CBD for canine arthritis. What do we know?

 
Cannabis-leaf-overlayed-with-CBD-chemical-formula
 

CBD for canine arthritis. What do we know?

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It is clear from online forum discussions among dog owners that there is interest in the perceived benefits of cannabidiol (CBD). Some dog owners either already give CBD to their dogs, or are interested in trying it, to relieve arthritis pain. Consequently veterinary professionals may be asked for advice about CBD or be asked to prescribe it. By doing this module you will:

  • understand what is known about the physiological effects of CBD in dogs;

  • know the legal status of CBD products, including whether they can be prescribed;

  • be aware of the published evidence on the clinical efficacy of CBD in dogs with osteoarthritis; 

  • be aware of what is known about the safety of CBD in dogs.

Cannabidiol (CBD) is one of many substances (collectively called cannabinoids) that occur naturally in the cannabis plant Cannabis sativa. Cannabis has traditionally been used by humans for its psychoactive effects, which are mainly due to the cannabinoid delta-9-tetrahydrocannabinol (THC). Unlike THC, CBD does not have psychoactive effects (WHO 2018). 

Mammals produce substances (which have become known as endocannabinoids) that interact with the same receptors in the body as cannabinoids. This has led to the notion that humans and dogs have an endocannabinoid system. However, the exact role of endocannabinoids in the body is not yet clear. They appear to be involved in various bodily functions, including the control of appetite, pain perception and memory formation (Grotenhermen 2004). CBD is used in humans for the treatment of seizures in rare forms of epilepsy, but the mechanism of anticonvulsant action, which appears not involve cannabinoid receptors, is not known (FDA 2018). So far, the precise mode of action that CBD might have in relieving pain is not understood, but more information is emerging from research. Endocannabinoids have been detected in the synovial fluid of dogs with osteoarthritis, although the relevance of this is not yet clear (Valastro et al. 2017). In rats with experimentally-induced osteoarthritis pain, injection of CBD into the joints reduced pain, and prophylactic use of CBD prevented pain and nerve damage in the joints (Philpot et al. 2017). 

There are two main pieces of UK legislation affecting cannabis: 

  • The Misuse of Drugs Act 1971 controls drugs that are “dangerous or otherwise harmful” under a 3-tier system of classification (classes A, B and C) (Misuse of Drugs Act 1971).  The class determines the penalties that apply to offences involving the different drugs, according to the harmfulness attributable to the drug when it is misused.

Class A drugs include cocaine, heroin, LSD, morphine. 

Class B drugs include cannabis, cannabis resin, codeine, ketamine, pholcodine. 

Class C drugs include benzodiazepines, tramadol.

  • The Misuse of Drugs Regulations regulate the availability of controlled drugs by placing them in one of 5 Schedules to the Regulations (Misuse of Drugs Regulations 2001). The Schedule primarily dictates the extent to which it is lawful to import, export, produce, supply, administer and possess the drug and also imposes requirements around prescription writing, record keeping, labelling and safe custody. Schedule 1 drugs are considered to have no therapeutic use and a Home Office licence is generally required for their production, possession or supply. 

Cannabis, cannabis resin and cannabinol (a cannabinoid formed from degraded THC) are classed as Schedule 1 drugs, making them illegal to possess or supply. This is the reason why the cannabis plant is not used in herbal medicine in the UK and why research into the therapeutic uses of cannabis and its constituents has been inhibited.

Cannabis for medical use (so-called “medicinal cannabis”) is legal in many countries (Connelly 2018). In these countries the government controls cannabis production, and supply is restricted to regulated outlets (e.g. pharmacies), although some countries allow self-cultivation. Some countries restrict the conditions for which cannabis can be prescribed. The UK government recently announced that it will consider applications from senior clinicians for the prescription of medicinal cannabis for specific human patients, and that it will review the scheduling of cannabis, but that this will not affect the classification of cannabis as a Class B controlled drug (Home Office 2018).

CBD does not come under the Misuse of Drugs legislation. However, in the UK, CBD is considered to be a veterinary medicine. The veterinary medicines regulator (the Veterinary Medicines Directorate [VMD]) made this clear on 14 September 2018 (VMD statement 2018) and has since written to UK CBD suppliers and manufacturers informing them of the position (Vet Record 2018). This means that without a marketing authorisation it is illegal to sell, supply or advertise CBD products for pets, with or without specific treatment claims. There are currently no authorised CBD products for animals in the UK. 

Products containing CBD that are marketed for medicinal purposes in humans are considered by the human medicines regulator (the Medicines and Healthcare Products Regulatory Agency [MHRA]) to be medicines, and so require a marketing authorisation (MHRA 2016). There are currently no products containing CBD alone authorised in the UK for medicinal use in humans. In the UK, there is an authorised medicine containing cannabis extract (which contains CBD and THC) for symptom improvement in people with spasticity due to multiple sclerosis (Sativex oral spray), and in the USA there is an authorised medicine containing CBD for use in humans with rare forms of epilepsy (Epidiolex oral solution).

In the UK, some companies market human CBD products as supplements. It is illegal for the companies to make specific medical claims for these without a marketing authorisation. These products are unregulated and not standardised. Studies in the USA have found that the amount of active ingredient in commercial unregulated CBD products varies widely, or is often inconsistent with the amounts stated on the label (Bonn-Miller et al 2017; US FDA 2017). 

Varieties of Cannabis sativa that contain very little cannabinoids (often referred to as hemp or industrial hemp) have been cultivated for their seed and fibre and to have low levels of THC. These, and the oil derived from seeds, are found in some herbal products (Stockley 2013), including some marketed for dogs. They may contain little or no CBD.

A study of the absorption of the raw material form of CBD in gelatin capsules given to 6 dogs (at a dose of 7.5mg/kg to 11.25mg/kg) found that oral absorption was poor and erratic (with none detectable in 3 of the dogs) (Samara et al. 1988). This may be due to the poor water solubility of CBD and a high degree of liver metabolism (first pass effect). After intravenous administration to dogs, CBD was widely distributed in the body and had a mean half life of 7 to 9 hours (Samara et al. 1988).

A study of the oral absorption of CBD from a formulation containing hemp extract in olive oil (equivalent to a CBD dose of 2mg/kg or 8mg/kg) found detectable levels of CBD in all 4 dogs and a half life of around 4 hours (Gamble et al 2018). 

In humans, CBD is metabolised in the liver by several cytochrome P450 isoenzymes and so has a potential for drug interactions, but the clinical relevance of this in dogs is not known (WHO 2018; FDA 2018). 

One randomised controlled trial of CBD in dogs has been published in full (Gamble et al 2018). The trial included 22 client-owned dogs with radiographic evidence of osteoarthritis, signs of pain according to owner assessment, visually detectable lameness, and painful joins on palpation. The dogs were allowed to continue on NSAIDs, fish oil, and/or glucosamine/chondroitin sulfate. 

This trial assessed a commercial industrial hemp extract in an olive oil base containing around 10mg/mL of CBD; the product also contained small amounts of THC and other cannabinoids. The dogs received CBD (at a dose of 2mg/kg) or placebo (olive oil containing anise and peppermint oils to give a similar herbal smell) twice daily for 4 weeks. This was followed by a 2-week washout period after which the dogs were switched to placebo or CBD for a further 4 weeks. Owners and vets were blind to treatment allocation. Veterinary clinical assessment (using a clinical scoring system) and owner-completed Canine Brief Pain Inventory (CBPI) (Pain and Activity Interference questions) and Hudson scale scores (assessing pain and lameness) were evaluated at baseline and at weeks 2 and 4. 

Among the 16 dogs that completed the trial, the researchers found a small but statistically significant decrease in pain and an increase in activity relative to baseline values at weeks 2 and 4 during CBD therapy as scored by owners using CBPI and Hudson scales. Mean CBPI (pain) score fell from 21 to 14 (on a scale of 0–40); mean CBPI (activity) score fell from 35 to 25 (on a scale of 0–60); Hudson score increased from 54 to 67 (on a scale of 0–110); scores did not change significantly with placebo. There were no changes in veterinary-assessed lameness, pain or weight-bearing. 

The trial has several limitations: a small number of dogs, a relatively short duration for a chronic condition with signs that wax and wane, and it was funded by the company that markets the hemp extract used in the study. It is also important to be aware that these results cannot be applied to other CBD products, which may contain different amounts of CBD. Other studies are ongoing but it is too soon to know whether CBD is effective at relieving pain in dogs. 

In the clinical trial described above, no adverse effects were detected with CBD apart from an increase in liver alkaline phosphatase enzymes, which increased significantly in 9 out of 16 dogs over the 4 weeks of the trial (Gamble et al 2018).  In humans taking CBD (at a dose of 10mg/kg/day) for the treatment of seizures, treatment was associated with hepatocellular injury (dose-related increases in liver transaminases) and somnolence and sedation (FDA 2018). It is possible that adverse effects may be caused by varying amounts of other constituents (e.g. THC) in commercial unregulated CBD products.

There are no licensed CBD products for animals. A vet may prescribe a human medicine for a pet in accordance with the veterinary prescribing cascade, which allows the clinical needs of an animal to be met with an unlicensed product (VMD 2015). There are no licensed human forms of CBD in the UK and one in the USA (Epidiolex). CBD supplements marketed for humans in the UK are unregulated. Given that the dose and benefit of CBD in animals is uncertain, it is difficult to see a justification for prescribing a CBD product for an animal, except in the context of a clinical trial using a standardised product. 

There are currently many uncertainties about whether CBD is beneficial for dogs with osteoarthritis, and no suitable veterinary or human products. If CBD is effective in dogs, we do not yet know the optimum dose. Little is known about the adverse effects of CBD in dogs; in one small trial it appeared to be generally well tolerated but liver enzymes were raised in more than half of the dogs while on CBD and there is a potential for CBD to interact with other medications. CBD products sold as supplements for humans are unregulated and so their contents are unstandardised. Research into the therapeutic effects of CBD is ongoing and may be made more possible through future changes in the legislation affecting cannabis.

PODCAST

If you prefer, you can listen to the whole audio presentation of this module using the following podcast. Don't forget that you can also download the podcast to your iPod, music player, tablet or smartphone using the Download link on the right of the audio player.

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How we produced this module

Our modules start with a detailed outline and electronic literature search. The collaborating author on this module was Andrea Tarr, a pharmacist and specialist in medicines evaluation. The draft is circulated unsigned to a wide range of commentators, including practising first-opinion vets, topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration. 

References

Search strategy: We searched PubMed via RCVS Discovery, and CAB Abstracts using the terms (CBD OR cannabidiol) AND (dog OR dogs OR canine OR canines).

Bonn-Miller MO et al. Labelling accuracy of cannabidiol extracts sold onlineJAMA 2017; 318: 1708–9.

Borgelt LM et al. The pharmacologic and clinical effects of medical cannabis. Phamacother 2013; 33: 195–209.

Connelly D. A quick guide to medical cannabis. Pharm J 2018; 301: 18–9.

Gamble L-J et al. Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in osteoarthritic dogs. Front Vet Sci 2018; 5: 165.

Grotenhermen F. Pharmacology of cannabinoids. Neuroendocrinol Letters 2004; 25:14–23.

Home Office. Cannabis and cannabis-related medicinal products, September 2018.

Misuse of Drugs Act 1971. [Accessed 25.10.18]

Misuse of Drugs Regulations 2001. [Accessed 25.10.18]

Medicines and Healthcare Products Regulatory Agency. MHRA statement on products containing cannabidiol (CBD), October 2016. 

Philpot et al. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in osteoarthritis 2017; 158: 2242–51.

In brief. Cannabidiol products should be regulated. Vet Record 2018; 183: 13.

Samara E et al. Pharmacokinetics of cannabidiol in dogs. Drug Metabolism and Disposition May 1988; 16: 469–72.

Stockley’s herbal medicines interactions. Williamson E et al (eds). Pharmaceutical Press, 2013.

US Food and Drug Administration. Warning letters and test results for cannabidiol-related products, February 2017. 

US Food and Drug Administration. Epidiolex (cannabidiol oral solution). Highlights of prescribing information, June 2018.

Valastro C et al. Characterisation of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: a pilot study. BMC Vet Res 2017; 13: 309.

Veterinary Medicines Directorate. The cascade: prescribing unlicensed medicines. [Accessed 25. 10.18].

Veterinary Medicines Directorate. VMD statement on veterinary medicinal products containing cannabidiol, September 2018. 

World Health Organization. Cannabidiol (CBD) critical review report. Expert Committee Review on Drug Dependence. 40th meeting, June 2018.