10 May 2021
Image: © Bikej Barakus / Adobe Stock
Research has indicated potential benefits of cannabidiol (CBD) administration (Crippa et al, 2018; The Academy of Medical Cannabis, 2020; Russo, 2008).
Many trials have been completed – and are ongoing – globally that show CBD may impact a variety of conditions. Data from these trials has been instrumental in supporting the approval of cannabis-based human medicines.
One in 10 trials are being carried out in the UK, with new data added weekly. Trials are researching the following conditions:
Several recent publications relate to CBD – this article highlights three of these:
Gamble et al (2018) published a double‑blind, placebo-controlled crossover study investigating the efficacy of CBD-based oil administered twice daily at a dose of 2mg/kg to dogs affected by OA:
“Single-dose pharmacokinetics was performed using two different doses of CBD‑enriched (2mg/kg and 8mg/kg) oil. Thereafter, a randomised placebo-controlled, veterinarian and owner-blinded, crossover study was conducted.
“Dogs received each of two treatments: CBD oil (2mg/kg) or placebo oil every 12 hours. Each treatment lasted for four weeks with a two-week washout period. Baseline veterinary assessment and owner questionnaires were completed before initiating each treatment, and at weeks two and four. Haematology, serum chemistry and physical examinations were performed at each visit. A mixed model analysis, analysing the change from enrolment baseline for all other time points, was used for all variables of interest, with a p≤0.05 defined as significant.
“Clinically, canine brief pain inventory and Hudson activity scores showed a significant decrease in pain and increase in activity (p<0.01) with CBD oil. Veterinary assessment showed decreased pain during CBD treatment (p<0.02). No side effects were reported by owners; however, serum chemistry showed an increase in alkaline phosphatase during CBD treatment (p<0.01).”
The study also established that the half‑life of CBD in dogs was 4.2 hours. The limitations of this study were that it involved a small sample size of only 16 dogs and was of short duration. Additionally, the dogs had a variety of presenting OA signs (Morrow and Belshaw, 2020).
McGrath et al (2019) undertook a 12-week randomised, blinded, controlled clinical trial to assess the effect of oral CBD administration in addition to conventional antiepileptic treatment on seizure frequency in 26 dogs with intractable idiopathic epilepsy:
“Dogs were randomly assigned to a CBD (n=12) or placebo (14) group. The CBD group received CBD-infused oil (2.5mg/kg by mouth) twice daily for 12 weeks in addition to existing antiepileptic treatments, and the placebo group received non-infused oil under the same conditions. Seizure activity, adverse effects and plasma CBD concentrations were compared between groups.
“Two dogs in the CBD group developed ataxia and were withdrawn from the study. After other exclusions, nine dogs in the CBD group and seven in the placebo group were included in the analysis. Dogs in the CBD group had a significant (median change 33%) reduction in seizure frequency, compared with the placebo group. However, the proportion of dogs considered responders to treatment (greater than or equal to 50% decrease in seizure activity) was similar between groups. Plasma CBD concentrations were correlated with reduction in seizure frequency. Dogs in the CBD group had a significant increase in serum alkaline phosphatase activity. No adverse behavioural effects were reported by owners.”
All dogs remained on their usual anticonvulsant medications, including phenobarbital and potassium bromide. Additional research is planned to determine whether a higher dosage of CBD would be effective in reducing seizure activity by greater than or equal to 50%.
This study is limited by the small number of candidates and relatively short trial period.
A recent study from Baylor College of Medicine in Houston (Verrico et al, 2020) evaluated CBD for its ability to modulate the production of proinflammatory cytokines in vitro and in murine models of induced inflammation, and assessed the bioavailability of liposomally encapsulated CBD.
Naked and liposomally encapsulated CBD were subsequently tested as analgesics in a four-week, randomised, placebo-controlled, double-blinded study in a spontaneous canine model of OA (client-owned animals), where clinical effect was assessed by the Helsinki Chronic Pain Index (HCPI):
“To validate that the CBD used for these studies might potentiate anti-inflammatory effects relevant to arthritis, two different inflammatory stimuli were applied to four different relevant cell populations and to mouse models of inflammation.
“In vitro and in vivo, CBD significantly attenuated the production of proinflammatory cytokines [interleukin] IL-6 and [total necrosis factor]-α, while elevating levels of anti‑inflammatory IL-10. The liposomal formulation significantly increased bioavailability of CBD in mice and in humans.
“In the veterinary study, CBD significantly decreased pain and increased mobility as assessed by the HCPI in a dose-dependent fashion, in dogs previously diagnosed with OA. Liposomal CBD (20mg/day) was as effective as the highest dose of non-liposomal CBD (50mg/day) in improving clinical outcomes.
“Hematocrit, comprehensive metabolic profile, and clinical chemistry indicated no significant detrimental impact of CBD administration over the four-week analysis period.“
Weaknesses of the study include the small cohort of animals involved (20 in total), the lack of explanation as to what joints were affected with OA, the duration since the diagnosis and the method by which this diagnosis was obtained. The short follow-up period for biochemical assessment is also worthy of note.
Three cannabinoid products are authorised for medical use in humans in the UK:
The hype around CBD is largely consumer driven, based on a belief it has certain medicinal benefits that have not yet been definitively proven scientifically. This belief has created a huge and largely unregulated market in human food supplements containing CBD, often with poor production standards.
A recent study showed this market in the UK was worth £300 million – that is more than the market for vitamin C and vitamin D combined. It is predicted to grow rapidly and be worth just short of £1 billion in 2025.
The BBC programme Trust Me, I’m a Doctor investigated CBD products available to the public, finding many of them to be of dubious quality (https://youtu.be/m6UWYFlcXUI).
Another survey carried out by The Centre for Medicinal Cannabis on CBD oils available on the high street revealed that one product being retailed for £90 contained no CBDs at all; 11 contained less than 50% of the stated CBD content; 8 contained levels of solvents or heavy metals above that permitted in foodstuffs; and 1 contained 3.8% alcohol, making it an alcoholic drink. Additionally, 45% of products contained levels of THC and another CBD – cannabinol – that were illegal.
In the UK, you can apply for a licence to grow industrial hemp containing less than 0.2% THC. According to the Home Office, the final product being sold must contain less than 1mg per unit THC: “No one component part of the product or preparation contains more than one milligram of the controlled drug.”
The smallest units sold are usually 10ml – this means 1mg in 10ml; in other words, 0.01% THC, or virtually zero. This legislation is often confused so that products may be sold that have higher‑than‑legal levels of THC. The legislation can be found at https://bit.ly/3aqf2u5
This fact sheet includes the following important statement:
“CBD as an isolated substance, in its pure form, would not be controlled under the Misuse of Drugs Act 1971 (MDA 1971) or the Misuse of Drugs Regulations 2001 (MDR 2001). If a CBD ‘product’ contained any controlled CBDs, however unintentionally or otherwise (such as THC or tetrahydrocannabivarin), then it is highly likely that the product would be controlled.
“It is our understanding that it is very difficult to isolate pure CBD, and in our experience many products in fact do not fully disclose their contents or provide a full spectrum analysis at an appropriate level of sensitivity to accurately and consistently determine their true content or control status.
“Against this background, the presumption has to be one of caution – that is, that a CBD‑containing product would be controlled under the MDA 1971/MDR 2001 as a result of its other cannabinoid content.”
Basically, the product must contain pure CBD only and any other cannabinoid present would render it a controlled substance. This underlines the importance for vets to choose their supply of CBD product with great care.
The Home Office also restricts the importation of CBD-containing products due to the difficulty in ensuring they do not contain the controlled substance, THC.
The legal situation regarding CBD for administration to animals is very different to that regarding human use as a result of the VMD statement in 2018.
CBD as a food supplement can be sold in shops for people, so long as no medicinal claims are made. It must not be available to buy for animals anywhere as it can only be administered to an animal once it has been prescribed by a veterinary surgeon as an unlicensed medication.
The VMD statement on CBD, published in September 2018, stated:
“We consider that veterinary products containing CBD are veterinary medicines and should be regulated as such. CBD products for use in animals, therefore, now require a marketing authorisation before they can be sold or supplied in the UK. There are currently no CBD-based products that have been granted a UK veterinary marketing authorisation.
“As there are currently no CBD products authorised in the UK for veterinary use, a veterinary surgeon may prescribe a legally obtained human CBD product under the provisions of the prescribing cascade
“Administration of an unauthorised product containing CBD without a veterinary prescription is an offence under Regulation 8 of the Veterinary Medicines Regulations. Companies supplying CBD products for human use in line with the requirements of the Medicines and Healthcare products Regulatory Agency must not indicate or recommend their products for use on animals.”
The conditions for cascade are clear:
“Where there is no suitable veterinary medicine authorised in the UK for the specific condition in the animal being treated, in particular to avoid unnecessary suffering, vets are permitted to use their clinical judgement to treat animals under their care in accordance with the cascade.”
The cascade is a risk-based decision tree. The steps, in descending order of suitability, are:
The availability of a human product (Epidyolex) means this product sits higher within the decision tree and should, therefore, be first choice under the cascade.
Epidyolex is currently only available to specialist doctors in hospital clinics. In situations where all efforts to source a human alternative have proved unsuccessful, vets are permitted to prescribe a legally obtained human CBD product under the guidance. Vets should ensure that any product they prescribe is of the highest quality and regulation available.
Vets who wish to prescribe CBD to a patient must, therefore, take both the VMD statement and the cascade into consideration. Additionally, the method of administration, quality and safety of the product – and any potential drug interactions – should be assessed.
Absorption of CBD has been shown to be highest with inhalation. Ingestion of oil results in a bioavailability of only 5% to 10% due to the first pass effect in the liver.
Several authors have suggested the sublingual route may increase the bioavailability by bypassing the liver. From the available research, the authors can conclude CBD is most available if administered in oil after a meal.
CBD is metabolised by cytochrome P450 (CYP) enzymes, specifically CYP2C and CYP3A. This gives the potential for interactions with co-administered medicines.
CBD may either reduce or prolong the effect of medicines such as anaesthetics and sedatives, certain antibiotics, antiepileptic drugs, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, antiarrhythmic medications, ageing and dementia drugs, and cytotoxic drugs. A knowledge of these potential interactions is essential if CBD is to be prescribed for our veterinary patients.
When dosing with CBD, the accepted protocol is to start low and go slow. Several animal models of anxiety/depression, however, have shown an inverted bell-shaped dose‑response curve produced by CBD, so achieving a clinically effective dose may be more complicated (Stott et al, 2013; Millar et al, 2018; Knaub et al, 2019; Bartner et al, 2018; Samara et al, 1988; Gamble et al, 2018; Zgair et al, 2017).
It is virtually impossible to ensure the quality and safety of an unauthorised over the counter CBD product.
The cannabis plant is an accumulator, which means it concentrates pesticides, heavy metals, solvents and other contaminants. Production of a CBD-containing product must ensure these unwanted contaminants are removed.
Every product should have a batch number traceable to a certificate of analysis (CoA) to confirm it contains 0% THC. The CoA is only as reliable as the producer and supply chain, so, ideally, independent analysis should be made available.
If the producer is unregulated, how will you know if the final product really contains what the CoA states? Self-certification is an obvious cause of concern.
High-quality products, such as those manufactured by medical specials companies, will be regulated by Good Manufacturing Practice and Good Distribution Practice guidelines. For more details, visit https://bit.ly/3tB1a7B
It is clear the area of phytocannabinoids is an interesting and rapidly expanding area. Research has revealed many potential areas where CBD may become clinically useful, but much has yet to be proven – both in the human and animal fields.
Many factors – both legal and clinical – need to be considered before a veterinary prescription for CBD is provided. For those “last resort” cases where no treatment is available, or the authorised treatment is not helping or tolerated, it could be an option – albeit one that should be approached with caution.
