Cannabinoids, Endocannabinoids, and ECS System

Learning Objectives

• Cannabinoids and endocannabinoids are examined
• Endocannabinoid signalling (ECS) system function is explored
• The important components of ECS pathways are identified
• Primary cannabinoid and endocannabinoid ligands are described
• The primary receptors are identified
• The reason ECS is of interest to human medicine is explained
• Therapy case studies include pain, inflammation, neurological disease, and cardiovascular disease (stroke)
• The future of therapy and current treatments being developed are highlighted

Cannabinoids and Endocannabinoids

• Cannabis sativa is commonly known as cannabis
• Cannabis sativa has recreational and medicinal uses for centuries
• Legal status limited research and exploitation for a long time
• Endocannabinoids are endogenously produced
• Endocannabinoids are natural
• Endocannabinoids play a role in the pathology of many disorders and often have a 'protective' role

Vertebrate Endocannabinoid Signaling

• EC-signaling is becoming more important in treating human disease

Phytocannabinoids

• The molecules are exogenous plant derived
• THC is psychoactive and was discovered in 1964
• CBD is non-psychoactive and used therapeutically
• It inhibits synaptic neurotransmission (retrograde) and alters sensory perception
• It modulates a range of physiological processes

Endocannabinoids

• They are produced in our bodies
• Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) are included
• It modulates complex neurobiology and pathologies, including sensory, motor, and reproductive functions

Endocannabinoid Signalling Pathways

• The three core components include:
  • Endocannabinoid (EC ligands)
  • Enzymes responsible for EC biosynthesis and degradation
  • Receptors that EC's bind to in the CNS
• Signalling occurs predominantly neurally in the CNS
• Some immune cell involvement affects peripheral organs

Endocannabinoid Ligands

• Cannabidiol (CBD) is a primary cannabinoid and therapeutic
• Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are two primary endogenous endocannabinoids
• EC ligands are synthesized on demand

Cannabinoid Ligand - Cannabidiol

• It is extracted from the Cannabis sativa plant
• It is non-psychoactive
• It is one of ~85 chemicals from C. sativa
• It makes up ~40% of cannabis extract
• It is used therapeutically and in consumer products
• It has analgesic, anticonvulsant, muscle relaxant, anxiolytic, antipsychotic, neuroprotective, anti-inflammatory, and antioxidant activity

Endocannabinoid Ligands - 2-AG

• 2-AG is the most prevalent endocannabinoid ligand in the body
• The roles of 2-AG include pain, appetite, and immune system functions

Endocannabinoid Ligands - AEA

• AEA is involved in brain reward circuitry
• AEA is the 'bliss molecule'
• AEA is responsible for things such as exercise highs and states of euphoria
• Other synthetic molecules mimic these ligands

Endocannabinoid Production and Recycling

• The Endocannabinoid Ligands AEA and 2-AG are synthesized on demand
• EC's are produced on cue in the body
• EC's are produced by specific enzymes
• DAGL = 2-AG synthesis
• NAPE-PLD = AEA synthesis
• EC's are then degraded by another set of specific enzymes
• Dysfunction occurs if degradation does not occur
  • This is due to increasing levels of endocannabinoid ligands that are not broken down effectively
• MAGL = 2-AG degradation
• FAAH = AEA degradation

Endocannabinoid Receptors

• CB1 and CB2 are included
• EC receptors receive messages in the form of EC's
• G-protein coupled or ‘serpentine’ receptors are part
• Retrograde signaling is included
• CB1 and CB2 are the components

Endocannabinoid Receptors CB1

• CB1 and CB2 were dicovered pre-synaptically
• CB1 Receptors were discovered in 1988
• CB1 is located in the brain and spinal cord (CNS)
• CB1 regulates appetite, pain, memory, emotion, and motor function

Endocannabinoid Receptors CB2

• The CB2 receptors were discovered in 1993
• CB2 receptors are located in the immune system, gut, and peripheral tissues
• CB2 reduces inflammation
• There are different tasks in different parts of body, but the overall goal is homeostasis (stability)

Endocannabinoid Signaling Discovery Timeline

• Endocannabinoid research is relatively recent
  • It has occurred only in the last ~50 years
• Research was long prevented because of legalities around cannabis use and misuse
• There is a record of therapeutic and recreational cannabis use for over 4,500 years
• 1988 - 1993: CB1 and CB2 bind EC’s
• Physiological function was indicated, but uncharacterised at that stage
• The Mid 1990’s: Discovery of EC ligands AEA and 2-AG occurred
• The final piece in puzzle is that the endocannabinoid system is designed to maintain balance and homeostasis in the body
• The challenge now is to understand the complexities of the system so that it can be safely exploited

Cannabinoid-Based Therapies in Human Medicine

• ECS has key physiological and pathophysiological roles
• These roles include: -Cannabis sativa -Secondary metabolites [e.g. cannabidiol (CBD)] -Novel cannabinoid-based synthetic drugs -All modulate ECS
• ECS inhibits metabolic pathways or agonizes/antagonises ECS receptors
• Modulation is differential expression/activity of ECS effectors, resulting in a physiological effect
• ECS effectors are active components, such as enzymes or receptors

Conditions Managed in Human Medicine

• The ECS is involved in managing many conditions and diseases, including: -Pain management -Mood and anxiety disorders -Inflammation -Epilepsy -Multiple Sclerosis -Rheumatoid arthritis -Inflammatory Bowel Disease -Diabetes -Stroke -Cancer -Dermatology -Eating disorders -HIV/AIDs

Case Study: Pain Management

• If there is pain, that is an outworking of many diseases and conditions
• C. sativa has been used for pain management for ~5000 years
• C. sativa, secondary metabolites (e.g. CBD) and synthetic cannabinoids can aid management of chronic pain
• Target ECS receptors e.g. GPR-55 = mitigate abnormally increased sensitivity to pain (hyperalgesia)
• ECS can also treat: -Rheumatoid arthritis pain -Fibromyalgia -Arthritis -Chronic back pain -Chronic abdominal pain due to surgery -Chronic pancreatitis -Headache -Facial pain
• ECS is a safer non-addictive alternative to opioids, non-steroidal anti-inflammatory drugs (NSAIDs) and other common painkillers
• ECS is useful as an adjuvant alongside other pain medications (opioids)
• ECS is not commonly prescribed for pain in the UK

Case Study: Inflammatory Disorders

• Inflammation accompanies many diseases, such as cancer, autoimmune disorders, and dermatologic conditions
• Cannabinoids and ECs are anti-inflammatory and immune-suppressive
• They downregulate cytokine and chemokine production, suppressing inflammatory responses
• CBD modulates a transient receptor potential vanilloid channel (TRPV-1), reducing the level of pro-inflammatory cytokines
• Animal model data includes: -Multiple sclerosis -Inflammatory bowel disease -Type 1 Diabetic Cardiomyopathy -Pneumococcal meningitis -Colitis -Alzheimer’s
• Translation to human therapeutics requires further work and safety profiling
• ECS can be prescribed for some MS patients

Case Study: Neurological Diseases

• These diseases involve inflammation, dysregulation, and/or death of neurons
• Examples include Alzheimer’s, Parkinson’s and Huntington’s disease
• ECS is not a cure, but cannabinoids can provide relief of some symptoms, such as pain and muscle spasm
• Cannabinoids are anti-inflammatory, neuroprotective analgesic, and immunosuppressive
• ECS is beneficial to some neurological disorders
• Some synthetic cannabinoids: -Demonstrate pro-neurogenic properties (encourage neural stem cells to produce neurons) -Protect against neuroanatomical changes in the brain

Case Study: Cardiovascular Disorders and Stroke

• Stoke = Lack of oxygen and nutrients to the brain due to interruption of blood supply
• Severe headache, loss of coordination, dizziness, confusion, blurred vision, temporary blindness, slurred speech, and paralysis of face and limbs all occur
• There are two types of stroke: haemorrhagic and ischaemic -Ischaemic is the most common
• THC: -Increases brain oxygenation and blood flow to the prefrontal cortex -Is useful for frontal lobe strokes
• CBD: -Has anti-muscle spasm properties to treat post-stroke muscle spasticity -Animal models show increased cerebral blood flow reduces risk of ischaemic stroke

The UK Situation - CBPM

• CBPM is Cannabis Based Products for Medicinal Use
• CBPM was rescheduled under UK law in 2018 -Now, it is legal to prescribe by certain SPECIALISED practitioners
• Medical cannabis medication must: -Contain cannabis, cannabis resin, cannabinol or a cannabinol derivative -Be produced for medicinal use in humans ONLY -Be regulated as a medicinal product, or an ingredient of a medicinal product in UK.
• Guidelines are required to ensure that where there is a clinical need, a patient will be able to access appropriate cannabis-based medicines and/or products to meet any prescription
• Prescribing is limited to clinicians on the Specialist Register of the General Medical Council

Medical Cannabis

• ONLY 'MEDICAL CANNABIS' is legal in the UK; this term is used for any sort of cannabis-based medicine licensed to treat disease
• Cannabinoids or cannabinoid derived products that are not licenced or prescribed for medical use are of: -Unknown content/quantity -Unknown quality -Unknown safety profile -May be illegal and dangerous
• There is absolutely no guarantee of quality, safety or health benefits even if products claim to contain medical cannabis in the form of CBD oil or hemp oil -They are entirely UNREGULATED!

Drugs licenced for use in the UK

• Epidyolex®, Nabilone, Sativex®
• Epidyolex® treats EPILEPSY -It can treat two epilepsy syndromes (Dravets syndrome and Lennox-Gastaut syndrome) -Is only prescribed in context of severe-treatment resistant epilepsy (in the news)
• Nabilone® treats NAUSEA (post-Chemo) -It can treat intractable nausea and vomiting (in context of cytotoxic chemotherapy) that is unresponsive to traditional antiemetics
• Sativex® treats MUSCLE SPASMS/STIFFNESS (MS) -It treats moderate to severe muscle spasticity in adults with multiple sclerosis -It is provided on a 4 week trial basis only if there is a 20% reduction in symptoms shown to continue -It is only used in patients with unsatisfactory response to conventional spasticity drugs
• Only prescribed when other treatments are not suitable or have failed

The Future of ECS Treatment

• Systemic distribution and the wide-ranging influence of the ECS that has been outlined shows promising therapeutic potential
• A full understanding of the molecular mechanisms of the ECS in the disease process is essential
• The ECS complex system involves understanding the broader consequences and side effects of treatment
• Single-molecule synthetic and plant extracts will serves as lead therapeutic compounds for several diseases
• Treatment has already demonstrated promise in palliative care and some other diseases
• Development requires validation, pre-clinical research, synthesis and delivery optimisation, and clinical research
• Other considerations include benefits, efficacies, mechanisms of action, risks, adverse effects, drug interactions, toxicities, drug synergies, and risk of misuse

Treatment Development Case Study – ARISTOCRAT, 2022

• In August 2021, a world-first UK trial assessed if Sativex could treat aggressive brain tumors (glioblastoma) that have returned following initial treatment
• Sativex is an oral spray containing cannabinoids THC and CBD
• Phase I shows more patients alive after one year on Sativex compared to placebo
• This study was not sufficiently powered to show survival impact
• A Phase II trial occurs across 3 years, involving 230 patients, and remains ongoing in 2022
• The aim is to extend life by adding to the current chemotherapy protocol
• It is thought treatment will delay tumour growth, improving the quality and duration of life
• ARISTOCRAT is a randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma