30 Mar 2021
Image: Oleksandrum / Adobe Stock
The use of cannabidiol (CBD) is a “hot topic” currently, but most veterinary surgeons have limited knowledge or understanding of this complex area and often feel less well informed than their clients. What is CBD, what can it do and why is it so controversial?
This is a wide-ranging two-part article designed to give vets an overview of the history of hemp and its prohibition in the UK, the botany and phytochemistry of the cannabis plant, the endocannabinoid system (ECS) and how cannabinoids interact with it.
In addition, it will summarise the current research into the pharmacology and potential clinical effects of CBD, what products are available in the UK and how we assess their quality, the legal situation for UK vets who wish to prescribe cannabidiol-containing products and, finally, suggest some simple prescribing guidelines.
Cannabis is one of the oldest crops cultivated by man. Evidence exists of medicinal use of cannabis for 2,500 years (Lawler, 2019; Russo et al, 2008). Increasing use of pharmaceuticals resulted in a decline in cannabis usage during the 19th and into the 20th centuries. The earliest recorded findings in the UK are hemp seeds, which were found in a well in a Viking settlement on Micklegate in York dating back to the 10th century.
Hemp was grown extensively in coastal areas for fibre production, which was used to make rope and fibre essential for the navy and fishing boats. It was an extremely important crop for the economy, and so in 1532 King Henry VIII mandated that all landowners with 60 acres or more sow at least a quarter of an acre with “linseed, otherwise called flax or hempseed”.
Queen Elizabeth I subsequently increased the quotas and the penalties for not meeting them. Indeed, it is thought the demand for more land to grow hemp for fibre was part of the driving force to colonise new lands (Earleywine, 2005; Cox and Dannehl, 2007).
Medicinal cannabis was first introduced to the UK by William Brooke O’Shaughnessy, a doctor from Limerick. He was working as a physician for the East India Company in Bengal and arrived back with some samples of Cannabis indica (Macgillivray, 2015). His initial experiments make interesting reading for veterinary surgeons and are described in the following paragraphs:
“His first series of cannabis experiments were conducted on an unfortunate menagerie of animals (fish, vultures and storks, among others) and also, perhaps not without controversy today, a few children — all subjected to various preparations and extracts of C indica. The first experiment, for instance, involved administering ‘ten grains of Nipalese [sic] Churrus, dissolved in spirit’ to a ‘middling sized dog’.
“O’Shaughnessy’s breathless notes read: ‘In about half an hour he became stupid and sleepy, dozing at intervals, starting up, wagging his tail as if extremely contented, he ate some food greedily, on being called to he staggered to and fro, and his face assumed a look of utter and helpless drunkenness’” (Mukherjee, 2017).
The prohibition of cannabis around the world explains why this interesting plant has only been extensively researched in recent decades.
In 1894 the British Indian Hemp Drugs Commission judged that “there was ‘little injury’ caused to society by the use of cannabis”.
However, in 1925 Egypt brought pressure to bear on the League of Nations International Opium Convention and as a result cannabis was erroneously classified as having the same potential for harm as opium and cocaine (Hall, 2019; Mills, 2012). As a result of the League of Nations decision, the UK prohibited cannabis in 1928 and it was added as an addendum to The Dangerous Drugs Act 1920.
Then, in 1961, the UN Single Convention on Narcotic Drugs consolidated previous treaties controlling opium, cocaine, heroin and cannabis into one treaty, and classified drugs as Schedule I to IV. Modern medicines that contained cannabis were in Schedule I of the convention and their prohibition was not recommended. Cannabis and cannabis resin, however, were included in Schedule IV of the convention, which meant the prohibition of their medical use was recommended (Mills, 2012).
The UN Convention on Psychotropic Substances and subsequent UK legislation (The Misuse of Drugs Act 1971) reclassified cannabis as a Class B drug. It remained as a Class B drug except for the period 2004-9 when it was classified as Class C before being moved back to Class B (Part II, Schedule 2 of the Misuse of Drugs Act 1971; Schedule 1 of the Misuse of Drugs Regulations 2001; and The Misuse of Drugs [Designation] [England, Wales and Scotland] Order 2015).
Despite this prohibition in 1974, Israeli scientists Raphael Mechoulam and Yehiel Gaoni of the Hebrew University of Jerusalem successfully isolated, identified and partially synthesised tetrahydrocannabinol (THC). THC is a plant origin or phytocannabinoid that is the principal psychoactive constituent of cannabis. Currently, cannabinoids except CBD are controlled substances in the UK (Hall, 2019; Mills, 2012).
Cannabis is a genus of flowering plants in the family Cannabaceae (Hillig and Mahlberg, 2004). Three species are recognised: Cannabis sativa, C Indica and Cannabis ruderalis. C sativa can be grown either as marijuana for medicinal use or hemp primarily for fibre, but also a source of CBD. It has been speculated that the ratio of THC:CBD in the original marijuana plant modulated the unpleasant side effects of THC.
Recreational drug users hybridised the plant to produce higher percentage THC and often lower percentage CBD (0.3% THC:0.5% CBD) resulting in a greater high, but also more unpleasant side effects of depression, suicidal thoughts and paranoia (Pacifico et al, 2007; McPartland and Small, 2020).
When C sativa is grown as industrial hemp, the plant is selected to produce high levels of fibre and to contain low levels of THC. In the UK you can apply for a licence to grow industrial hemp that has a THC content of less than 0.2%. However, the final CBD product should contain less than 0.01% THC. Hemp seed oil does not contain any significant amounts of CBD, but may be used as a carrier for CBD (Pollio, 2016).
Phytocannabinoids are cannabinoids of plant origin. Cannabinoid is an umbrella term covering CBD, THC, cannabinol and many others. Chemically, C sativa contains more than 100 phytocannabinoids including THC and CBD, plus terpenes and flavonoids. Terpenes and flavonoids are also being investigated for their medicinal effects.
Terpenes – for example, beta‑caryophyllene, limonene and linalool – are responsible for the flavour and odour of plants. The characteristic pungent aroma of a lemon when you cut into it is due to the terpene limonene (Goldstein, 2016).
Flavonoids cannflavin A and B have been found to have 30 times more potent anti-inflammatory effect than aspirin (Rea et al, 2019).
The different chemical compositions of C sativa plants are sometimes referred to as chemovars of the plant. Some herbal doctors and vets believe the combination of terpenes, flavonoids and cannabinoids that present naturally in the plant will have a greater therapeutic effect than single purified molecules. This is known as the entourage effect (Russo, 2011; Russo and Guy, 2006).
It is important to be aware that the chemical constitution of a plant can vary depending on the weather, soil, year, field, aspect and even water supply. For this reason, merit exists in using single isolated molecules for the purposes of research so that comparative studies are more meaningful.
The ECS is a biological system of retrograde neurotransmitters (endocannabinoids) that bind to G protein‑coupled cannabinoid receptors (CB1R and CB2R).
Retrograde signalling (retrograde neurotransmission) is the process by which a messenger, such as anandamide (an endocannabinoid) or nitric oxide, is released by a postsynaptic dendrite or cell body, and travels backwards – that is, in a retrograde manner – across a chemical synapse to bind to the axon terminal of a presynaptic neuron.
Endocannabinoids are produced at the postsynaptic membrane in response to depolarisation of the presynaptic nerve. They act as retrograde neurotransmitters on the cannabinoid receptors on the presynaptic membrane, and are then degraded and removed (Zou and Kumar, 2018; Castillo et al, 2012).
Endocannabinoids have a homeostatic role in the body achieving balance in systems – for example, descending pain inhibitory pathways. They are involved in motor coordination, memory, pain modulation, appetite, neuroprotection and immunomodulation.
All vertebrates are born with a fully developed ECS. Five endocannabinoids have been identified so far, including anandamide and 2-arachidonoylglycerol. There are two types of G protein-coupled cannabinoid receptors – type one receptors (CB1Rs) and type two receptors (CB2Rs; Zou and Kumar, 2018).
CB1Rs have been identified in the brain, CNS, lungs, vascular system, muscles, gastrointestinal tract and reproductive organs. In the brain they are found in those regions associated with sensation of pain; memory and learning; emotion, anxiety, depression and fear; motor control and coordination; appetite; nausea and vomiting; and pleasure and reward.
CB2Rs are present in the spleen, bones and skin, and have been found on immune cells including macrophages, monocytes, B-cells, T-cells, and in the spleen and tonsils. The association of CB2Rs with immune cells has resulted in research into the use of CBD as an immunomodulator.
Both receptors are found in the heart, reproductive system, skin, immune system, liver, pancreas and bone marrow.
It is of interest that cannabinoid receptors can be upregulated or downregulated according to need. CB2Rs can be expressed in peripheral nerves after injury or inflammation, and can help decrease the sensation and perception of pain.
Cannabinoid receptors have been found in increased numbers in the brains of animals that have seizures and in the intestines of animals with colitis-type illness. Autistic children have increased numbers of type-two receptors on their white blood cells and cannabinoid receptors were found to be upregulated in people with depression who committed suicide (Goldstein, 2016).
You can see more about the ECS in this video:
Phytocannabinoids such as THC and CBD may exert clinical effects by modulating the endocannabinoid receptor system. The psychotropic phytocannabinoid THC acts mainly at CB1Rs. CBD has a very low affinity and shows little agonist activity at the G protein-coupled ECS receptors, CB1R and CB2R.
One proposed mode of action is as an allosteric modulator of the endocannabinoid receptors, influencing compounds that bind to the receptors – it impacts multiple target molecules. Any mechanism that inhibits the degradation or reuptake of endocannabinoids can prolong their action at the cannabinoid receptors. One theory suggests that with age or illness the body develops a “deficient ECS”.
Modulation of endocannabinoids by inhibition of reuptake or degradation may increase their concentration or prolong their action, hence correcting a deficient ECS. For example, studies have shown that CBD may activate cannabinoid receptors, and influence the ECS through anandamide and vanilloid receptors, and/or indirectly via its effect on fatty acid amide hydrolase (FAAH).
FAAH is an integral membrane enzyme that hydrolyses the endocannabinoid anandamide and related signaling lipids (Caterina et al, 2000; Costa et al, 2004; Zou and Kumar, 2018; Zygmunt et al, 1999; Russo, 2008).
CBD has been demonstrated by basic science research to have many molecular targets within and outwith the ECS, resulting in multiple potential clinical effects with wide therapeutic range (Crippa et al, 2018; Earleywine, 2005; Goldstein, 2016). These effects, however, have, for the most part, yet to be proven definitively by clinical trials.
The molecular targets include the following lists (Ibeas Bih et al, 2015):
Thank you to Anthony Ordman MBBS, FRCA, FFPMRCA, FRCP for his criticism and constructive comments on the manuscript. Dr Ordman is a senior, full-time specialist in pain medicine and founder of the Royal Free London’s pain management service.
Thanks also go to Canidol Pharmaceutics for use of its images.
