The dried leaves of Cannabis sativa plant have long been used for both medicinal and recreational purposes (Bonini et al, 2018), but research into its potential medicinal applications started growing significantly only in the 1990s following the discovery of the cannabinoid system in the brain.
At the same time, efforts to liberalise marijuana laws have led to breakthroughs in several Western nations, including in 36 states in the United States that provide some access to cannabis at the moment (NCSL.org). Growing political acceptance and more importantly medical research have made cannabis an increasingly accepted part of the cultural fabric (Carliner et al, 2017). From a medical standpoint, the emergence of cannabis-related products as potential therapeutics has become a challenge for physicians. Medical cannabis is now accessible to many patients who have an interest to try it, often as a last resort measure, but robust data are still lacking. The demand is outpacing the clinical evidence, leaving it unclear how and when it should be prescribed.
Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain hundreds of compounds, including terpenes and flavonoids, but cannabinoids are the most important compounds for medicinal applications. Phytochemistry and medical studies have identified several potentially useful cannabinoids. The psychoactive compound tetrahydrocannabinol (Δ9-THC) is also the most abundant cannabinoid in marijuana. The next most abundant cannabinoid is cannabidiol (CBD), which is the non-psychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation, but there are many others, the investigation of which are more problematic due to low concentrations, for example cannabichromene (CBC), cannabigerol (CBG) and others (ElSohly et al, 2017). Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’s various compounds can work synergistically to produce a so-called entourage effect; however, this is still being debated (Russo and Marcu, 2017).
Compounding the issue of lack of data there is now a range of cannabis-related products, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (ie via smoke, vapor, ingestion, topical administration or oromucosal spray), all of which can alter their effects. To date the FDA has approved one cannabis-derived product Epidiolex (purified CBD, GW Pharmaceuticals, approved in 2018, expected 2021 sales of $730m) for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged two years and older. The FDA has also approved three synthetic cannabis-related drug products: Marinol / Syndros (dronabinol, synthetic THC, approved in 1985), and Cesamet (nabilone, a synthetic cannabinoid similar to THC, approved in 1985). All three are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients. Another cannabis-derived product Sativex (nabiximols, 1:1 THC and CBD extract, GW Pharmaceuticals; oromucosal ethanol spray formulation) is approved in Europe, but not in the United States, to alleviate muscle spasticity resulting from multiple sclerosis.
CB1 and CB2 have been characterised as two major types of cannabinoid receptors, however, both THC and CBD have been found to exert their therapeutic effects via several other targets (Bih et al, 2015). Because of these varied targets, THC and CBD induce varying pharmacologic responses depending on the formulation, dose and patient characteristic (Borgelt et al, 2013).
Historically, cannabis has been listed as a scheduled drug in most countries. In the United States, the FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is >0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration. Regulatory restrictions regarding medical cannabis vary considerably throughout the world, which makes it difficult to conduct well-designed, large-scale international trials. However, and somewhat paradoxically, medicinal cannabis is being made available by many governments at the discretion of a prescribing physician. This disincentivises investments in large, well-designed trials with the most common formulations, as it will be difficult to protect the product from generic competitors. We believe a differentiated product with a good data package is what is needed for a commercially viable product. Epidiolex is a good example. Developed by UK-based GW Pharmaceuticals, it demonstrated a clear benefit in a niche indication. The consensus expectation is for sales of $730m in 2021, growing to $1.4bn in 2026 (EvaluatePharma). In February 2021, Jazz Pharmaceuticals announced the acquisition of GW Pharmaceuticals for a total consideration of $7.2bn (or $6.7bn net of GW cash). In addition to Epidiolex’s commercial success, Jazz cited the potential to expand the label with other forms of epilepsy and GW’s pipeline of other cannabinoid products in earlier stages.
In the context of medicine, relief from chronic pain (cancer or non-cancer related) is the most common reason cited by patients for the use of cannabis (Ilgen et al, 2013). In 2015, a systematic literature review assessed 28 randomised controlled trials of the use of cannabinoids for chronic pain (Whiting et al, 2015). The researchers found that a variety of formulations resulted in a ≥30% reduction in pain compared with placebo. Another systematic review and meta-analysis conducted by Aviram and Samuelly-Leichtag (2017) reviewed 43 randomised controlled trials and concluded that cannabis-based treatment could be effective for chronic pain. However, another meta-analysis of five randomised control trials involving patients with neuropathic pain found ‘the proportion of patients with an at least 30% reduction in chronic pain as minimally clinically important difference ... about one in every five to six patients treated’ with inhaled, vaporized cannabis (Andreae et al, 2015). The US National Academies of Sciences, Engineering, and Medicine (NASEM) concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.
Other studies have found that cannabinoid-based therapeutics could be useful add-ons or a replacement to other types of pain medication (Yanes et al, 2019). The potential of cannabis to reduce or replace the use of opioids is a major interest area in pain medicine currently. One study found that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by >60% (Boehnke et al, 2016).
With evidence of efficacy growing in chronic neuropathic pain in general, efforts have been made to investigate cannabis-related prodcuts in a subset of patients with cancer-induced pain. Five clinical trials performed to date, however, did not meet the primary efficacy endpoint (Boland et al, 2020). These were the efforts by GW Pharmaceuticals to develop its cannabis-derived product Sativex for pain, which were not successful (Sativex is now approved for muscle spasticity resulting from multiple sclerosis). NanaBis, however, has been demonstrated to have a different pharmacokinetic/pharmacodynamic (PK/PD) profile to Sativex (as described below).
The types of cannabis-related product formulations in clinical trials ranged from vaporised cannabis to oral/oromucosal routes of administration of cannabis as herbal crude or dry leaf cannabis extracts, to synthetics of THC (dronabinol, nabilone) and plant-derived extracts of THC/CBD oromucosal spray (nabiximols, Sativex, GW Pharmaceuticals). Oral administration with gastrointestinal absorption leads to highly variable systemic concentrations of active compounds leading to slow and erratic onset of action (Russo, 2019). Inhaled cannabis preparations require too frequent dosing to maintain the pain relief, as the half-life is less than 20 minutes. In addition, the THC blood concentration reaches very high levels via this administration route leading to unwanted psychoactive effects, which is a side effect in this setting. The non-optimal delivery via oral or inhaled administration routes of medicinal cannabis led to a search for novel routes of administration (Bruni et al, 2018). Cannabinoids are lipophilic molecules and the delivery is a challenge. In this context, Medlab decided to investigate its nanomicellar delivery technology NanoCelle for the transbuccal delivery of cannabinoids for cancer-induced pain.