By Carrie Jurney DVM DACVIM (Neuro)

Medical Marijuana in Veterinary Medicine

With the rise in popularity of medical marijuana for humans, it is inevitable that veterinarians are faced with questions from their clients about marijuana use in pets. The goal of this lecture is to allow the clinician to have a better knowledge base about medical marijuana, and to understand the complicated legal landscape of medical marijuana as it currently stands in the United States.

1. Cannabis

a. Annual herbaceous plant of the Cannabis genus, in the Cannabaceae family.

b. Three species commonly used in medicine and recreation.

i. Sativa

1. Relatively high in CBD

2. Tends to be more stimulating than psychoactive

ii. Indica

1. Relatively high in THC

2. Tends to be more psychoactive

iii. Ruderalis

1. Originally found mostly in Russia

2. Used frequently in hybrids because it is auto-flowering, unlike the other strains that require light cycles to flower.

3. Relatively high in CBD

c. There is a high level of hybridization in the market place, and therefore when speaking of the effects of a product, it’s more effective to discuss the actual chemical makeup. Unfortunately, that information is not always readily available.

2. Cannabinoids

a. Endocannabinoids: endogenous chemicals that interact with the endocannabinoid system

i. Anandamide

ii. 2-Arachidonoylglycerol

b. Phytocannabinoids: plant based chemicals that interact with the endocannabinoid system

i. THC

ii. CBD

iii. Many others (113+)

c. Synthetic Cannabinoids

i. Referencing manufactured chemicals that interact with the endocannabinoid system.

1. Most often referring to street drugs (“Synthetic Marijuana”)

2. May also refer to cannabinoid based pharmaceuticals/research compounds

a. See below for pharmaceuticals

b. HU 331: synthesized from CBD, topoisomerase II inhibitor

d. Pharmaceuticals

i. Marinol (Dronabinol):

1. FDA approved synthetic THC.

2. Anorexia associated with HIV

3. Antiemetic for chemo

ii. Cesamet (Nabilone):

1. FDA approved for chemo associated antiemetic.

2. Not approved in US, but used in other countries for chronic pain management

iii. Levonantradol:

1. Potent THC analog- 30x more potent than THC

2. Mostly used in research.

3. Both analgesic and antiemetic effects.

4. Cb1 &Cb2

iv. Rimonabant (Acomplia): CB1 inverse agonist previously used as an anti-obesity drug.

v. Epilodex:

1. 99% CBD

2. In phase 3 clinical trials for severe forms of childhood epilepsy.

vi. Sativex:

1. THC and CBD used for spasticity. Approved in Canada

3. Terpenes/Terpenoids

a. Organic compounds that are a major component of resin (also essential oils)

b. Responsible for smell and taste of a compound.

c. Broadly two categories:

i. Terpenes: Hydrocarbons

ii. Terpenoids: Have additional functional groups

d. Some, like Caryophyllene, interact directly with endocannabinoid system.

e. Some may modulate actions of cannabinoids while others have direct effects on serotonin and dopamine systems.

4. Endocannabinoid System

a. G-coupled receptors, two are the focus of most of the relevant literature to date:

i. CB1:

1. Location:

a. Mainly in the brain

b. Also found in autonomic nervous system, testes and vascular endothelium

ii. CB2:

1. Location:

a. Found in immune and hematopoietic systems mainly

b. Also found in bone and liver cells.

iii. Other receptors are identified, but less studied

1. CB4: present on endothelial cells

2. CB6: related to decreased inflammation

5. Medicinal Use of Marijuana and Cannabinoids in Humans

a. Nausea

i. Tramer et al:

1. Design

a. Meta-analysis of 30 randomized controlled trials published between 1975 and 1997

b. 1366 patients involved in studies comparing cannabis to placebo or an active control (conventional antiemetics including drugs like metoclopramide, prochlorperazine, etc)

c. The cannabinoids in the study were generally pharmaceutical versions (Dronabinol, Nabilone, Levonantradol)

2. Results

a. Cannabinoids were more effective than active and placebo controls, albeit only slightly

b. “Six to eight patients needed to be treated with cannabinoids for one to benefit who would have vomited or had nausea had they all received a conventional antiemetic”

c. Cannabinoids were effective for “medium emetogenic settings” but no more effective in severe/extreme nausea.

3. Adverse Events:

a. Cannabinoids were associated with a high rate of side effects

b. Patients on cannabinoids were more likely to withdraw from studies due to side effects.

b. Appetite

i. Jatoi et al:

1. Design

a. 469 advanced cancer patients

b. Randomized to conventional therapy with megestrol vs dronabinol or both

2. Results:

a. Megestrol: 75% improvement in appetite, 11% improvement in weight gain

b. Dronabinol: 49% improvement in appetite, 3% improvement in weight gain.

c. Combination therapy showed no additional benefit

3. Similar side effect profiles between groups.

c. Pain

i. Campbell et al:

1. Systematic review of randomized placebo-controlled trials

a. 9 trials, 222 patients

b. Study end points were too different to do a meta-analysis so results were described qualitatively

2. Cancer pain studies:

a. Benzopyranoperidine not as effective as codeine and no better than placebo

b. Oral THC better than placebo

i. Dose response adverse events

c. Oral 10mg THC equivalent to 60mg codeine. 20mg THC equivalent to 120mg codeine for pain control, but had unacceptable side effects.

d. Synthetic nitrogen analogue of THC

i. Better than placebo, equivalent to 50mg of codeine

ii. better than placebo and to 50mg of secobarbital (barbiturate).

iii. In both instances use of this nitrogen analogue was found to have unacceptable levels of side effects.

3. Chronic nonmalignant pain:

a. Only 2 patients. Both had crossover trials.

b. Patient with familial Mediterranean fever- THC was no better than placebo on pain scores, but morphine use significantly reduced breakthrough pain

c. Spinal cord ependymoma patient with neuropathic pain and spasticity: For pain, 5mg THC was equivalent to codeine 50mg and both better than placebo. THC had an added benefit for spasticity.

4. Post-operative Pain

a. 36 patients.

b. Levonantradol more effective than placebo when give IM.

c. Mild adverse events were common.

5. Adverse effects were common and sometimes severe in 6/8 trials where cannabis showed efficacy.

d. Spasms and Stiffness

i. Zajicek et al:

1. Design:

a. 22 UK Multiple Sclerosis centers

b. Double blinded, placebo controlled groups (cannabis vs placebo)

c. Cannabis was an extract containing 2.5mg THC (main cannabinoid), and 0.8-1.8mg of CBD

2. Results

a. Cannabis group showed about double the response rate for stiffness, body pain and sleep quality.

b. Muscle spasms also improved with cannabis, but to a lesser degree.

3. Adverse Events

a. Cannabis group showed higher adverse events (93% vs 74.6% of controls).

b. 21% of the cannabis group withdrew from the study vs. 6.7% of the placebo group.

c. 95% of the adverse events were mild or moderate, and most reverse shortly after treatment stopped.

e. Seizures

i. Many studies show a positive effect of cannabinoids, particularly CBD. Exact molecular target is unknown.

1. Endocannabinoids have been shown to be upregulated after seizures and can be neuroprotective

2. Activation of CB1 receptors reduces seizure severity

3. CBD is also a potent inhibitor of the cytochrome P450 system, so may elevate blood levels of other anticonvulsants.

4. CBD also has calcium modulating effects and can reduce calcium influx in hyperexcitable states.

ii. Devinsky et al. 2016

1. Design:

a. Open label trial

b. 214 patients enrolled (162 included in the safety and tolerability analysis and 137 in the efficacy analysis)

c. Severe intractable childhood onset epilepsy, ages 1-30, average age 10.5y

d. 4-week diary pre-treatment, 12-weeks treatment period

e. 2-5mg/kg of CBD daily, titrated up until intolerance or max of 50mg/kg/day (site dependent)

2. Results:

a. Reduction of seizures

i. Total Seizures: reduced 34.6%

ii. Focal seizures: reduced 55%

iii. Atonic seizures: reduced 54.3%

iv. Tonic seizures: reduced 36.5%

v. Tonic-Clonic seizures: reduced 16%

vi. Two patients were seizure free.

b. People on clobazam seemed to have a better response

i. Maybe due to a cytochrome P450 inhibition

3. Adverse Events

a. 79% of the group with 12 weeks of follow up (safety group) had AE

b. 12% had severe AE thought to be related to the drug

c. 3% discontinued treatment due to AE

d. Patients at 12 weeks seemed to no longer have somnolence/fatigue, but might still have diarrhea & weight loss (especially at high doses).

iii. Devinsky et al. 2017

1. Design

a. Double-blind, placebo-controlled trial

b. 120 children and young adults.

c. 20mg/kg/day CBD vs placebo

d. Convulsive frequency of a 4-week baseline vs 14-week treatment period

2. Results

a. Median reduction in seizures: 38.9% (vs 13.3% in placebo)

b. 43% in CBD group had a >50% seizure reduction (vs 27% in placebo)

c. 3 patients in CBD group became seizure free (no placebo patients did)

d. 62% of caregivers judged child’s overall condition to be improved with CBD (vs 34% of placebo)

3. Adverse events

a. 93% of CBD group (vs 75% of placebo) had AE.

i. 89% AE were mild to moderate in severity

ii. Serious events were reported in 10 in the CBD group and 3 in placebo group.

b. 75% in CBD had AE determined to be related to drug vs 36% in treatment group.

c. 8 patients withdrew due to AE from CBD group, 1 from placebo group

d. Elevated Liver enzymes occurred in the 12 patients in the CBD group and 1 in placebo (all also on valproate)

f. Current Studies in Veterinary Medicine

i. Dr. McGrath at Colorado State is doing a CBD trial on dogs who are currently on conventional anticonvulsants and having at least two seizures a month. http://csu-cvmbs.colostate.edu/vth/veterinarians/clinical-trials/Pages/efficacy-of-cannabidiol-for-the-treatment-of-epilepsy-in-dogs.aspx

ii. Dr. Boothe’s lab at Auburn will measure cannabinoids in both your patients' serum/plasma as well as in the product they have been given. This testing is free of charge.

iii. http://www.vetmed.auburn.edu/veterinarians/clinical-labs/

g. Summary

i. Cannabinoids have shown positive effects in several arenas.

ii. Many studies are understandably focused on single molecules/purified extracts, but this removes the possibility of the Entourage Effect

iii. Many studies are focused on oral administration- but bioavailabity is better with inhaled product.

iv. Control of some symptoms, like pain, appetite and nausea, is often equivalent or only mild improvement over conventional therapies. Other symptoms like seizures and spasticity show improvement over conventional therapies.

v. There is a fairly high report of adverse events. Most reported are mild to moderate and are generally reversible.

6. Dosing Issues in Veterinary Species

a. Toxicity & Safety

i. No current safety and tolerability studies in veterinary medicine

ii. 338 clinical toxicity cases reported in the veterinary literature

1. 2 fatalities

2. Meola et al noted a sharp increase in cases with legalization

3. Neurologic symptoms are most common

4. In Meola et al 21% had combined chocolate toxicity

iii. Toxicity Symptoms in Dogs

1. Mentation changes: Depression/dullness/obtunded/stupor/coma

2. Hypersalivation

3. Vomiting

4. Hyperesthesia

5. Tremors

6. Ataxia

7. Mydriasis (Hippus)

8. Hypothermia

9. Leaking Urine

10. Bradycardia

iv. Testing for toxicity

1. There is debate in the veterinary community about the accuracy of urine screening for exposure.

2. Meola et al. Six of 131 tested dogs with known exposure had a false negative on urine screen. 95% sensitivity.

v. Other safety concerns

1. An additional concern is reports of pesticides in dispensary obtained marijuana products. In one such report, 84% of tested samples had unacceptable levels of pesticides. Legal regulation and enforcement of pesticide use on marijuana are still in development in most states.

b. Bioavailability

i. Cannabis undergoes significant first pass effect when taken orally

ii. Samara et al: 6 dogs given CBD. No CBD could be detected in 3 dogs. In the other three dogs, bioavailability ranged from 13 to 19%

1. The dimethylheptyl homolog of CBD was also looked at in 8 dogs. 4/8 had no detectable CBD. In the other four bioavailability ranged from 3 to 43%

iii. Zgair et al showed that in rats, systemic absorption of both THC and CBD was increased by 2.5 and 3-fold respectively when co-administered with lipids.

iv. Humans are reported to have a 6% oral bioavailability of both THC and CBD. Bioavailability increases with other routes of administration and carrier molecules. For example, inhaled bioavailability for CBD is 31%.

7. Legality

a. Legalization of Marijuana

i. Approved in 28 states for humans, including Pennsylvania. Zero states have approval for veterinary medicine

ii. Approved for recreational use in 8 states and Washington DC

b. Even in states where it is legal, there continue to be challenges

i. Raids on licensed dispensaries continue despite the Rohrabacher-Farr amendment

c. Is CBD Marijuana?

i. There is some confusion whether products containing less than 0.3% THC are legal or not.

1. The DEA clarified their position on 12/14/16 that all cannabinoids were in fact marijuana, and therefore CBD is a schedule 1 substance.

2. The Hemp Industrial Association objected to this characterization, as they see it as violating Sec 7606 of the Farm Bill, which is the provision allowing for the sale of products with less than 0.3% THC.

3. There is a lawsuit pending.

d. The current Attorney General, Jeff Sessions, has publicly taken a dim view of all marijuana use, be it medical or not.

i. Recently quoted in the press as trying to repeal the Rohrabacher–Farr amendment, which prohibits the federal government from interfering with the implementation of state marijuana laws

e. State Veterinary Medical Boards

i. Generally, VMBs, even in recreational legal states, stand firmly against medical marijuana in pets.

ii. Oregon allows for veterinarians to discuss medical marijuana, with appropriate warnings about unknown efficacy and safety, and with signed consent for non-standard treatment.

f. AVMA: The AVMA has no official policy, however in their At Work blog, they put forth the following statement:

“Veterinarians making treatment decisions must use sound clinical judgment and current medical information, and must be in compliance with federal, state and local laws and regulations.

Medications do not necessarily work the same in animals as they do people, which underscores the value of extensive studies showing safety and efficacy, and also the value of the FDA’s approval process for drugs used in animals.