N I C O L E G U MA , D V M, D A C V E C C , D A C V I M ( S A I M)

MEDICINAL CANNABINOIDS

PRESENTATION OVERVIEW

• Cannabis• Endocannabinoid system• Medicinal uses in humans• What is known in veterinary medicine

• Studies• Toxicity

• Legal implications

HISTORY OF CANNABIS

• Thought to have first been used in Romania 5,000 years ago• Ashes containing Δ9 tetrahydrocannabinoid (THC) found

400AD identified medicinal use• Used medicinally in US as early as 1850• Marihuana tax act passed in 1937 banned sale and use of

cannabis• Legal penalties instituted in 1950s, limited research• 1996 California 1st state to permit legal access to medicinal

cannabis under physician supervision

CANNABIS SATIVA

• All parts of the plant• Marijuana

• Short/bushy with lots of flowers• Grown indoors, females only• Fertilization lowers THC• THC concentrated in trichromes

(resin filled glands) on the flowers

• THC in marijuana plant 10-30%

• Hemp grown all over the world • Food, oil, fiber• Male and females grown close

together• Tall and hardy plant• Hemp is stalk and contains little

THC (<0.3%)

ENDOCANNABINOID (ECB) SYSTEM

• Complex• Receptors found in all vertebrate species• In humans

• Nervous system• Internal organs• Connective tissue• Immune cells

• Homeostatic role• Eat, sleep, relax, forget and protect

• Pathologic role• Clinical eCB deficiency syndromes

• Migraine, fibromyalgia, IBS• Deficiency in signaling—depression• Other potential deficiencies

• Schizophrenia, multiple sclerosis, Huntington's’ disease, Parkinson's disease, anorexia, motion sickness

ECB RECEPTORS

• G protein coupled receptors• Cannabinoid receptor type 1

• Most abundant, within the cell cytoplasm• Found in the central nervous system

• Substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum and amygdala

• Adipocytes, hepatocytes, connective tissue, musculoskeletal system, gonads

• Dopaminergic pathway stimulated by CB1• Inhibition of nociception, anxiolytic, appetite stimulant, anti-

emetic• CBD 2 receptor

• Mostly found on immune cells > CNS• Targets/reduces inflammation/pain, immune suppression

ENDOCANNABINOIDS

• Anandamide(AEA) and sn-2-arachidonoyl glycerol (2-AG)• Released upon demand from cell membrane phospholipid

precursors by post synaptic neurons• Both are derivatives of arachadonic acid• 1st identified in 1992• AEA high affinity for CB1

• Other receptors targeted• Serotonin, opioids, NMDA, GABA, TRPV1

• The effects of AEA and 2-AG can be enhanced by “entourage compounds”—inhibit their hydrolysis and prolong their action

• Such compounds include N-palmitylethanolamide (PEA), N-oleolytheanolamide (SEA), cis-9-octadecanoamide (OEA)• PEA down regulates mast cell degranulation• Reduces pruritus, neuropathic pain

CANNABIS CONTAINS

• Phytocannabinoid• Δ-9tetrahydrocannabinol (Δ9-THC)

• THCA, TCHV, • Δ-8 THC/THCA• Cannabidiol (CBD)• Cannabichromene (CBC)• Cannabigerol (CBG)• Cannabinol (CBN)• Similar in structure to eicosanoid arachadonic acid

• Terpenoids• Different based on particular plant• May result in serotonergic effect• May affect benzodiazapene receptors• Scent

PHYTOCANNABANOIDS

• Exogenous• Δ9-THC

• Major psychoactive component of cannabis• Activates CB1 receptor in CNS• Analgesic, anti-inflammatory, antioxidant, bronchodilatory, muscle relaxant,

anti-pruritic• CBD

• Weak or no psychoactivity• Exerts pharmacologic effect without interacting or antagonizing at

CB1 or CB2 receptor• Antianxiety, anticonvulsant, anti-emetic, anti-oxidant, cytotoxic,

therapeutic effect for neurologic diseases • CBC

• Anti-inflammatory, analgesic, antifungal, antidepressant• CBG

• Antidepressant, anti-inflammatory, anti-bacterial

PHARMACOKINETICS/ADMIN

• In people• Inhalation (Smoking, vaporization), ingestion, transdermal• Can affect the onset, intensity and duration of

psychoactive effect• Pharmacokinetic research is challenging

• THC rapidly absorbed by blood after inhalation• Max effect 15-30 mins, taper in 2-3 hours

• THC is highly lipophilic• Oral THC absorption is slower and more erratic with lower plasma

concentrations over inhaled• Oral—max effect 30-90 mins, max effect 2-3 hours and last 4-12 hours

DRUG INTERACTIONS

• Cytochrome p450 isoenzymes 2C9 and 3A4• Metabolize THC and Cannabinol (CBD)• Ketoconazole may increase THC and CBD

OPPONENTS TO USE (HUMAN)

• Well designed randomized trials to confirm benefits and harms lacking

• Standardization absent• Adverse health effects • Potential for dependence, addiction, abuse• Costs

PRO CANNABIS HUMAN MED

• Evidence to support medicinal cannabis in the treatment to a variety of conditions, particularly when refractory to other therapy

• Relatively safe with few deaths reported from use• Self titratable by patient• Relatively inexpensive

FORMULATIONS

• Plant derived, synthetic• Inhaler

• Syqe• Metered-dose pharmaceutical-grade cannabis inhaler

• Oral mucosal spray of plant derived THC and CBD• Nabiximol (Sativex)

• Produced in Great Britain (GW pharmaceuticals), used in Europe for MS spasticity• Nabilone (cesamet)

• Synthetic cannabinoid mimicking THC• Produced by Valeant• Capsule• Used for chemotherapy induced nausea• Used for pain for fibromyalgia, multiple sclerosis

• Dronabinol (Marinol, Syndros)• Synthetic TCH mimicking natural Δ9 THC• FDA approved for

• Used for chemotherapy induced nausea• Appetite stimulant for AIDs patients

• Capsules

SELECT MEDICAL CONDITIONS AND DISEASES

• Alzheimer's Disease• HIV/AIDS• Amyotrophic lateral sclerosis (ALS)• Cancer• IBD

• Crohns, ulcerative colitis• Multiple sclerosis• Parkinson's disease• Post traumatic stress disorder• Glaucoma

DEBILITATING MEDICAL CONDITIONS OR ASSOCIATED SYMPTOMS

• Cachexia, anorexia or wasting syndromes• Severe or chronic pain• Severe or chronic nausea• Seizure disorders• Skeletal muscle spasticity (MS)

CHRONIC PAIN

• Fibromyalgia• Data obtained from 2 hospitals in Israel

• 26 patients• All patients reported a significant improvement and 50%

stopped other medications for fibromyalgia• 30% had mild adverse effects

• Neuropathic pain, fibromyalgia, rheumatoid arthritis, mixed chronic pain• 15/18 studies demonstrated a significant analgesic effect of

cannabinoids compared with placebo• Cannabinoid use generally well tolerated• Evidence that cannabinoids are safe and moderately

effective in neuropathic pain

• Cannabis based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% vs 17%)

• Cannabis based medicine probably increases the number of people achieving pain relief of 30% or greater compared to placebo (39 vs. 33%)

• More nervous system adverse events with cannabis based products compared to placebo

• 61% vs. 29%• Psychiatric events in 17% compared to 5% placebo• Authors conclusions:

• The potential benefits of cannabis-based medicine in chronic neuropathic pain might be outweighed by their potential harms.

• Quality of evidence reflects exclusion of patients with substance abuse, comorbidities, small sample size

NAUSEA/VOMITING

• Chemotherapy related• Not enough evidence to use routinely• A review of 23 RCT using cannabis based products

• Less nausea in treatment arm compared to placebo• Similar bouts of nausea using conventional anti-emetics• Patients liked cannabis products better• Side effects more common—feeling high, dizzy, dysphoria• Maybe useful for refractory nausea using traditional agents• Trials were of low to moderate quality, used older chemo

agents

NEUROLOGIC DISORDERS

• Multiple Sclerosis• American Academy of Neurology

• Oral cannabis extract is effective for reducing patient reported spacity scores and central pain or painful spasms

• Limited evidence to support the use of cannabis extracts for treatment • Huntington disease• Levodopa-induced dyskinesia• Parkinson's• Reducing severe tic in Tourettes

• J Neurol Neurosurg Psychiatry, Sydney AUS• March 2018• 36 studies identified, 6 RCT, 30 observational studies• Mean age of participants 16.1 (range 0.5-55yr)• 48% of patient reported 50% reduction in seizures (17

observational studies• In 14 observational studies 8.5% were seizure free• 12 observational studies reported improved QOL 55.8%• 50% adverse effects and 2.2% serious adverse effects• Pharmaceutical grade CBD as adjuvant treatment in

pediatric onset drug-resistant epilepsy may reduce seizure frequency

ADVERSE EFFECTS

• Short term• Impaired short term memory• Impaired motor coordination• Paranoia/psychosis at higher doses

• Long term• Addiction• Poor educational outcomes• Diminished life satisfaction• Chronic bronchitis• Schizophrenia• Depression• Myocardial infarct, stroke, TIA

ADVERSE EFFECTS

• Review of 23 randomized controlled trials• 96% of adverse effects deemed not serious• Most common serious adverse effects

• Relapse of MS• Vomiting• UTI?

VETERINARY MEDICINE

• Endocannabinoid system • Pending Studies• Products• Toxicity• Pharmacokinetic monitoring• Legal implications

WHAT ABOUT IN VETERINARY MEDICINE?

• 10 dogs enrolled in the study• All dogs had radiographic OA• Arthrocentesis of stifle performed prior to surgery in

OA + normal knee• AEA< 2-AG, OEA and PEA were measured in all

synovial fluid samples• Significant increase in 2-AG and OEA noted in the knees

with OA when compared to contralateral knee

CATS WITH EOSINOPHILIC PLAQUES

• Synthetic analogue of PEA (PLR 120 at10mg/kg/d) x 30 days, no other therapy• PLR 120 down regulates mast cell degranulation via CB2• 15 cats, histopathology study• 64.3% improved in pruritus, erythema and alopecia• 66.7% improved in the extent and severity of lesions• Cure rate only 6%• Not a placebo controlled, randomized study• Patients may have needed longer than 30 days• No side effects associated with treatment

HEMP PRODUCT

• ABSTRACT• Objectives• The objectives of this study were to determine basic oral pharmacokinetics, and assess safety and analgesic

efficacy of a cannabidiol (CBD) based oil in dogs with osteoarthritis (OA).•• Methods• Single-dose pharmacokinetics was performed using two different doses of CBD enriched (2 mg/kg and 8 mg/kg)

oil. Thereafter, a randomized placebo-controlled, double-blind, crossover study was conducted. Dogs received each of two treatments: CBD oil (2 mg/kg) or placebo oil every 12 hours. Each treatment lasted for 4 weeks with a 2-week washout period. Baseline veterinary assessment and owner questionnaires were completed before initiating each treatment and at weeks 2 and 4. Hematology, serum chemistry and physical examinations were performed at each v isit. A mixed model analysis of variance was utilized for all variables with a p value of < 0.05 deemed significant.

•• Results• Pharmacokinetics revealed an elimination half-life of 4.2 hours at both doses and no observable side

effects. Clinically, canine brief pain inventory and Hudson activ ity scores showed a significant decrease in pain and increase in activ ity (p < 0.001) with CBD oil. Veterinary assessment showed decreased pain during CBD treatment (p < 0.03). No side effects were reported by owners, however serum chemistry showed an increase in alkaline phosphatase during CBD treatment (p = 0.005).

•• Clinical significance• This pharmacokinetic and clinical study suggests that 2 mg/kg of CBD twice daily can help increase comfort and

activ ity in dogs with OA.•• Keywords• Cannabidiol; CBD oil; hemp; canine; osteoarthritis; pharmacokinetic

PENDING CLINICAL TRIALS

• Colorado State University CVM• CBD being studies

• Osteoarthritis• Dr. Felix Duerr—sports medicine• 24 dogs with arthritis and CBD oil for six weeks vs. placebo• Double blinded• Results anticipate in May

• Auburn University CVM• Dr. Dawn Boothe• Epilepsy trial planned but challenging due to Schedule I status

of CBD • Funding from Canna-pet/Pet Conscious

CANNABINOID MONITORING

• Auburn University Therapeutic drug monitoring• Dr. Dawn Booth• Cannabinoid assay

• Offered for both toxicity and efficacy• No Charge (normally $150)• Also recommend sending a portion of the preparation• They quantitate THC, CBD, CBG, CBN and CBC—samples batched and not run immediately• Submit 0.5ml of serum or plasma—two samples at peak—2 hours after dosing and trough—

just prior to second dose• Information must be complete on form (online at vetmed.auburn.edu/veterinarians/clinical-

labs/cannabinoid-therapy-submission-form/• Dosing information

• Preparation information (oil, plant etc)• Source (company)• Dose (mg/kg)• Interval• Duration of therapy• What is being treated• I f the patient has responded

CONSUMER PERCEPTIONS HEMP

• Wide discrepancies between what a product is labeled for and what is found in the product

• Survey distributed over 1 month via a link on a commercial website for hemp product

• 632 people responded• Female 83%• Most > 35yrs• Most had higher education• From CA/WA• 77% used for a condition diagnosed by a vet

• Seizures, cancer, anxiety, arthritis• Most discontinued due to expense (20%), 17% not effective,

4.5% side effects

CONSUMER PERCEPTIONS

• Did it help?• Moderately or a great deal• Relief from pain 64%• Sleep 50%• Relieving anxiety 49.3%• Side effects

• Sedation 22%• Overactive appetite 15%

• Cats?• Only 11% responded for use in cats (63 respondents)• Moderate to a great deal of help with

• Pain—66%• Reduction of inflammation? 56%• Help with sleep 44%

• Side effects• Sedation 19%• Over active appetite 16%

CONSUMER PERCEPTIONS

• How did they hear about hemp products?• The internet 50%• Friend 16%• Veterinarian 14%• 50% spoke with their veterinarians about the product

• 61% of vets responded positively• 7.7% negatively• 30.7% didn’t have an opinion

• 34% did not tell their veterinarian• 88% rated the product as very safe• 62% felt the product worked better than any or most of

some other treatments

• 4 fold increase in incidence of marijuana toxicities • 2 dogs that ingested medical grade marijuana

butter/chocolate died• Unknown amount of THC• Suspected aspiration?

• Urine dip stick analysis unreliable for detection of marijuana

• Since 2009 calls to ASPCA PC have increased 50% for marijuana

TOXICITY

• High LD50 (>3g/kg) but dogs are sensitive to THC • Depression • Incontinence • Ataxia • Vomiting • Tremor • Mydriasis • Hypothermia • Tachycardia• Hypotension• Seizures

• Treatment• Induction of emesis/activated charcoal if not depressed

• Multiple doses of AC due to enterohepatic circulation• Supportive care/down dog care PRN• Minimize external stimulation• Sedation may be needed (benzodiazapene)• Anti-emetics• Keep warm/normotensive• Lipid therapy?

• Severe cases

CBD PRODUCTS

• Based on a Google search, NOT experience• ElleVet

• 1-2mg/kg PO BID• CannaPet• HempRx• Innovet CBD oil• Kurapet• Many others marketed as hemp oil

DEA CLASSIFICATION

• Currently considered a schedule 1 controlled drug• Defined as having a

high potential for abuse• No currently accepted

medicinal use• Lack of accepted

safety data for use of the treatment under medical supervision

• Except as specifically authorized

• Marijuana, heroin, LSD, Mescaline, MDMA

REGULATORY IMPLICATIONS

• Complex, schedule I drugs difficult to research• Possession, cultivation and distribution of this substance,

regardless of purpose remains illegal at the federal level• States that permit medicinal cannabis use have established individual laws

• Physicians cannot legally “prescribe” medicinal cannabis therapy given its schedule I classification but can recommend/certify

• Medical cannabis expenses are not reimbursable though government medical assistance programs or private health insurers

• Center for Medicinal Cannabis research at UCSD• Access to funding, marijuana at different TCH levels, approval for a

number of clinical research trials• Failed to recruit patients to conduct five major trials which were canceled

• patients deterred as they could not drive while on the trial…• Leads to anecdotal claims

STATES THAT ALLOW MEDICAL CANNABIS

• 28 states, DC, Guam and Puerto Rico allow comprehensive public medical marijuana and cannabis programs

• Alaska• Arizona, Arkansas• California• Colorado• Connecticut• Delaware• DC• Florida• Hawaii• Illinois• Maine

• Maryland• Massachusetts• Michigan• Minnesota• Nevada• New Hampshire• New Jersey• New Mexico• New york• North Dakota• Ohio• Oregon• Pennsylvania• Rhode Island• Vermont• Washington

WHAT ABOUT MARYLAND?

• The state has decriminalized marijuana to some degree• Since 2014• No prison time or criminal record for first time possession for a

small amount of personal consumption• Medical marijuana approved

• 30 day supply, edibles not permitted• Cannot home cultivate• 19,450 registered participants• Qualifying conditions

• Cachexia, anorexia, wasting syndrome• Chronic pain• Nausea• Seizures• Severe or persistent muscle spasms

WHAT ABOUT HEMP/CBD?

• The Agricultural Act of 2014 (Farm bill)• “Section 7606 authorizes institutions of higher education

(universities) and state departments of agriculture to grow and cultivate industrial hemp (defined under the act as marijuana with a TCH content of 0.3% or less) for agricultural research purposes where permitted under state law

• However the agricultural act does not permit such entities or anyone else to produce non-FDA approved drug products made from cannabis

• Thus the CSA and FDA restrictions mentioned above remain in effect with respect to the production of Charlottes Web/CBD oil for human consumption”.

FROM AVMA

• MD Board complies with AVMA standards• Marijuana products are being marketed to treat diseases in

animals• While both marijuana and industrial hemp products are

available, no studies, doses or uses in veterinary medicine have been determined

• Furthermore, FDA has not approved the use of marijuana or hemp in any form in animals, and the agency cannot ensure the safety or effectiveness of these products

• For these reasons, FDA and AVMA cautions pet owners against the use of such products

• Many of these products are marketed as CBD oil or chews• These product, despite contrary claims, are illegal for use in

pets

HOW DO WE TALK TO OUR CLIENTS ABOUT CBD?

• AVMA • Council on botanicals and therapeutics

• Point of contact Dr. Jeffrey Powers • Bills being worked on in NY and CA for veterinarians to be

able to legally discuss cannabis/hemp• Maryland State Board of Veterinary Medical

Examiners• Point of Contact Vanessa Orlando

• Office of Controlled Substances Administration, MD Dept of Health• Point of contact James W. Polek, P.D.

WHAT CAN WE DISCUSS WITH CLIENTS?

• Cannot prescribe THC or CBD products• We can counsel clients

• Risks, unknown effects• Side effects and toxicity of THC• Potential therapeutic benefits of CBD?

• Probably best not to carry them in your hospital• Recommend evaluation of certificate of analysis?

• Type of CBD and concentration• Important to have elemental analysis, pesticides, bacterial analysis• According to Dawn Boothe

• Ask about their quality control and procedures• There can be inaccuracies in the certificate of analysis

• Consider send samples to her lab• Clients are pursuing these therapies on their own

• Be informed

WHAT’S ON THE HORIZON

• Mitch McConnell (R-KY)• Introduced legislation to remove low THC hemp from

federal controlled substance act• Identical legislation also introduced in the house

• Trump administration pledges non-interference in legal marijuana states

• Chuck Schumer (D-NY)• Legislative priority for Democratic Party to remove

marijuana from DEAs list of controlled substances

USEFUL WEBSITES

• NORML.org• Working to reform marijuana laws

• FDA.gov• Congress.gov• Avma.org• Hobanlaw.com• Procon.org

THANK YOU SPONSORS!!