinguishing the problematic health behaviors completely the problematic health behaviors completely or permanently. or permanently. Hawk, M., Coulter, R. W. S., Egan, J. E., Fisk, S., Reuel Friedman, M., Tula, M., & Kinsky, S. (2017). Harm reduction principles for Hawk, M., Coulter, R. W. S., Egan, J. E., Fisk, S., Reuel Friedman, M., Tula, M., & Kinsky, S. (2017). Harm reduction principles for healthcare settings. Harm Reduction Journal, 14, 70. https://doi.org/10.1186/s12954-017-0196-4 healthcare settings. Harm Reduction Journal, 14, 70. https://doi.org/10.1186/s12954-017-0196-4
System In the 1960s, research by Dr. Raphael Mechoulam at the Hebrew University of Jerusalem led to the isolation of THC, the psychoactive compound in cannabis. Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✗ This discovery sparked further investigations into the body's response to cannabis, ultimately leading to the identification of the endocannabinoid system.
on Drugs" President Richard Nixon declared drug abuse "public enemy number one" in 1971. Berman, D., & Kreit, A. (2020). Marijuana Law and Policy. Carolina Academic Press. ✘ The Controlled Substances Act (CSA) was enacted in 1970, establishing a federal classification system for controlled substances. ✗ Cannabis was placed in Schedule I, the most restrictive category, alongside drugs with a high potential for abuse and no currently accepted medical use.
for Abuse: These drugs have a high likelihood of leading to dependence and addiction, both psychological and physical. ✗ No Currently Accepted Medical Use in Treatment in the United States: This doesn't necessarily mean they have no potential therapeutic benefits, but it signifies a lack of rigorous scientific evidence supporting their medical efficacy and safety. ✗ Lack of Accepted Safety for Use Under Medical Supervision: Even under controlled medical settings, Schedule I drugs are deemed to have a high potential for misuse and pose a significant risk to patients.
the late 1980s, researchers discovered anandamide, the first endocannabinoid identified in the human body. Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✘ Anandamide, meaning "bliss" in Sanskrit, plays a crucial role in regulating mood, pain perception, memory, and appetite. ✗ Its discovery confirmed the existence of an internal cannabis-like system, prompting further exploration of the endocannabinoid system or ECS.
Bill Distinction The 2018 Farm Bill federally legalized hemp, defined as cannabis plants containing less than 0.3% delta-9 THC on a dry weight basis. Berman, D., & Kreit, A. (2020). Marijuana Law and Policy. Carolina Academic Press. ✗ Hemp cultivation and production of derived products like CBD oil became legal under federal law, with individual states potentially imposing stricter regulations. ✗ This distinction between hemp and marijuana (cannabis with higher THC content) is crucial for understanding the legal landscape surrounding cannabis products.
CBN ✗ THC (Tetrahydrocannabinol): The psychoactive compound responsible for the "high" associated with cannabis use. ✗ CBD (Cannabidiol): A non-psychoactive compound with potential therapeutic benefits for a variety of conditions. ✗ CBG (Cannabigerol): The precursor molecule from which other cannabinoids are synthesized. ✗ CBN (Cannabinol): A non-psychoactive compound formed from the degradation of THC, with potential sleep-inducing properties.
The two main types of cannabinoid receptors are: Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✗ CB1 receptors: Primarily found in the central nervous system (CNS) and involved in functions like memory, mood, pain perception, and movement. ✗ CB2 receptors: Primarily found in the peripheral nervous system and immune system, playing a role in inflammation and immune response.
Primarily found on presynaptic neurons in the CNS. Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✗ Structure: G protein-coupled receptors (GPCRs) with seven transmembrane domains. ✗ Secondary Messengers: Activation leads to the inhibition of adenylyl cyclase. ✗ Ionic Gating: CB1 receptor activation generally leads to a decrease in neuronal firing.
Location: Primarily found on immune cells and tissues throughout the body. Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✗ Structure: Similar to CB1 receptors, CB2 receptors are also GPCRs with seven transmembrane domains. ✗ Secondary Messengers: The specific secondary messenger pathways activated by CB2 receptor stimulation can lead to the production of IP3 and DAG which modulate gene expression.
Inflammation When stimulated by endocannabinoids or certain cannabis- derived cannabinoids, CB2 receptors can trigger a cascade of anti-inflammatory effects such as: ✗ NF-kB: A protein complex that promotes inflammation. ✗ Cytokines: Signaling molecules involved in the immune response. ✗ Prostaglandins: Lipid molecules that contribute to pain and inflammation. ✗ Leukotrienes: Lipid molecules involved in allergic reactions and inflammation. ✗ Interleukins: Signaling molecules crucial for immune cell communication and inflammation.
as the "bliss molecule," is the most abundant endocannabinoid produced by the human body. Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✗ It plays a role in regulating mood, pain perception, memory, sleep, and appetite. ✗ Anandamide binds to both CB1 and CB2 receptors, exerting its effects throughout the body.
Anandamide is synthesized "on-demand" within cells, primarily in neurons and immune cells. Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✗ Its precursors are phospholipid molecules embedded in the cell membrane, which contain arachidonic acid.
The synthesis of anandamide involves a two-step enzymatic process: ✗ Step 1: Phospholipase enzyme breaks down a phospholipid molecule, releasing arachidonic acid. ✗ Step 2: N-arachidonoyl phosphatidylethanolamine (NAPE) through hydrolysis by phospholipase D (PLD) forms anandamide.
and prednisone bind to glucocorticoid receptors within the phospholipid bilayer of cells. ✗ This inhibits the phospholipase enzymes that release arachidonic acid thus limiting the endogenous production of anandamide. ✗ The action of corticosteroids may quell inflammation while altering our sense of well-being.
Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✗ By binding to cannabinoid receptors, primarily CB1 receptors located on the presynaptic neuron, endocannabinoids inhibit further neurotransmitter release. ✗ This feedback mechanism helps regulate neuronal activity and prevents excessive stimulation.
by the body. Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✗ It primarily targets CB1 receptors, influencing functions like pain perception, appetite, and memory. ✗ 2-AG is broken down more quickly than anandamide, leading to shorter-lasting effects.
produced in neurons, 2-AG is synthesized in a wider range of cell types, including: Clark, C. S. (2021). Cannabis: A handbook for nurses. Wolters Kluwer. ✗ Neurons ✗ Immune cells ✗ Glial cells ✗ Adipose cells
Bassir Nia, et. al. Bassir Nia, et. al. (2019) (2019) review the impact of trauma review the impact of trauma on the endocannabinoid system’s ligands and on the endocannabinoid system’s ligands and receptors. receptors. Bassir Nia, A., Bender, R., & Harpaz-Rotem, I. (2019). Endocannabinoid System Alterations in Posttraumatic Stress Disorder: Bassir Nia, A., Bender, R., & Harpaz-Rotem, I. (2019). Endocannabinoid System Alterations in Posttraumatic Stress Disorder: A Review of Developmental and Accumulative Effects of Trauma. Chronic Stress, 3, 2470547019864096. https://doi.org/10.1177/2470547019864096 A Review of Developmental and Accumulative Effects of Trauma. Chronic Stress, 3, 2470547019864096. https://doi.org/10.1177/2470547019864096 – Childhood trauma results in a reduction in BOTH Childhood trauma results in a reduction in BOTH eCB ligand production and CBr expression. eCB ligand production and CBr expression. – Adult trauma results in decreased levels of eCB Adult trauma results in decreased levels of eCB ligands and increased expression of CBrs. ligands and increased expression of CBrs.
✗ FABP (Fatty acid binding protein): Transports endocannabinoids within the cell for degradation. ✗ FAAH (Fatty acid amide hydrolase): The primary enzyme responsible for breaking down anandamide. ✗ MAGL (Monoacylglycerol lipase): The enzyme responsible for breaking down 2-AG. Onaivi, E., Sugiura, T., & Marzo, V. (Eds.). (2006). Endocannabinoids: The Brain and Body’s Marijuana and Beyond. CRC Press.
Kaczocha, M., Sun, J., Balius, T. E., Rizzo, R. C., Haj-Dahmane, S., Ojima, I., & Deutsch, D. G. (2012). Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs. PLOS ONE, 7(12), e50968. https://doi.org/10.1371/journal.pone.0050968
& FAAH Acute stress triggers an increase FAAH- Acute stress triggers an increase FAAH- mediated hydrolysis of AEA especially seen mediated hydrolysis of AEA especially seen in the basolateral amygdala in the basolateral amygdala (BLA) (BLA) thus thus magnifying fear and pain responses magnifying fear and pain responses Paulus, M. P., Stein, M. B., Simmons, A. N., Risbrough, V. B., Halter, R., & Chaplan, S. R. (2021). The effects of FAAH inhibition on the Paulus, M. P., Stein, M. B., Simmons, A. N., Risbrough, V. B., Halter, R., & Chaplan, S. R. (2021). The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: A randomized clinical trial. Neuropsychopharmacology, 46(5), neural basis of anxiety-related processing in healthy male subjects: A randomized clinical trial. Neuropsychopharmacology, 46(5), 1011–1019. https://doi.org/10.1038/s41386-020-00936-w 1011–1019. https://doi.org/10.1038/s41386-020-00936-w
(CBD) is a naturally occurring compound found in the cannabis plant. Unlike its psychoactive cousin tetrahydrocannabinoid (THC), CBD does not produce an intoxicating effect.
a class of compounds called phytocannabinoids, derived from the cannabis plant. ✗ Its structure is similar to THC, but with a slight variation in the arrangement of a few atoms. ✗ This subtle difference translates to significantly different effects on the body.
with Receptors Unlike THC, which directly activates CB1 receptors, CBD may act as an allosteric modulator. ✗ This means CBD may indirectly influence CB1 and CB2 receptor activity by changing their response to natural endocannabinoids like anandamide and 2- AG.
TRPV-1 ✗ FABP (Fatty Acid Binding Protein): CBD may interact with FABPs, which transport fatty acid molecules within cells. This interaction could influence cellular processes like inflammation and metabolism. ✗ PPARs (Peroxisome Proliferator-Activated Receptors): CBD may activate PPARs, which are nuclear receptors involved in gene regulation. This could influence various cellular functions, including energy metabolism and inflammation. ✗ TRPV-1 Receptors: CBD may have modulatory effects on TRPV-1 receptors, which are involved in pain perception and temperature regulation.
Enzymes in the liver, particularly cytochrome P450 enzymes, break down CBD into various metabolites. ✗ The rate of CBD metabolism can be influenced by factors like genetics, medications, foods, and overall health.
A Word of Caution A Word of Caution Enzymes in the liver, particularly cytochrome P450 enzymes, break down CBD into various metabolites. ✗ CBD's interaction with the liver's metabolism system raises potential concerns about drug interactions. ✗ CBD may induce or inhibit the activity of certain enzymes involved in metabolizing medications. ✗ This could lead to altered drug levels in the bloodstream, potentially increasing or decreasing their intended effects, or even causing side effects.
Medications like Warfarin (Coumadin) can have their effects intensified by CBD, potentially increasing the risk of bleeding. ✗ Anticonvulsants: Certain anticonvulsant medications, such as Clobazam (Onfi) and Lamotrigine (Lamictal), may be affected by CBD, potentially altering their seizure control. ✗ Immunosuppressants: Medications used to suppress the immune system, like Cyclosporine (Sandimmune) and Tacrolimus (Prograf), can be impacted by CBD, potentially affecting their effectiveness after organ transplantation or for autoimmune diseases. ✗ Antidepressants: Some antidepressant medications, particularly those metabolized by CYP3A4 enzymes, may interact with CBD, potentially altering their effectiveness or side effects.
entourage effect describes the potential synergy between various compounds found in cannabis, including cannabinoids, terpenes, and flavonoids. ✗ These compounds may interact with each other and the ECS in unique ways, potentially enhancing the overall therapeutic effects. ✗ The entourage effect highlights the importance of considering the full spectrum of compounds in cannabis, not just isolated cannabinoids.
2-AG Emerging research suggests that linalool may inhibit FAAH and MAGL, the enzymes that breaks down anandamide and 2-AG. Johnson, S. A., Rodriguez, D., & Allred, K. (2020). A Systematic Review of Essential Oils and the Endocannabinoid System: A Connection Worthy of Further Exploration. Evidence-Based Complementary and Alternative Medicine : eCAM, 2020, 8035301. https://doi.org/10.1155/2020/8035301 ✗ By inhibiting FAAH and MAGL, linalool may lead to increased levels of anandamide and 2-AG, potentially enhancing its mood-boosting, pain- relieving, and anti-inflammatory effects.
Unlike most plant-derived cannabinoids, BCP directly activates the CB2 receptor. Johnson, S. A., Rodriguez, D., & Allred, K. (2020). A Systematic Review of Essential Oils and the Endocannabinoid System: A Connection Worthy of Further Exploration. Evidence-Based Complementary and Alternative Medicine : eCAM, 2020, 8035301. https://doi.org/10.1155/2020/8035301 This might offer potential benefits for various conditions: ✗ Chronic pain: BCP's anti-inflammatory properties may contribute to pain relief. ✗ Inflammatory bowel disease (IBD): CB2 activation by BCP could help modulate the immune response and reduce inflammation in the gut. ✗ Neurodegenerative disorders: Emerging research explores the potential neuroprotective effects of BCP through CB2 activation.
FAAH, the enzyme that breaks down anandamide, potentially boosting its mood- elevating effects. Johnson, S. A., Rodriguez, D., & Allred, K. (2020). A Systematic Review of Essential Oils and the Endocannabinoid System: A Connection Worthy of Further Exploration. Evidence-Based Complementary and Alternative Medicine : eCAM, 2020, 8035301. https://doi.org/10.1155/2020/8035301 ✗ Eugenol also interacts with TRPV1 receptors influencing pain perception and inflammation.
β-Myrcene is believed to increase the maximum saturation level* of the CB1r which means the effects of Δ-9-THC and other endocannabinoids can be potentiated. Lupoi, Jason. (2019). The Cannabis Terpene Experience. MACE Media Group. ✗ β-Myrcene may exert analgesic effects by desensitizing nociceptors via TRPV-1 interactions. Jansen, C., Shimoda, L. M. N., Kawakami, J. K., Ang, L., Bacani, A. J., Baker, J. D., Badowski, C., Speck, M., Stokes, A. J., Small-Howard, A. L., & Turner, H. (2019). Myrcene and terpene regulation of TRPV1. Channels, 13(1), 344–366. https://doi.org/10.1080/19336950.2019.1654347 ✘ Myrcene is found in mangoes, thyme, lemongrass, cardamom, hops, and hemp *positive allosteric modulation
like quercetin and apigenin, may inhibit FAAH, the enzyme that breaks down anandamide. ✗ By slowing anandamide degradation, these flavonoids may lead to increased levels of this "bliss molecule," potentially enhancing its mood-elevating and pain-relieving effects.
kaempferol has shown potential to inhibit FAAH activity in laboratory studies. Thors, L., Belghiti, M., & Fowler, C. J. (2008). Inhibition of fatty acid amide hydrolase by kaempferol and related naturally occurring flavonoids. British Journal of Pharmacology, 155(2), 244–252. https://doi.org/10.1038/bjp.2008.237 ✘ Inhibiting FAAH could lead to increased levels of anandamide, potentially enhancing its mood- regulating and pain-relieving effects. ✘ Kaempferol is found in many beans, fruits, and cruciferous vegetables
FAAH Biochanin A acts as a competitive inhibitor of FAAH. Armeli, F., Bonucci, A., Maggi, E., Pinto, A., & Businaro, R. (2021). Mediterranean Diet and Neurodegenerative Diseases: The Neglected Role of Nutrition in the Modulation of the Endocannabinoid System. Biomolecules, 11(6), 790. https://doi.org/10.3390/biom11060790 ✗ It binds to the same active site on FAAH as AEA, the natural substrate. ✗ This competition prevents FAAH from breaking down anandamide. ✗ Increased anandamide levels can modulate the endocannabinoid system
PPAR, COX, & FAAH Apigenin interacts at micromolar concentrations with PPAR, inhibits COX2, and is a potent competitive inhibitor of FAAH. It can also cross the BBB. Armeli, F., Bonucci, A., Maggi, E., Pinto, A., & Businaro, R. (2021). Mediterranean Diet and Neurodegenerative Diseases: The Neglected Role of Nutrition in the Modulation of the Endocannabinoid System. Biomolecules, 11(6), 790. https://doi.org/10.3390/biom11060790
Pinto, A., & Businaro, R. (2021). Mediterranean Diet and Neurodegenerative Diseases: The Neglected Role of Nutrition in the Modulation of the Endocannabinoid System. Biomolecules, 11(6), 790. https://doi.org/10.3390/biom11060790
Singing increased plasma levels of AEA Singing increased plasma levels of AEA by 42% by 42% (P < 0.05) (P < 0.05) and improved positive mood and improved positive mood and emotions and emotions (P < 0.01) (P < 0.01) . . Stone, N. L., Millar, S. A., Herrod, P. J. J., Barrett, D. A., Ortori, C. A., Mellon, V. A., & O’Sullivan, S. E. (2018). An Analysis of Stone, N. L., Millar, S. A., Herrod, P. J. J., Barrett, D. A., Ortori, C. A., Mellon, V. A., & O’Sullivan, S. E. (2018). An Analysis of Endocannabinoid Concentrations and Mood Following Singing and Exercise in Healthy Volunteers. Frontiers in Behavioral Endocannabinoid Concentrations and Mood Following Singing and Exercise in Healthy Volunteers. Frontiers in Behavioral Neuroscience, 12, 269. https://doi.org/10.3389/fnbeh.2018.00269 Neuroscience, 12, 269. https://doi.org/10.3389/fnbeh.2018.00269
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