The earliest dated writings about the medicinal use of cannabis can be found in the Chinese pharmacopoeias as early as the second century BCE proving that cannabis sativa, even before pharmacological advances, had been viewed as medicinal. Although the therapeutic effect of cannabis sativa has been known for approximately more than two millennia, it was only roughly 20 years ago that this interest sparked a cause to make cannabis widely available for use for a variety of ailments. In 1980, the anticonvulsant property of marijuana was discovered, however, it was only in 1985 that pharmacological companies were given a go-ahead to start synthesising delta-9-THC preparations for use as therapies. These preparations are dronabinol, nabilone, Sativex and Epidiolex (derived from CBD) from which therapeutic benefits can be derived.
Therapeutic benefits of synthetic cannabinoids
Chronic pain: Chronic pain remains as the main reason for the medical intake of cannabis. Although cannabinoids can be used to combat chronic pain, their use for this condition has not been approved by the FDA, despite this, there is a continuing rise in the replacement of approved opioid analgesics for medical cannabis
Breast cancer therapy: The cannabinoids act on different forms of the breast cancer cells such as oestrogen-resistant breast cancer cells, oestrogen receptor-positive cells, triple-negative breast cancer cells and human EGF (epidermal growth factor) receptor 2 positive cells. The cannabinoids although mostly administered at advanced stages of the disease, can also be given at earlier stages in order to combat the progression of breast tumours. Cannabinoids such as CBD and THC play a role in breast cancer therapy by inhibiting the proliferation of breast cancer cells, by binding to the G protein-coupled cannabinoid receptors that is CB1R and CB2R.
Neurodegenerative disease: Cannabinoids are crucial for maintaining the peripheral and central nervous system by promoting neuronal homeostasis and survival. The drug therapies that have been developed over the last 15 years for neurodegenerative diseases exert their neuroprotective effect by inhibiting the effect of neurotoxic stimuli like inflammation and oxidative stress on neuronal architecture. These therapies include cannabinoid agonists and endocannabinoid inactivation inhibitors. This is important for the treatment of conditions such as brain trauma, neonatal ischemia, amyotrophic lateral sclerosis (ALS), Huntington's, Alzheimer's and Parkinson's disease, as well as for treatment of psychiatric conditions like autism, depression, schizophrenia, addiction and anxiety.
HIV: The synthetic cannabinoids, nabilone and dronabinol, are used as therapies for Aids-related symptoms such as cachexia, neuropathic pain, vomiting, nausea, anorexia and the side effects of antiretroviral therapy. Aids-wasting syndrome is the involuntary reduction of more than 10% of a person's body weight, accompanied by diarrhoea, weakness and fever for greater than 30 days - this condition can be improved by nabilone and dronabinol.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): This Covid-19 causative virus penetrates the body via epithelia lining the tongue, lungs and bronchi and binds to angiotensin-converting enzyme 2 (ACE2) via its viral peaks which contain the S1 glycoprotein. This is eventually followed by viral entry into the cytoplasm of the host cell and the infected person then transmits the virus via droplets. As the administration of hydroxychloroquine and corticosteroids as therapies for Covid-19 was not globally successful, additional therapies were needed. In this case, CBD could be considered as it has anti-oxidative and anti-inflammatory effects which explains why it can potentially be used for the treatment of pneumonia, cytokine storms and ARDS (acute respiratory distress syndrome).
Risks associated with use of illicit synthetic cannabinoids
The predominantly detected compounds in illicit synthetic cannabinoids include JWH compounds (John W. Huffman), CP compounds (part of the Charles Pfizer-CP family) and HU compounds (developed at Hebrew University by Raphael Mechoulam) which were later banned, but this met retaliation by the illegal markets which developed new recreational cannabinoids such as JWH-073 (a butyl homolog of JWH-018, JWH-250, AM-694, JWH-398, RCS-4, AM22333) to bypass the legal ramifications. In 2020, two new synthetic cannabinoids were found by EMCDDA (European Monitoring Centre for Drugs and Drug Addiction) and these are 4F-MDMB-BICA (4F-MDMB-BUTICA) and MDMB-4EN-PINACA. The risks associated with the illicit synthetic cannabinoids are described below.
Cannabinoids and psychiatric disorders
Cannabis is one of the predominant drugs used by patients with severe mental illnesses but has merely been speculated as a therapy for depression and anxiety. The main negative psychiatric effect of cannabis use is psychosis, but this is normally predisposed by cannabis dependence. THC is the main psychoactive compound responsible for these adverse effects with a less significant role played by CBD. THC and CBD exert their effects via the endocannabinoid system receptors explaining why this system is crucial in the emergence of many psychiatric illnesses such as phobias, depression, anxiety, post-traumatic stress disorder, addictive disorders, eating disorders and psychoses. Cannabis dependence has been commonly associated with the induction of panic disorder and anxiety. It also increases the likelihood of depression in individuals with consistent use and has been found in high levels in suicide scenarios therefore is one of the risk factors for suicide.
Respiratory effects
The inhalation of these cannabis compounds causes destruction of the protective surfactant lining the alveoli and the epithelial lining of the bronchi, which disrupts gaseous exchange causing acute respiratory distress syndrome (ARDS), hypoxia, cases of severe respiratory depression and pneumothorax. Additionally, it causes pulmonary inflammation, bronchial hyperresponsiveness, pulmonary embolism and emphysema even in the absence of CB1R stimulation.
Cardiovascular system impacts
There has been an increase in the cardiovascular effects of cannabis over the years with the most common conditions being acute coronary syndrome (ACS), cardiac arrhythmias, stress cardiomyopathy, stroke and death. Cardiac arrhythmias such as atrial fibrillation are a result of the decrease in myocardial contractility caused by the cannabinoids.
Hepatic effects
Cannabis use is associated with hepatomegaly. In addition, recent research has demonstrated that hepatitis C virus patients who consume cannabis do not develop liver fibrosis but individuals who couple cannabis use with a moderate to high alcohol intake are most likely to suffer from liver fibrosis. Additionally, it causes an increase in serum levels of the liver enzyme alanine aminotransferase consistent with liver injury.
Industrial benefits of cannabinoids
Hemp is a cannabis product that contains considerably lower levels of THC (0.2-0.3%) with significantly higher levels of non-psychoactive CBD. It has been focused on as it can be used in animal feeds, drinks, as a nutritional supplement and as dry super food in the midst of earthquakes, quarantines and wars. Additionally, it can be used in the textile industry for manufacturing fibre, paper, clothing and textiles, and in the construction industry provides hempcrete or hemp-lime for construction and insulation. In the beauty sector, hemp is used in lotions, shampoos and cosmetics as a treatment for inflammation and acne. The former relies on the antioxidant properties of CBD.
Hemp seeds are considered to be beneficial as they contain carbohydrates (20 to 30%), essential amino acids (20 to 25%), polyunsaturated fatty acids (omega-3 and omega-6 fatty acids), minerals (potassium, zinc, calcium, iron, phosphorus, magnesium, selenium and manganese), fibres, fat-soluble and insoluble vitamins (A, B, E and C) and numerous antioxidants. These are all valuable nutrients for health. Hempseed oil, formed through cold-pressing of hemp seeds, contains numerous polyunsaturated fatty acids and is advantageous against cancer, inflammation and cardiovascular disease.
Conclusion
Despite the numerous benefits of cannabinoids, there is still more research which is required to create a strict distinction between medicinal cannabis, illicit recreational cannabis and industrial cannabis/hemp which would better our understanding of cannabis as a whole. However, we should continuously be cautious about the blurred line that exists between cannabis therapy and dependence.
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