South Africa’s cannabis industry was kickstarted in September 2018 by a Constitutional Court ruling which held that it is no longer a criminal offence to use, possess or grow cannabis in private for personal consumption. This was closely followed by the announcement, in May of this year, that preparations containing cannabidiol (CBD) are now excluded from being scheduled in terms of the Medicines and Related Substances Act of 1965 as long as they meet criteria set by the National Department of Health. Cannabidiol (CBD), a Cannabis sativa constituent, has in recent years drawn increasing interest as a treatment for a range of health disorders.

If a patient with chronic pain and their healthcare provider work together through first- and second-line treatment modalities without success, a trial using CBD may be a reasonable next step.

It is a 21-carbon terpenophenolic compound which is formed following decarboxylation from a cannabidiolic acid precursor, although it can also be produced synthetically. CBD can be converted to tetrahydrocannabinol (THC) under experimental conditions; however, this does not appear to occur to any significant effect in patients undergoing CBD treatment. New research suggests an ever-expanding potential role for CBD in the emerging healthcare system, with some scientific studies confirming it may ease symptoms of ailments ranging from chronic pain and anxiety to Parkinson’s disease.

Many different cultures have used the cannabis plant to treat a plethora of ailments. Practitioners in ancient China used cannabis to target malaria, menstrual symptoms, gout, and constipation. During medieval times, cannabis was used for pain, epilepsy, nausea, and vomiting, and in Western medicine it was commonly used as an analgesic. While CBD is a component of marijuana, by itself it does not cause patients to feel high, since, unlike THC, it has no psychoactive psychotoxic effects. CBD has demonstrated preliminary efficacy for a range of physical and mental healthcare problems and is likely to play an ever-increasing role in modern medicine. It is therefore necessary for doctors to know the facts regarding this breakthrough phytocannabinoid.

The body’s endocannabinoid system (ECS) is involved in regulating a variety of functions including sleep, appetite, pain and immune system response. Recently, the benefit of the endocannabinoid system modulation in chronic pain treatment has been demonstrated clearly by a number of well-documented studies. Cannabinoids bind to cannabinoid receptors and act as agonists. Cannabinoid receptors are cell membrane receptors, members of the G protein-coupled receptors. They are activated by three major groups of ligands: endocannabinoids, phytocannabinoids and synthetic cannabinoids. 

PAIN

Effective therapeutic options for patients living with different forms of pain are limited, since opioids and anti-inflammatory drugs as first-line medications for the treatment of pain in patients with malignant diseases do not always provide satisfactory results. CBD has been noted for its analgesic effects for centuries and pain relief is the most commonly cited reason for the medical use of CBD. The analgesic effect of cannabinoids as a result of binding of cannabinoids to cannabinoid receptors has been confirmed, and the role of the endocannabinoid system in pain relief has been verified in various types of pain: somatic, visceral and neuropathy.

Classical analgesics, nonsteroidal anti-inflammatory drugs or opioids, paracetamol and antidepressants (with an analytical effect in some conditions) increase the activity of the endocannabinoid system. In humans, pharmacodynamic studies have demonstrated the effect of cannabinoids on provoked somatic pain (e.g., thermal stimulation), capsaicin-induced hyperalgesia, painful spasms in patients with multiple sclerosis (MS), and neuropathic pain in HIV/AIDS patients. This suggests that, if a patient with chronic pain and their healthcare provider work together through first- and second-line treatment modalities without success, a trial using CBD may be a reasonable next step.

ANXIETY AND RESTLESSNESS

Recently, the endocannabinoid (ECB) system has gained attention for its role in learning and memory. The ECB system is comprised of two classes of receptors: CB1 and CB2, endogenous cannabinoids (ECBs); anandamide and 2-arachidonylglycerol (2-AG) and enzymes for their hydrolysis. Pre-synaptic CB1 receptors (CB1Rs) are expressed most densely in the hippocampus, amygdala and prefrontal cortex and modulate the firing of both excitatory glutamatergic and inhibitory GABAergic neurons in the amygdala. They thus play an important role in emotional learning and it is likely that they play a critical role in both the acquisition and maintenance of conditioned fearful responses. As such, the ECB system may be an important target for improving the efficacy of treatment for anxiety disorders.

A recent study examined the effects of CBD on extinction and consolidation of contextual conditioned fear memory. CBD administered after extinction learning led to a generalised attenuation of explicit fearful responding during recall and reinstatement. CBD administered either pre- or post-extinction also produced a trend-level reduction in reinstatement of contextual responding on skin conductance response. This suggests that CBD can potentiate consolidation of extinction memory in humans, leading to extinction trace dominance at recall.

These findings have important implications for the use of CBD as an adjunct to extinction-based pharmacotherapies for anxiety disorders, particularly PTSD, where aversive memory persistence and reinstatement are major contributors to maintenance of pathological fearful responding. Enhancing consolidation of extinction learning and increasing flexibility of memory with CBD could therefore be an excellent strategy for improving efficacy of behavioural therapy in these patients. Furthermore, reducing reinstatement of contextually fearful responding following extinction-based therapy is critical for long-term relapse prevention in anxiety disorders.

SLEEP DISORDERS

Many studies have suggested that the use of THC and THC-derivatives, alone or in combination with CBD, may improve self-reported sleep quality, sleep disturbances, and decrease sleep onset latency. Despite this, the vast majority of these studies investigated sleep as a secondary outcome. Although “sleep” remains one of the main reasons people seek medicinal marijuana, to date there is a surprising lack of placebo-controlled controlled trials examining the use of cannabinoids specifically for treatment of sleep disorders.

Many studies have suggested that cannabinoids could improve sleep quality, decrease sleep disturbances, and decrease sleep onset latency. The role of sleep in cannabis use and withdrawal is not surprising as recent work has demonstrated that the ECS is involved in the regulation of the circadian sleep–wake cycle, including the maintenance and promotion of sleep. A lack of normal sleep causes dysregulation within the ECS, while elevation in the ECS at the receptor level is involved in the homeostatic recovery of sleep after non-normal sleep.

Medium-/high-dose CBD is associated with an increase in the percentage of total sleep. This is supported by a pilot study in humans showing that high-dose CBD was associated with improved sleep. However, when combined with THC, it may result in a decrease in slow wave sleep. A preliminary study has also suggested that CBD may suppress REM behaviour disorder in individuals with Parkinson’s disease.

CROHN’S DISEASE

Crohn’s disease is a chronic inflammatory disorder that can affect any part of the gastrointestinal tract from the mouth to the anus. About 30–40% of patients do not respond to currently available medical therapies. Recent experimental data support an important role of natural cannabinoids in gastrointestinal diseases. In fact, cannabis has been proposed for the treatment for gastrointestinal disorders ranging from enteric infections and inflammation to disorders of motility, emesis, and abdominal pain. Cannabidiol is an attractive option for treating inflammatory diseases due to its lack of any central effect.

In a study of 21 patients with Crohn’s Disease Activity Index (CDAI) scores greater than 200 who did not respond to therapy with steroids, immunomodulators, or anti–tumour necrosis factor-α agents, it was found that a short course (8 weeks) of THC-rich cannabis produced significant clinical, steroid-free benefits to 10 of 11 patients with active Crohn’s disease, compared with placebo, without side effects. Subjects receiving cannabis also reported improved appetite and sleep.

ULCERATIVE COLITIS

CBD exhibits anti-inflammatory properties that could be exploited for the symptomatic relief of IBD. CBD has demonstrated the capability to mediate a strong inhibition of neutrophil chemotaxis and proliferation and this has been considered at the basis of its great efficacy as an anti-inflammatory drug. The beneficial and immunomodulatory effects of CBD have been widely evidenced in IBD treatment models. CBD possesses an extraordinary range of beneficial effects that may slow the course of IBD, ameliorate symptoms and potentially increase the efficacy of the drugs actually available for the therapy of invalidating gut disorders. Because of its well-known low toxicity even in humans and its complete lack of any psychotropic unwanted effects, CBD may represent a novel molecule or a lead compound to develop new pharmacological approach to ameliorate the current therapy of IBD with fast translation from pre-clinical studies to clinical practice.

PARKINSON’S DISEASE

Current therapies to deal with Parkinson’s disease (PD) are inadequate. Medications have improved the prognosis of PD, but also have problematic adverse effects. Psychosis is common in PD, affecting nearly one-third of patients particularly in later stages of the disease. Open case studies of patients with schizophrenia treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with amisulpride have suggested that CBD may be a safe and effective alternative possibility to be developed as an antipsychotic drug. CBD is believed to provide neuroprotection against the progressive degeneration of nigrostriatal dopaminergic neurons occurring in PD.

In an open-label pilot study to directly evaluate the efficacy, tolerability and safety of CBD on PD patients with psychotic symptoms, it was determined that the observed rapid onset of the antipsychotic effect in the PD patients may be attributed to changes in dopaminergic neurotransmission. Because the psychotic symptoms of these patients were possibly associated with the use of the dopaminergic drugs, the observed antipsychotic effect of CBD may have occurred through the attenuation of dopaminergic activity in areas related to the production of psychotic symptoms.

This is consistent with the preclinical evidence that CBD has previously been shown to attenuate the stereotyped behaviour and the hyperlocomotion induced by dopaminergic drugs. The results of this pilot study showed that CBD may be effective, safe and well tolerated for the treatment of the psychosis in PD.

EPILEPTIC SEIZURES

Despite the availability of several treatment options, a prospective observational study of 470 previously untreated children, adolescents, and adults with epilepsy showed that only 47% of patients had a response to initial monotherapy and only an additional 13% responded to a second monotherapy. In an open-label study on the effects of cannabidiol oral solution on patients with treatment-resistant epilepsy, it was shown that cannabidiol is effective in controlling the frequency of seizures due to epilepsy of multiple aetiologies in children and adults.

CANCER-RELATED SYMPTOMS

Cancer pain is a common problem, and 70%–90% of patients with advanced cancer experience significant pain. Opioids remain the keystone for the treatment of moderate to severe cancer pain; however, some patients experience inadequate pain relief with opioids and standard adjuvant analgesics despite dose adjustments, and unacceptable side effects are common. Both THC and CBD have shown promise in relieving cancer-related pain.

A two-week (two-day baseline and two-week treatment), multicentre, double-blind, randomised, placebo-controlled, parallel-group study of cannabidiol found it be a useful adjunctive treatment for relief of pain in patients with advanced cancer who experience inadequate analgesia despite chronic opioid therapy. Patients experienced reductions in pain scores, and it was found that these were neither because of a change in opioid background medications nor because of an increase in use of breakthrough medication. Therefore, it was concluded that the observed reduction in pain scores is attributable to the positive analgesic effects of cannabidiol.

SAFETY

The most notable benefit of cannabis as a form of treatment is safety. There have been no reports of lethal overdose with either of the cannabinoids and, outside of concerns over abuse, major complications are very limited. Current research indicates that cannabis has a low overall risk with short-term use, but more research is needed to clarify possible long-term risks and harms.

CBD may have a high drug interaction potential as it modulates numerous cytochrome P450 enzymes responsible for xenobiotic metabolism. Of particular concern is the risk for CBD-induced hepatotoxicity. Studies have determined that the involvement of numerous enzymatic pathways in response to CBD exposure suggests that liver injury associated with this cannabinoid occurs via various mechanisms. Of particular concern was the up-regulation of genes associated with oxidative stress, in particular Hmox1, Nqo1 and Txnrd1.

These findings, coupled with increased levels of oxidized glutathione, infer a strong pro-oxidant trait to CBD and indicate that, despite the beneficial effects of CBD in the treatment of certain therapy-resistant seizures, it poses a risk for liver injury. The probability of CBD-drug interactions appears quite high and additional studies are needed to examine the toxicity of chronic low-dose CBD exposure as well as explore CBD’s potential to interact with other medications.

Conclusion

An ever-increasing list of clinical studies have proven the effectiveness of cannabidiol treatment for everything from pain, cancer symptoms, neurological and neuropsychiatric disorders, sleep and gastroenterological complaints like ulcerative colitis and Crohn’s disease. While CBD is by no means a wonder drug, it is an extremely safe, affordable and readily available solution, or adjunct, to existing therapies that are often sub-optimal.