Bones and Joints: The Endocannabinoid System in Health and Disease

Joel Ehrenkranz MD Utah Dept. of Health Product Review Board Utah Dept. of HealthMedical Cannabis Compassionate Use Board

Nothing to disclose Learning Objectives

• Review the endocannabinoid system • physiology • pathology • pharmacology

• Discuss the principles of medical cannabis prescribing • indications • dosing • toxicity • monitoring

• Provide guidance on regulatory compliance with Utah Medical Cannabis Act A Woman With Congenital Endocannabinoid Excess

66 year old female with bilateral pantrapezial osteoarthritis • underwent trapeziectomy • no postoperative pain or analgesia use • Past medical history • Age 65: painless osteoarthritis of the hip • Longstanding memory lapses • forgets words in mid-sentence • misplaces keys • Never panics • Surgical history • No analgesia requirement • hip replacement • varicose vein and dental procedures • painless injuries • laceration suturing • fracture left wrist • cuts and burns • Family and Social History • Father and son: little requirement for pain medications • Physical Exam • optimistic and happy affect • 0/21 on generalized anxiety questionnaire A Woman With Congenital Endocannabinoid Excess Due to FAAH Gene Deletion FAAH Pseudogene Deletion: Molecular Pathology

X Humans Have Used Cannabis for Millenia.

Chromatograms of the ancient cannabis and the inner charred surface of the wooden brazier M25:2. (A) Total ion current (TIC) chromatogram of the ancient cannabis from the Jiayi Cemetery, Turpan showing the presence of C16:0 (hexadecanoic acid), C18:0 (octadecanoic acid), and CBN. (B) Chromatogram in select ion mode (SIM) of the ancient cannabis showing several cannabinoids: CBN, cannabidiol (CBD) and cannabicyclol (CBL); (C) TIC chromatogram of the internal charred fragment of wooden brazier M25:2 from the Jirzankal Cemetery; and (D) SIM chromatogram of the internal charred fragment of wooden brazier M25:2 Eminence-Based Medicine: Cannabis Ethnopharmacology

“The Scythians take kannabis seed, creep in under the felts, and throw it on the red-hot stones. It smolders and sends up such billows of steam-smoke that no Greek vapor bath can surpass it. The Scythians howl with joy in these vapor-baths, which serve them instead of bathing, for they never wash their bodies with water.” Herodotus, A. D. Godley. Trans. The Histories (Harvard Univ. Press, 1920).

Heat converts THCA to THC. The Endocannabinoid System

endocannabinoids endocannabinoid receptors downstream intracellular signaling

• TRPV1 : vanilloid receptor: involved in pain and temperature sense Cellular signaling: • GPR 18, 19, 55, 119: • cAMP + MAPK orphan nuclear receptors • arrestins • PPAR α and γ • ceramide Endocannabinoid Receptors

• CB1 receptor • Present in all chordates. • CB2 receptor • Human CR1 gene located on chromosome 6q15 • CNR2 gene located on 1p36.11 • Widely expressed in multiple tissues • Arose as CNR1 gene duplication 400 MYA • Mediates psychoactive effects • RNA expressed in: • lymphocytes • lymph nodes • spleen • tonsils • appendix • bone • microglia • Increased protein expression • MS and ALS • experimental peripheral neuropathy Endocannabinoids and Sepsis

Endocannabinoids are involved in the host response to sepsis. • Endotoxin: • Increases endocannabinoid receptors gene transcription • Increases intracellular endocannabinoid levels • CB1 receptors • Activated by anandamide from macrophages and 2-AG from platelets • Contributes to hypotension • CB2 receptors • Decrease innate immune response • reduces generation of pro-inflammatory cytokines • increases bacterial phagocytosis • Phytocannabinoids • Have anti-bacterial, anti-viral, and anti-parasitic activity • Bind to nonribosomal antibiotic peptides Cannabinoids in Diabetic Ketoacidosis

endocannabinoid In adults with T1DM: cannabis use within the previous 12 months was associated with an increased risk of DKA compared with no cannabis use. JAMA Internal Medicine November 5, 2018 5, 2018 Clinical Implication literatureClinical Implications • No literature on chronic cannabis use and type 1 diabetes. • No literature on cannabis’ role in DKA. • on chronic cannabis use and type 1 diabetes. Cell Metabolism 2018 • No literature on cannabis’ role in DKA. Endocannabinoids and Trauma Orthopedic literature: fractures of long bones, when associated with traumatic brain injuries, frequently heal with excessive callus and faster than normal.

• CNS injury elevates endocannabinoids. • Endocannabinoids regulate bone growth and remodeling • Osteoblasts, osteoclasts, osteocytes, fibroblasts, chondrocytes contain: • endocannabinoids and endocannabinoid mimetics (lipoamines: oleoyl serine) • enzymes for endocannabinoid synthesis and degradation Endocannabinoids and Bone Cannabis Effects on Bone: Epidemiology

• UK heavy recreational cannabis users – Self-reported cannabis use – Decreased hip and lumbar spine BMD – Increased fracture rate – Increased type 1 C-teleopeptides and procollagen – Decreased bone mineral density – Secondary to decreased BMI • US NHANES data – Adults ages 20-59 – No association of self-reported cannabis use with bone mineral density – Decreased BMI Endocannabinoids: Human Bone Pathology

• Chrondocytes from osteoarthritic joints – Express CNR1 and 2, TRPR 1, GPR 18 and 55 – Expression does not correlate with amount of joint damage • Synovial biopsies in patients with osteoarthritis and rheumatoid arthritis – Express CNR1 and 2 RNA and protein – Contain increased levels of endocannabinoids – Not seen in controls • Gene Linkage studies – CNR2 SNP’s linked to osteoporosis in some human populations – 1p36 (location of CNR2 gene) associated with decreased bone density Cannabidiol (CBD)

Pharmacology and toxicology • weak CB1 and CB2 antagonist • ? blocks clearance of endocannabinoids • lacks psychoactive effects • does not cross-react in cannabinoid immunoassays.

• In rats: – decreases inflammatory response to disc injury – decreases inflammation in experimental arthritis models – improves fracture healing

• In humans: – decreases inflammation in vitro • peripheral neuropathy • periodontitis • hepatic ischemia Endocannabinoid Mimetics

• Endocannabinoid receptor ligands found in non-Cannabis plants – Liverwort: CB1 agonist – Cornflower: CB2 agonist • Cannabinoid receptor ligands present in foods – β-caryophyllene: CB2 agonist • blocks cisplatin nephrotoxicity in a mouse model • inhibits inflammation in mouse model of inflammatory colitis • in mouse bone marrow cultures, – increases osteoblastic mineralization – decreases osteoclastogenesis and adipogenesis – Guineensine: (black pepper): decreases 2-AG reuptake – Falcarinol (carrots, parsley, celery): CB1 antagonist • Reloxifene / SERMS – CB2 agonist: may account for anti-osteoporotic effects • Pregnenolone: - CB1 antagonist: blunts psychoactive effects of THC Medical Cannabis Indications

Conclusive or substantial evidence: • chronic pain • chemotherapy-induced nausea and vomiting • spasticity with multiple sclerosis • Lennox-Gastaut and Dravet syndromes

Moderate evidence of effect • sleep disturbance

Limited evidence of effect • appetite and weight gain • PTSD • social anxiety

No or insufficient evidence • cancer • epilepsy • ALS, Huntington’s, Parkinson’s • irritable bowel Abrams D. Eur. J. Int M. 2018 • Opiate addiction “The absence of evidence does not mean of absence” www.pnas.org/cgi/doi/10.1073/pnas.1903434116

Cannabis availability ~ opiate overdoses Medical Cannabis Contraindications

• contraindicated in pregnancy and lactation • contraindicated in heart disease – angina due to tachycardia – hypotension due to THC • relative contraindication < 21 years old • in addiction and dependency (controversial) • smoking and vaping in patients with COPD and asthma. Medical Cannabis Recommending

• Preferred formulation: – Nabiximols: oromucosal whole plant extract – CBD-predominant chemovars with the smallest amount of THC • optimal improvement in symptom control and quality of life • fewest adverse events

European Journal of Internal Medicine 49 (2018) 12–19 Cannabis Recommending: Standards of Care

• Utah State Dept. of Health Requirements – Medical cannabis program will launch in early 2020. • 7 dispensaries state-wide • 18 Dept. of Health offices will fill medical cannabis recommendations. – Registered cannabis recommender • 4 hours of continuing medical education – Compassionate Use Board • Medical cannabis recommending – identical to prescribing of other controlled drugs – review of prior medical records if available – comprehensive history and physical – discussion of the pros and cons of cannabis – plans for appropriate follow-up care – proper documentation of the consultation – Communicate with other care-givers. Cannabis Toxicology: Point-of-Care Drug Testing

• Driving / Safety Sensitive Operations • should be avoided for 4 h after inhaled cannabis use • 6 h after ingested cannabis use • 8 h if euphoria was experienced • safety-sensitive industries (aviation): no use within 28 days of work • Urinary cannabinoids • presence of cannabinoids persists for days to weeks • easy to convert positive to negative • Oral Fluid cannabinoids • present for 1-2 hours after inhalation or ingestion • brushing teeth removes cannabinoids from oral fluid • uninterpretable in patients with dentures • Serum cannabinoids • present for 1-2 hours after inhalation or ingestion • DOT regulations (impairment: > 5 ng/ml whole blood): can be challenged • Hair cannabinoids + - • unreliable • false positives and negatives from environmental exposure and hair products • Medical cannabis use makes interpretation of positive marijuana drug tests problematic • Presence of cannabinoids in biological fluids does not correlate with impairment • A cannabinoid test is not positive until a confirmatory test (e.g. HPLC-mass spectrometry) is positive. Cannabinoid Pharmacognosy: • First document action • Then figure out mechanism of action cannabinoids

SGLT2 inhibitors Medical Cannabis: How to Recommend and What to Monitor

Indications: • chronic pain • chemotherapy nausea and vomiting • spasticity with MS • sleep • appetite and weight gain • PTSD • social anxiety

Recommending: • registered recommender • start low; go slow • Good initial choice • inhalation bioavailability is ~ 3X ingestion bioavailability • CBD:THC = 20:1 • CBD: 2.5 - 10.0 mg/kg p.o. in 2 divided doses • vaping • THC • 5 second inhalation • maximum: 10 mg p.o. q8h • exhale after 10 seconds • > 30 mg/day • q20-30 minutes prn • increases adverse events • induces tolerance • does not improve efficacy Follow-up of Medical Cannabis Patients • Monitor • Treatment response • drug-drug interactions • bone density Start Go • LFT’s • hyperemesis • Treatment of THC tolerance – drug vacation > 48 h – cannabis withdrawal syndrome • headache • diminished sleep quality • irritability • lasts ~3 days Medical Cannabis: An Arrow in the Pharmaceutical Quiver

• Medical cannabis and CBD are not cure-alls.

• Medical cannabis = aspirin + benzodiazapene.

Utah Department of Health [email protected] health.utah.gov/medical-cannabis Thank you for your time and attention. ?

[email protected] 801-503-6332