Clinical evidence on the medicinal properties of cannabis

SUMMARY

This report examines the scientific evidence and studies that support and substantiate the medicinal or therapeutic use of Cannabis or medicines based on its active ingredients: cannabinoids.

Cannabis and its derivatives have generated great social, scientific and economic interest in recent years, not only because several European countries are developing policies in this field, but also because the international framework regarding Cannabis is constantly changing following the review by the WHO Expert Committee on Drug Dependence in 2018.

The Ministry of Health of the Spanish Government repeatedly claims that there is insufficient evidence to support the medicinal use of this plant, but this is not supported by the facts, nor is it supported by the scientific community in our country (and in many other countries).

It is worth noting that the risks of consuming Cannabis are extremely low, if we talk about a therapeutic/medical and controlled context or if we compare it with pharmaceutical drugs legally sold in our country.

Most EU countries allow or are in the process of considering allowing the medical use of Cannabis or cannabinoids in some form. However, the approaches taken vary widely both in terms of the products permitted and the regulatory frameworks governing their supply.

In this context, this article aims to provide a brief summary of the scientific knowledge. This report also aims to inform and educate an audience of interested readers, such as policy makers, pharmaceutical and medical professionals in our country, potential patients and the general public, to understand the scientific and clinical issues that arise when considering the possibility of Cannabis or cannabinoids being used to treat the symptoms of medical diseases, from cancer to skin conditions such as Psoriasis or even derivatives of COVID-19.

Conclusion

Cannabis clearly offers significant therapeutic benefits for a wide range of conditions without substantial risks to human health.

What scientific evidence is available?

PubMed peer-reviewed published studies and clinical trials refer to more than 27,000 studies or reviews published under the search terms Cannabis, cannabinoids or marijuana; almost half of these studies have been published in the last eight years.

Cannabinoids are natural substances found in the Cannabis plant that act on specific receptors in the brain and the human body in what is called the Endocannabinoid System. The two best known molecular substances are tetrahydrocannabinol (THC) and cannabidiol (CBD), but some of the other 103 compounds, including minor cannabinoids, terpenes and flavonoids in the Cannabis plant are also being shown to have medical uses (Russo and Marcu, 2017). Cannabinoids are also found endogenously in the human body (endocannabinoids), but those consumed for medical use can be sourced from the Cannabis plant (also known as phytocannabinoids) or synthesised in the laboratory (synthetic cannabinoids). Synthetic cannabinoids can produce similar effects to phytocannabinoids (Iversen, 2007), although studies have shown greater efficacy for those extracted from the plant than for synthetic cannabinoids, as their chemical structure can vary from that of a natural cannabinoid.

Compared to some of the medicines or drugs in everyday use today, very few of them have undergone multiple large-scale clinical trials or have thousands of years of actual experience behind them as Cannabis and cannabinoids have. A recent analysis showed that, in countries such as the United States, about one third of pharmaceutical drugs were approved on the basis of a single clinical trial, and many of these trials were conducted with very few subjects and of short duration. The reality, therefore, is that there is an enormous amount of scientific literature on Cannabis that supports its relative safety when used as a medicine, and at a much more rigorous and comprehensive level than for most pharmaceuticals.

Archaeological and historical evidence also indicates that mankind has been using Cannabis for at least 10,000 years.

Side effects and risks

Cannabis, like any other medicine or drug, is not free from side effects, mainly caused by its psychoactivity (THC). However, the evidence for harms caused by smoking or vaporising Cannabis is weak when adjusted for tobacco or alcohol use, with some studies suggesting a protective effect against cancer and neurodegenerative diseases (OrrinDevinsky et al. 2015). The evidence linking Cannabis use to psychosis is very well documented, especially in recreational use at an early age of first use, but the risks are extremely low in a therapeutic context compared to legal pharmaceutical drugs.

Short-term health risks associated with the medical use of Cannabis and cannabinoids, according to the trials conducted, were similar to those of other commonly used medicines and were related to symptoms such as dizziness, dry mouth, disorientation, nausea, euphoria, confusion and drowsiness. Documented adverse effects are rare. There is less evidence on the health risks of long-term medical use of cannabinoids, but overall those reported are similar to those reported for short-term use.

Clinical Studies and Trials

Cancer

The anti-cancer properties of various phytocannabinoids, such as THC (tetrahydrocannabinol), CBD (cannabidiol), CBG (cannabigerol) and other cannabinoids (i.e., CBN, THCa, CBDa) are well established. Scientists have been researching them since the early 1970s and more than 1400 papers have been published on cannabinoids and cancer.

It is also well established that Cannabis helps to alleviate the side effects of cancer treatments, especially nausea and lack of appetite. Cannabis is also able to alleviate anxiety, depression, insomnia and mood disorders in cancer patients.

In general, while there is strong evidence of anti-cancer properties in vitro (human cell lines) and in vivo (animals), notably in our country, Cannabis is not a toxic product. However, few would deny that the palliative value of Cannabis is very beneficial for many cancer patients.

Clinical trials on cancer pain and brain glioma treatment are ongoing:

Cannabinoids for cancer treatment: Progress and Promise. Cancer Res. 2008. http://cancerres.aacrjournals.org/content/68/2/339

Cannabidiol induces programmed cell death in breast cancer cells by coordinating the interaction between apoptosis and autophagy. Mol Cancer Ther. 2011. http://mct.aacrjournals.org/content/10/7/1161.long

Cannabinoids: a new hope for breast cancer therapy? Cancer Treat Rev. 2012 http://www.ncbi.nlm.nih.gov/pubmed/22776349

Guzman et al,. 2021 reported: "Plant, synthetic and endogenous cannabinoids have been shown to control a wide variety of biological processes, including cell fate regulation in cancers. Their promise as broad-based anti-tumour agents in preclinical models has led to the initiation of pilot clinical trials. Session 5 of the National Cancer Institute's Symposium on Cannabis, Cannabinoids and Cancer Research provides an overview of this research topic." (https://www.liebertpub.com/doi/pdf/10.1089/can.2018.0009)

Epilepsy

Many parents have children with intractable epilepsy. This group of parents have reported that Cannabinoid-rich oils, such as CBD (Cannabidiol), reduce the frequency and severity of their children's seizures or epileptic seizures (Devinsky et al., 2016; Hussain et al., 2015; Press et al., 2015). These reports have been strongly supported by a large open-label trial (Devinsky et al., 2016; Devinsky et al., 2017). A systematic review of clinical trials conducted since then (Stockings et al, 2018) found that the addition of CBD to conventional antiepileptic drugs produces a significant reduction in both seizure frequency and intensity in children with Dravet syndrome.

British Epilepsy Association, 2021.

"A recent review of the evidence found that one in 8 people taking CBD would have a 50% or greater reduction in seizures. Far fewer (less than 1 in 150) would be seizure-free. Patients have reported very mild and occasional side effects from taking CBD."

Chronic pain

Chronic pain is the disease for which Cannabis is most commonly used. It seems to be particularly effective in neuropathic pain for which opioids, NSAIDs and other drugs are ineffective. It also appears to reduce the dose needed when used in conjunction with opioids.

THC, CBD and other cannabinoids each have different effects both as analgesics and on pain perception. Patients often report that, even if the pain is not eliminated, cannabis helps them to cope with it, altering their perception and allowing them to concentrate on something else.

There is a large body of scientific evidence, including clinical trials, demonstrating the efficacy and safety of Cannabis in the treatment of chronic pain. The evidence supporting Cannabis and cannabinoids in the treatment of pain, including migraine and headache, with associated neurobiological mechanisms of pain modulation, has been well described (Medical Cannabis for the Treatment of Chronic Pain: A Review of Clinical Effectiveness and Guidelines, 2019).

Pain relief is one of the medicinal and therapeutic actions of cannabinoids for which there is most evidence in both preclinical and clinical studies. In fact, all reviews or meta-analyses agree on this (for example, official reports from Health Canada or the US National Academy of Sciences affirm the therapeutic potential of these Cannabis-derived compounds). The mechanism of action in our body is similar to that of opiates, without the side effects of opiates. Cannabinoid CB1 receptors are
are located, almost identically to opioid receptors, in virtually all nerve pathways involved in pain control (both ascending and descending and both central and peripheral pathways).

2007. American Journal of Pain.

"This study adds to a growing body of evidence that cannabis can be effective in improving neuropathic pain, and may be an alternative for patients who do not respond to or cannot tolerate other drugs.

2008. Journal of American Neuropsychopharmacology.

"Smoked Cannabis was generally well tolerated and effective when added to concomitant analgesic therapy...."

Andreae et al., 2015 reported a meta-analysis of 178 patients with various types of neuropathic pain in five randomised controlled trials, in which inhaled and vaporised herbal cannabis was administered. Patients were evaluated for 2 weeks. The authors found that patients who vaporised cannabis were three times more likely to report a 30% pain reduction compared to those who received a placebo.

COVID-19

The spread of SARS-CoV-2 and the current COVID-19 pandemic highlight the need for new treatments.

"Here we report that cannabidiol (CBD) inhibits SARS-CoV-2 infection in cells and mice (lung epithelial cells). CBD acts after virus entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by regulating the endoplasmic reticulum (ER) stress response of host RNAsa(enzyme) and interferon signalling pathways. The use of non-medicinal formulations, including edibles, inhalants or topicals, as preventive or treatment therapy is currently discouraged. " (Long Chi Nguyen et al,. 2022)

"In follow-up virus neutralisation assays, cannabigerol acid (CBGa) and cannabidiolic acid (CBDa), two components present in the flowers of Cannabis plants, prevented infection of human epithelial cells by a pseudovirus expressing the protein... and prevented the entry of live SARS-CoV-2 into the cells". (Richard B van Breemen et al., 2021)

Crohn's disease

Crohn's disease, ulcerative colitis and other forms of inflammatory bowel disease (IBD) are widely and successfully treated with cannabis.

A clinical trial with cannabis extract to treat ulcerative colitis was concluded by GW Pharmaceuticals in 2014. Anecdotally, there are many studies claiming undeniable improvements in symptoms shortly after cannabinoid use, for example, cessation of rectal bleeding or increased appetite.

Recent clinical trials have produced dramatic results with 50% of Crohn's patients achieving complete remission and more than 90% achieving substantial improvement.

2013. Clinical gastroenterology and hepatology

"In this trial, cannabis induced clinical remission in 50% of patients. Considering that our participants had long-standing Crohn's disease, with an 80% of non-response or intolerance to anti-TNF-a, this result is impressive."

2014. Journal of Pharmacology

"Cannabis sativa has lived up to expectations and has proven to be highly efficient in cases of inflammatory bowel diseases... Cannabis produces significant clinical benefits in patients with Crohn's disease".

2019. Cannabis in inflammatory bowel disease (IBD)

"The two main components of cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC), have been extensively studied and proven to cause anti-inflammatory effects. The properties of these compounds in the symptomatic control of multiple intestinal diseases have been widely described. Nevertheless, high-quality studies are suggested to further evaluate the efficacy and safety of cannabis use in IBD patients" (Camilo Castañeda Cardona et al. 2019).

Psoriasis/Eczema

National Psoriasis Association (USA), 2021: "CBD has the ability to bind to receptors in the body that are part of the human cannabinoid system, called endocannabinoids, which can influence pain, itch and inflammatory mechanisms," says Dr Friedman. "We know that when CBD binds to CB2 [cannabinoid receptor type 2], as well as other receptors, it can participate not only in anti-inflammatory activity, but it can facilitate a number of activities that resolve inflammation. It can stimulate the secretion and recruitment of cells that are important for clearing debris and allowing proper maturation and healing of the skin."

"The topical administration of CBD (Cannabidiol) cream is a safe and effective non-invasive alternative to improve the quality of life of patients with some skin disorders, especially of the inflammatory type" (B. Palmieri et al. 2019) "Although a body of preclinical evidence suggests that topical application of CBD may be effective for some skin disorders, such as eczema, lapsoriasis, pruritus and inflammatory conditions, confirmed clinical efficacy and elucidation of the underlying molecular mechanisms have yet to be fully identified." (Sudhir M Baswan, et al 2020)

Multiple sclerosis (MS)

Multiple sclerosis is the disease that has been most associated with the therapeutic use of cannabis. It was the increasing illicit use of cannabis to treat MS that led to the House of Lords Science and Technology Committee enquiry in 1998. The approval of Sativex (nabiximols) for the treatment of spasticity in multiple sclerosis is the first cannabis medicine authorised in the modern world.

Most MS patients also suffer from chronic pain, for which evidence has been presented for medical cannabis.

Clinical trials have evaluated the efficacy of cannabinoids in treating muscle spasm and neuropathic pain in patients with the neurodegenerative disorder multiple sclerosis. The most tested product has been nabiximols (Sativex), a standardised cannabis extract with approximately equal amounts of THC and CBD in aerosol form.

There is a clear consensus among scientists and physicians that cannabis is safe and effective as a palliative treatment for MS. Further promising research is investigating whether cannabinoids can have a curative effect by promoting myelin sheath repair.

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