The following document is the research review paper I authored some time ago. It was written in a scientific format and submitted for publication in a veterinary journal. The language of the paper reflects this fact as it was originally intended for an audience with a medical background. I have decided to post it on VetGuru.com in an effort to more expediently raise awareness about the issue (and in response to the many inquiries I have received from pet owners and veterinarians).

Unfortunately, I was advised by my legal council to redact some information that they felt may constitute “aiding and abetting”; which might expose me to some negative legal ramifications.  Please note that this paper was not intended to be an endorsement of the use of medical marijuana (MM) on pets. There are clearly toxicity issues that represent some very real risks to your pet’s health. I do not recommend that pet owners administer MM products to their pets at this time.  Thank you for taking the time to educate yourself.

Dr. Douglas Kramer

Medical Marijuana for Pets: A review of the Existing Research

Overview of article:

1. 1. Introduction and Background
2. 2. Available Cannabinoid Delivery Systems
3. 3. Veterinary Therapeutic Uses and Reviews of Existing Research
4. 4. Tolerability and side effects
5. 5. Quality Control & Standardization
6. 6. Regulation & Legal Considerations
7. 7. Conclusion

Importance of the field:

The therapeutic virtues of cannabinoids present in the plants of the cannabis genus have been extensively described for a wide range of medical indications in human beings. Recent research suggests that the endocannabinoid system may also play an important analgesic role in managing pain in animal patients as well. Given the rather limited pain control options available to the veterinary practitioner cannabis may offer an effective and safe alternative or adjunctive treatment for post-operative or intractable pain control as well as for palliative care. In addition, it may prove to be a safer anti-inflammatory and anti-emetic agent as well.

Areas covered in this review:

This article will attempt to present existing research concerning marijuana’s use as an analgesic and therapeutic agent in veterinary medicine. The main objective is to provide veterinarians with a summary of more contemporary literature, data and research exploring the analgesic properties of marijuana. Furthermore, it  aims to explore the possibly of employing marijuana in the practice of veterinary medicine to treat patients afflicted with painful  conditions resistant to traditional medications. Their adjunctive addition to the pharmacological armamentarium for treatment of pain is potentially beneficial.

 

Introduction and Background:

Cannabinoids and their receptors (most notably CB1 and CB2) are involved in a variety of physiological processes including appetite, mood, and the sensation of pain. The most notable cannabinoids are Delta-9–tetrahydrocannabinol (Herein referred to simply as “THC”) and cannabidiol (CBD).  THC is a partial CB1 receptor agonist while cannabidiol acts as a CB1 receptor antagonist. Cannabidiol is of particular interest as it promotes anti-inflammatory and analgesic effects.

The cannabinoid receptors CB1 and CB2 have received the most attention from the scientific community. The CB1 and CB2 receptors of the endocannabinoid system are activated by the major psychoactive component of marijuana; THC (Grotenhermen, 2004). CB1 cannabinoid receptors are highly localized in both peripheral and central nervous system (CNS) sites and have been shown to have a particular predilection for nocioceptive areas (Herkenham et al 1990; Hohmann et al 1999; Fox et al 2001; Dogrul et al 2003).  Furthermore, a synergistic relationship between peripheral and central cannabinoid receptor function has been clearly demonstrated (Dogrul et al 2003). CB2 receptors predominate in lymphoid and immune tissues outside the CNS and are believed to modulate immune function (Ralevic, 2003).  This receptor is also reported to be an important mediator for suppressing both pain and inflammatory processes (Mackie 2006).

Other important scientific discoveries revolve around the discovery and exploration of endogenous cannabinoid ligands referred to as “endocannabinoids”. These ligands include anandamide (arachidonylethanolamide, AEA) discovered in porcine brain and 2-arachidonylglycerol (2-AG) discovered  in canine gut tissue (Devane et al 1992; Mechoulam et al 1995). These chemical messenger molecules act in the brain to help regulate pain, anxiety, hunger, and vomiting.  Together with the cannabinoid receptors the endocannabionoid ligands and their metabolizing enzymes are referred to as the “endocannabionid system”. The endocannabinoid system appears to be an endogenous pain control system in both humans and animals.

 

Figure 1: Molecular structures THC and four cannabinoids:

 

 

Available Cannabinoids and Delivery Vehicles:

The field of medicinal marijuana has spawned an entire industry of developing novel and innovative delivery systems (fig 2).  Administration of medicinal marijuana is no longer limited to smoking (combustion) and edible products. Additional forms of administration include dissolving oral strips, liquid misting sprays and transdermal patches. Synthetic Cannabinoids have been developed to be delivered by a wide variety of routes. Researchers are currently working on a THC aerosol delivery system administered to the patient via a metered-dose inhaler (Wilson, D.M. et al 2002).Rectal suppositories have been found to be effective in treating colic, spasticity and pain (Brenneisen R. et al 1996). Topical products are being investigated for their analgesic effects as well (Dogrul, A et al 2003).  Even a water-soluble analog of THC is being developed for possible intravenous use (Pertwee R.G et al 2000). The cannabinoids are soluble in lipids and alcohols. As such, anything that can be produced using butter or oil as an ingredient can be made into an oral delivery system for medicinal marijuana.

 

Figure 2 (table) Cannabinoid Delivery Vehicles:

Administration Route	Examples
Oral	Edibles & Liquid Solutions including “cannabutter”, biscuits, cookies, soda pop, tinctures, extracts
Inhalation	Second Hand Smoke (Combustion of dried Plant material), vapor, resin, hashish(hash), kief, hash oil, electronic cigarette with liquid THC, THC “wax”
Topical	Lotions, Ointments, salves, poultice
Intraocular	Eyes Drops
Sublingual & Buccal	Dissolving Thin Films, Liquid Sprays
Transdermal (Unproven)	Transdermal Skin Patches
Rectal	Suppositories
Intravenous	water-soluble analog of THC

 

A Brief History of the use Of Medicinal Marijuana in Veterinary Medicine:

Prior to its prohibition, the active ingredients found in marijuana were found in veterinary products designed to treat a wide variety of ailments. “Rawleigh’s Colic and Bloat Compound” for example was administered orally to both bovine and equine patients. “Pratts Brand Veterinary colic remedy” is another marijuana-based medication of old. Today, in many countries marijuana products are used as treatments for animals. Cannabis is widely used in Asia where it is fed to elephants and oxen to relieve fatigue. It also reportedly gives the animals’ greater strength and endurance (Robinson, R. 1995).  The Marijuana plant is also used in parts of the world to fatten and increase egg production in poultry. Dried, crushed cannabis seeds fed to broiler chicks dramatically increased their growth rates and food conversion rates while decreasing the amount of food they consumed and the associated costs to the producer (Khan et al 2010).  It is clear that in many parts of the world the use of marijuana on animals is commonplace.

 

 

Veterinary Analgesic  uses and clinical trial review:

Clinical trials focusing primarily on domestic animals are limited and difficult to locate. However, scientific research has confirmed the existence of cannabis receptors in many different species of animals (Berdyshev, 2000).  Neuronal cannabinoid receptors, for example, have been found in rat, guinea pig, dog, monkey, pig and human brains and peripheral nerves. Indeed, cannabinoid receptors are preserved across the animal kingdom, which suggests that they play an important developmental and physiologic role (Salzet, 2000; Fride, 2004). The existing data supports the suggestion that cannabis may act as therapeutic agent for pain, nausea, anxiety and neurologic disorders in pets (Fig 3).

There have been several important clinical studies suggesting promising therapeutic potential for CB1and CB2 agonists in domestic animals. We now know that the endocannabinoid system is active both centrally and peripherally where CB1 stimulation reduces pain, inflammation and hyperalgesia (Richardson et al 1998c). Recent experiments in mice have even suggested the paramount importance of peripheral over central CB1 receptors in nociception of pain (Agarwal et al 2007). The evidence of analgesic properties has in fact been known for over a quarter-century.  Researchers have long been aware that THC possesses analgesic activity similar to morphine in rats (Sofia et al 1975). More recently, it has been observed that mice exposed to marijuana smoke experienced analgesia as a result of the THC constituent acting at CB1 receptors (Varvel et al 2005).

Equally as significant scientific evidence lends credence to the belief that the cannabinoids may act synergistically with opiods, allowing veterinarians to use opiod drugs more sparingly and perhaps mitigating some of the adverse effects of the opiod drug class. These effects include dysphoria, anxiety, and nausea. THC has also been shown to stimulate beta-endorphin production and may allow opiate sparing in clinical application by acting synergistically with mu-receptor agonists to amplify antinociception. Researchers found that THC and morphine administered to mice at 20mg/kg each resulted in equally effective analgesia in both control and morphine-tolerant patients (Manzanares et al 1998; Cichewicz et a 1999; Welch, S. 1999).  This indicates that there is no cross tolerance observed in patients treated with an analgesic combination of THC and morphine. While some THC tolerance was observed, morphine tolerance did not occur after 7 days of treatment. This study brings up the possibility that medicinal marijuana may help prevent morphine tolerance issues (a topic not often addressed in veterinary medicine). One can reasonably infer that combinations of these drugs may be useful in chronic pain patients over morphine administration alone. In fact, other researchers have noted that the cannabinoids may also act to decrease the test subjects’ overall sensitivity to pain.  (Johanek LM & Simone  2004; Ibrahim et al 2005)

In short summary the limited existing animal research indicates that there is sound scientific evidence that marijuana does indeed act as an analgesic agent in animal test subjects. It is clear that marijuana has potential effects on the control of pain at many different levels of analysis. As one researcher, who discovered that THC functions as a reward system in squirrel monkeys, noted: “Most of what we know about cannabinoid reward comes from animal research” (Panlilo et al 2010).

 

Figure 3: Possible Therapeutic Uses for cannabis in pets:

Therapeutic Use	Examples
Analgesia Pain	Post-Op Pain, Palliative Care (Hospice Use to increase quality of life), Intractable Pain associated with medical conditions (Eg. Osteosarcoma), adjunct to opiod use
Anxiolytic ( Anxiety)	Separation anxiety, Dementia
Nausea & Appetite Stimulant	Alleviate clinical signs associated with chemotherapy
Neurologic Disorders	Epileptic Seizures

 

Additional Medical Benefits:

Cannabinoids may offer significant therapeutic benefits beyond analgesia. These include the following:

1.Antiemetic Properties:

Many researchers believe that the most well-established palliative effect of THC is the inhibition and mitigation of chemotherapy-induced nausea and vomiting.  Animal studies have indicated endocannabinoid modulation of emesis. (Darmani et al. 2001.)  Research has also demonstrated that CB1 receptor agonists reduced cisplatin-induced emesis in the Least Shrew (Petitet et al 1998). The cannabinoid CBD also has been demonstrated to possess similar antiemetic properties (Pertwee 2005). In addition, cannabinoid agonists have been shown to suppress the maintenance of vincristine-induced allodynia through activation of CB1 and CB2 receptors in the spinal cord (Rahn et al 2007).

2. Anti-inflammatory Properites:

The anti-inflammatory properties of THC have long been known and documented. THC is known to inhibit PGE-2 synthesis (Burstein et al 1973). More recent studies indicate that neither THC nor CBD produce significant cyclo-oxygenase  (COX)  inhibition at normal dosage levels. In contrast to most NSAID’s, these agents demonstrate no COX inhibition at all (Stott et al 2005a). This means that these cannabinoids present less of a risk of gastrointestinal ulceration (COX-1 agents) and possibly myocardial infarction (COX-2 agents) for the patient. In fact, THC has twenty times the anti-inflammatory potency of aspirin and twice that of hydrocortisone (Evans 1991).

3.Anxiolytic Sedative Properties:

Several studies support the belief that CB1 receptor antagonists, both endogenous and exogenous, have anxiolytic properties (Onaivi et al 1998). The discovery of the synthetic CB1 antagonist SR141716 have lent additional credibility to this hypothesis (Rinaldi-Carmona et al 1994).

4.Additional Medicinal Applications:

Tumor necrosis:

It has been demonstrated that THC and CBD possess the ability to produce apoptosis in malignant cells and inhibit cancer-induced angiogenesis (Kogan 2005; Ligresti et al 2006). Furthermore, CBD is able to inhibit tumor necrosis factor-alpha (TNF-alpha) in its own right in a rodent model of rheumatoid arthritis (Malfait et al 2000). Researchers have discovered that both cannabinoids possess neuroprotective antioxidant properties as well (Hampson et al 1998).

Research into the potential medicinal uses of marijuana to benefit both human and animal patients continues today at a rapid rate. New discoveries and scientific research papers are being published regularly. The more the scientific community delves into this subject, the more therapeutic potential is uncovered.

Tolerability and side effects :

Nearly every veterinary practitioner has had to treat a case of suspected marijuana toxicity.  The clinical signs of marijuana poisoning are almost entirely dose-dependent but THC has a very wide margin of safety (Small Animal Toxicology p.540-541). Clinical signs include weakness, vomiting, ataxia, tremors, urinary incontinence, bradycardia, and behavioral changes. Preliminary studies indicate that the clinical signs of marijuana toxicity in humans (almost exclusively oral ingestion) mimic those observed in dogs and cats. Despite extensive research we are unable to confirm a single fatality in a dog or cat attributed solely to the ingestions of excessive quantities of marijuana

(Paragraph Redacted)

In nearly all cases of marijuana poisoning treatment involves minimizing absorption (basic rules of treating ingestion of a toxic substance) and supportive care. Patients recover well usually within 72 hours post-exposure.

Reasonable Dosing Guidelines: (REDACTED)

Quality Control & Standardization:

The greatest problem concerning the use of medicinal marijuana is the clear lack of regulation and oversight. Recently, several commercial laboratories have emerged to help fill part of this void. These laboratories use gas chromatography (GC) and liquid chromatography–mass spectrometry (LC-MS) machines to generate a “cannabinoid profile” of a given MM sample (fig 4). In addition, the samples are tested for pesticide contamination and can be cultured to screen for fungal spores. However, these laboratories are independent operations that do not share standardized protocols or procedures. Sample analysis may vary wildly depending on the practices and equipment of the individual laboratory. Furthermore, there is no state or federal oversight to regulate the laboratories or guarantee quality control of the services provided.

Figure 4. Example of a Laboratory Analysis of a Medicinal Marijuana Sample:

 

 

 

 

Regulation & Legal Considerations:

At this time, there is no legal precedence for the use of medicinal marijuana on pets anywhere in the United States. Human physicians are recommending the use of medicinal marijuana despite its federal classification of being a schedule 1 controlled substance. The DEA and the federal government maintain the position that marijuana has no medicinal value whatsoever. This is why doctors write recommendations for the use of MM by their patients rather than writing them an actual prescription.  It’s not a case of semantics (recommendation vs prescription) but rather an important legal differentiation.  Furthermore, the courts have ruled that it is indeed legal for physicians to recommend the use of MM for their patients as they are protected from prosecution by the 1^st amendment. Some attorneys have suggested that veterinarians would be treated the same as their human counterparts by state and federal legal systems.  This remains to be seen. Ideally medical marijuana would be regulated by the FDA just like any other controlled substance. This cannot happen, however, until the medical community succeeds in getting the federal government to reschedule marijuana.

Conclusion:

Overwhelming documented and empirical evidence suggests that there is a role for medicinal marijuana in veterinary medicine. In many, many scientific studies, THC and its synthetic derivatives have been shown to be effective in most animal models of pain. The Issue cannot be summarized more clearly than the following passage: “the potent antinociceptive and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that cannabinoids exhibit significant potential as analgesics.” (lynch 2005).

(PARAGRAPH REDACTED)

*This research review paper represents proprietary work and may not be duplicated or referenced without the express written consent of Vet Guru, Inc.

 

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