Cannabis sativa is one of the original plants that was cultivated for human use in Central Asia, particularly in the regions now found in Mongolia and south Siberia. It is the oldest cultivated crop with fossil records as old as 12,000 years and is one of the five sacred plants according to Vedic philosophy, which exists to provide human satisfaction and overcome our fears. Its use began approximately around 6,000 BC as a form of food in China whereas, by 4,000 BC, "hemp" was used to design textiles.

From this plant, approximately 100 chemical compounds known as phytocannabinoids have been derived. The main phytocannabinoids are delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) based on their various therapeutic roles.

These compounds derived from plants also influence various bodily systems including the nervous, cardiovascular, respiratory, and gastrointestinal systems. This occurs through their interaction with receptors in the endocannabinoid system. The endocannabinoid system has numerous roles in maintaining homeostasis within the body. It is made up of endocannabinoids (the main examples being AEA and 2-AG), and their respective cannabinoid receptors (mainly the CB1 and CB2R). These receptors are widely dispersed throughout the body, with the CB1R predominantly found in higher centres of the brain, which explains the role of the endocannabinoids in learning and memory, sensory and motor responsiveness, and behaviour control. CB2R are mainly found within the immune system in which they play a vital role in the functioning of the immune system, pain regulation in inflammatory bowel disease, intestinal inflammation and contraction.

Synthetic cannabinoids are divided into therapeutic (approved) and recreational synthetic cannabinoids. The therapeutic cannabinoids are those which have been approved for medical purposes and include Sativex, Marinol, Syndros, Cesamet and Epidiolex.

There is a wide range of recreational synthetic cannabinoids and they exert their effect via cannabinoid and non-cannabinoid receptors. These compounds contain one or more synthetic cannabinoids in different mixtures to bypass legal framework but are generally developed to mimic or even heighten THC's effects on cannabinoid receptors, predisposing one to THC intoxication.

Although the term marijuana and cannabis are used interchangeably, there is a variation in their meaning. The term "marijuana" arose as a form of Mexican slang among soldiers who smoked the plant, it refers to the output from the crop that contains relatively high amounts of THC whereas cannabis is a group of all products derived from cannabis sativa. Substances that contain low levels of THC are referred to as industrial hemp.

 

The main phytocannabinoids

Delta-9-THC is the main psychotropic component of cannabis. This compound can either be taken orally or via smoking. Once taken orally in the form of cannabis edibles and other oral formulations, THC exerts a slightly different effect than when smoked with its levels in blood plasma rising higher when taken orally than when smoked. Within the liver, THC is metabolised to its active form 11-hydroxy-THC (psychoactive) or 11-nor-9-carboxy-THC, the main non-psychoactive metabolite form.

It exerts its psychoactive effects through binding to the CB1 receptor causing catalepsy, hypothermia, analgesia and hypolocomotion. Through binding to the CB2R it inhibits inflammation, muscle spasms and mediates neuroprotective actions. The therapeutic role of THC lies in the treatment of tumours, cancer, Alzheimer's anxiety, inflammatory bowel disease and insomnia.

CBD is a non-psychoactive compound unlike THC with no effect on temperature or cognitive function or motor activity. CBD can also be ingested orally similar to THC but has a poor oral bioavailability. When metabolised in the intestine and the liver, CBD is activated to 7-carboxy-cannabidiol (7-COOHCBD). The compound, in a similar manner to THC, performs its function through binding to the endocannabinoid receptors, however, it causes effects different to those of THC when bound. When bound to the CB1R it produces a low effect (unlike THC), however, its main anti-inflammatory and immunosuppressive effects are mediated via the CB2 receptor. Therapeutically, CBD provides stress relief and antidepressant effects, opposes or equilibrates the psychoactive effects of THC, and is for the treatment of numerous ailments like Huntington's disease, Parkinson's, Alzheimer's, anxiety, cancer, inflammatory bowel disease and insomnia.

 

Minor phytocannabinoids

Some of the minor phytocannabinoids include:

• Delta-8-THC for treatment of vomiting during chemotherapy, nausea and pain
• Cannabinol (CBN) has anti-inflammatory and antimicrobial effects
• Cannabigerol (CBG) for treatment of Huntington's disease, inflammatory bowel disease and bladder dysfunction
• Cannabichromene (CBC) for acne treatment and migraine therapy
• Delta-9-tetrahydrocannabivarin (delta-9-THCV) for treatment of insomnia and tumours

 

Approved synthetic cannabinoids

To date, the Food and Drug Administration (FDA) has approved three synthetic cannabis-related drug products - Marinol (dronabinol), syndros (dronabinol) and cesamet (nabilone), as well as one cannabis-derived drug product-Epidiolex from CBD. An additional drug is Sativex, which has not been approved in the US but in other countries in 2011 to 2012. However, the FDA has not approved any other cannabis-derived products available on the market which are therefore deemed as illegal. These FDA-approved drugs are not available over the counter and are only commissioned when prescribed by a licensed healthcare provider.

• Nabilone is used as a supplemental therapy in cancer patients to treat vomiting and nausea, for treatment of neuropathic and chronic pain, post-traumatic stress disorder (PTSD) and spasticity related to multiple sclerosis.
• Dronabinol is used as an analgesic in patients with breast cancer with bone metastases, and as a supplemental therapy to opiates for chronic pain. Similar to nabilone, it is also used to reduce nausea and vomiting in cancer patients and additionally to stimulate appetite in patients with Aids.
• Epidiolex is used as a therapy for two severe forms of childhood epilepsy in which it is administered orally; these are Dravet syndrome and Lennox-Gaustat syndrome. The latter is characterised by seizures that begin before four years of age together with cognitive impairment and the former, also known as severe myoclonic epilepsy of infancy (SMEI), develops in childhood specifically by one year of age and can be triggered by hyperthermia.
• Another FDA-approved drug is Sativex or Nabiximols. It is administered in the form of an oromucosal spray for the treatment of spasticity associated with multiple sclerosis mainly in the UK, Switzerland, Germany and Canada.

 

Illegal or recreational synthetic cannabinoids

The illegal synthetic drugs represent the largest class that has been detected by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). The use of these illegal or recreational synthetic cannabinoids has rapidly increased globally because of the creation of novel structural analogues as alterations of the original THC compound. These newly formed compounds have been associated with significant adverse effects on health. These synthetic cannabinoids over the years have accumulated different brand names such as spice, K2, Bombay blue, black mamba, herbal incense, Scooby snax, mojo and cloud 9. They are also termed as ecstasy in Europe and in the US, heroine containing synthetic cannabinoids have been sold. They have been made more available in the form of chocolate brownies, candies, gummy bears and vapes, which has increased their popularity among younger ages and exposed them to the risks of cannabis use. Due to their abuse, they have been associated with numerous risks. Unfortunately, these risks have been difficult to alleviate as most of the current drug screening tests are not able to detect their consumption.

 

Conclusions

In summary, cannabinoids have enabled the development of therapies for numerous medical ailments and this all stems from our understanding of the interactions, efficacy and potency of various therapeutics that act on cannabinoid and non-cannabinoid receptors. Despite this positive outcome, the adverse health effects of cannabis dependence cannot be overshadowed; there has been a continued rise in the number of cannabis addicts, especially among youths as cannabis is viewed as a "soft drug". Despite aims by the government to ban these drugs, numerous formulations are still present and thriving on illegal markets, which raises the question of how many illegal synthetic cannabinoids are hiding in plain sight.

 

Renald Blundell is a biochemist and biotechnologist with a special interest in Natural and Alternative Medicine. He is a professor at the Faculty of Medicine and Surgery, University of Malta

 

Stacey Nimungu is currently a medical student at the University of Malta