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  • The clandestine status of cannabis and its attendant risks are beginning to erode
  • The idea of cannabis as an evil drug is a relatively recent phenomenon
  • Plants have been the historical source of medicine for most of human history, and cannabis is no exception
  • There is a large and growing pharmacological and clinical interest in cannabis as medicine
  • Two distinct legal markets for cannabis are emerging: the tightly regulated pharmaceutical market and the less regulated market of herbal preparations
  • The FDA has approved cannabis-related drugs, which are used for a number of indications
  • There may be a recognizable pathway leading to more cannabis compounds becoming medicine
  • To become accepted as a medicine that doctors prescribe, pharmacists supply and healthcare providers support, cannabis compounds need to demonstrate their biochemical uniformity, stability, safety and efficacy
 
Medical cannabis and modern healthcare

Today, cannabis medicine for most people involves the black market with its attendant risks and lack of quality control. But this is changing to a more desirable alternative. As legal opinion changes, and clinical studies increase; the clandestine nature of cannabis and its attendant risks are beginning to erode, and two distinct legal markets for medical cannabis are emerging. One is the tightly regulated pharmaceutical market where medical cannabis provides safe and effective pharmaceutical solutions, which doctors prescribe, pharmacists’ supply, and healthcare providers support, and the other is the less regulated market of herbal preparations. A report by ArcView Market Research reported that 2016 annual sales of legal cannabis in the US grew by 25%, to US$6.7bn, and projects sales will reach US$21.8bn by 2020. This Commentary focuses on the pharmaceutical market, which relies on randomized clinical studies to demonstrate biochemical consistency, safety and efficacy.
 
The cannabis plant and its main properties

Cannabis is a genus of an annual herbaceous flowering plant, which includes 2 familiar sub-species or chemovars: ‘C sativa’, and ‘C indica’. Modern molecular techniques applied to the taxonomic classification of cannabis have resulted in many more classifications, which, in time, will become increasingly relevant as the plant’s medicinal qualities are increasingly identified. Cannabis is an indigenous plant of central Asia and India, but can be grown in almost any climate in any part of the world, and is increasingly being cultivated by means of indoor hydroponic technology. The cannabis plant contains more than 100 cannabinoids, which are chemical compounds secreted by cannabis flowers. About 60 of these have been identified as pharmacologically active, with the primary active cannabinoids being delta-9-tetrohydro-cannabinol, commonly known as THC, and cannabidiol, which is commonly known as CBD. THC provides the principal mind-altering ingredient, while CBD does not affect the mind or behavior.
 
Cannabis as medicine

Medical cannabis refers to using extracts from the cannabis plant - cannabinoids - to treat a range of conditions or their symptoms. Cannabinoids can be administered orally, sublingually, or topically; they can be smoked, inhaled, mixed with food, or made into tea. When cannabis is consumed, cannabinoids bind to receptor sites throughout the brain and body. Different cannabinoids have different effects depending on which receptors they bind to. For example, THC binds with receptors in the brain called CB-1, while CBD has a strong affinity for CB-2 receptors located throughout the body. By aiming the right cannabinoid at the right receptors, different types of relief are achievable. THC is the most active cannabinoid; it has dominated research into medical cannabis and resulted in FDA-approved drugs. Although CBD is one of the least active cannabinoids, it has come to dominate more recent research into medical cannabis as it is considered to have a relatively wide scope of potential medical applications with fewer side effects than THC.
 
Pot-ted history

Plants have been the historical source of medicine for most of human history, and continue to account for the base material of about 25% of modern pharmaceuticals. Approved medicines of botanical origin are relatively common, but require evidence-based randomized clinical studies to demonstrate their biochemical uniformity, stability, safety and efficacy. Medical cannabis is no exception, and the FDA has approved drugs derived from cannabinoids and synthetic cannabinoids. However, regulators have not approved the entire cannabis plant as medicine because there are insufficient clinical studies to demonstrate its benefits against its potential risks to patients it is meant to treat.

For centuries the cannabis plant has been used throughout the world for medicinal purposes. Only in recent history has it acquired the status of a dangerous drug and banned. Its first recorded use is 4000 BC when an extract from the cannabis plant was used in China as an anesthetic during surgery. The Chinese went on to use cannabis compounds extensively for a range of conditions including malaria, constipation, rheumatic pains, "absentmindedness" and "female disorders."
 
From China, cannabis travelled throughout Asia into the Middle East, Africa, Europe, and eventually to the US. Galen, a prominent Greek doctor and scientist in the Roman Empire, noted cannabis as a remedy. In India it was used to lower fevers, quicken the mind, induce sleep, cure dysentery, stimulate appetite, improve digestion, relieve headaches, and cure venereal disease. The Vikings and medieval Germans used cannabis for toothache, and for relieving pain during childbirth. In Africa it was used for a variety of fevers including malaria. Despite its extensive medicinal use in early history, there were warnings against the over-use of cannabis as it was said to result in “seeing demons”.

 
Opinion changing

The idea of cannabis as an evil drug is a relatively recent phenomenon. Despite its contemporary clandestine status, there is a large and growing pharmacological and clinical interest in cannabis as medicine, and a recognizable pathway leading to its return to mainstream medicine. As early as 1985 the FDA approved cannabinoids as medicine. As of June 2016, 25 American states and Washington DC, have legalized cannabis for medical use. Germany is now expected to follow suit. In the UK, more than half of its national parliamentarians, including the former deputy Prime Minister, want to see the legalisation of medical cannabis. In March 2017, Oxford University announced that it is to launch a £10m global centre of excellence in cannabinoid research. The program, which is a partnership between the University and Kingsley Capital Partners, a private equity business based in London, will examine the role of cannabis medicines in treating pain, cancer and inflammatory diseases.
  
FDA approved

The FDA has approved two cannabis-related drugs: dronabinol and nabilone. The former contains the psychoactive compound THC extracted from the resin of C-sativa. The latter contains a synthetic cannabinoid, which mimics THC; the primary psychoactive compound found naturally occurring in cannabis. Both treat chemotherapy-induced nausea and vomiting (CINV), and extreme weight loss caused by HIV/AIDS, among a number of other indications.

Nabiximols, a CBD extract of cannabis, has been approved in 27 countries as a mouth spray to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Although it has not yet undergone clinical studies, scientists have recently developed Epidiolex, a CBD-based liquid drug to treat certain forms of childhood epilepsy.

 
Chemotherapy-induced nausea and vomiting
 
Chemotherapy-induced nausea and vomiting (CINV), is one of the most common and feared adverse events that can be experienced by cancer patients. Its occurrence depends on the dose and the type of chemotherapy agent used, but it tends to be more prevalent in anxious woman under 50 who do not drink alcohol, and who have a history of sickness during pregnancy. Despite advances in the prevention and treatment of emesis, of the 70% to 80% of cancer patients who experience CINV, many delay or refuse future chemotherapy treatments, and contemplate stopping all treatments because of fear of further nausea and vomiting. 
 
There are several drug classes for the prevention and management of CINV. In 1985 the FDA approved a cannabinoid, dronabinol, for the treatment of CINV in patients who have failed to respond adequately to conventional antiemetic treatment. The number of people taking cannabinoids for therapeutic purposes is increasing, but very few medicines based on cannabis have yet been developed on rigorous scientific principles. Ahmed Ahmed, professor of gynaecological oncology at Oxford says, “This field holds great promise for developing novel therapeutic opportunities for cancer patients.
 
The endogenous cannabinoid system is a significant pathway involved in the emetic response. Cannabinoids can reduce or prevent chemotherapy-induced emesis by acting at central CB-1 receptors by preventing the pro-emetic effects of endogenous compounds, such as dopamine and serotonin. In addition, by acting as an agonist to CB-1, cannabinoids used as a treatment result in an antiemetic effect. Notwithstanding, few studies have evaluated medical cannabis alone or in combination to treat CINV. The published studies that have been conducted have mixed results. THC has to be dosed relatively highly, so that resultant adverse effects may occur comparatively frequently. Some investigations suggest that THC in low doses improves the efficacy of other antiemetic drugs if given together.

 
Some additional indications

In addition to its ability to reduce nausea, THC is effective as an appetite stimulant in both healthy and sick individuals, and is used to boost appetite in patients with cancer, HIV-associated wasting syndrome, and patients with anorexia.

Another common use of medical cannabis is as an analgesic. Studies suggest that THC activates pathways in the central nervous system, which work to block pain signals from being sent to the brain. THC has been shown to have some effect against neuropathic, cancer and menstrual pain, headache, and chronic bowel inflammation.

The high, which users get from cannabis THC is also associated with temporary loss of memory. For most people this would be concerning, but for people with post-traumatic stress disorder (PTSD), memory loss can be positive. PTSD is a chronic, disabling mental health condition triggered by a significant event, and results in traumatic flashbacks, nightmares, and emotional instability. A 2013 study published in the journal Molecular Psychiatry reported a correlation between the quantity of cannabinoid CB-1 receptors in the human brain and PTSD, and concluded that oral doses of THC could help relieve PTSD-related symptoms.

Review of clinical studies

In 2015 a systematic review of the pros and cons of cannabinoids was published in the Journal of the American Medical Association. The paper analyzed 79 clinical studies of cannabinoids, involving 6,462 participants, for a number of indications including: CINV, chronic pain, appetite stimulation in HIV/AIDS, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, and Tourette syndrome.

Most studies in the review showed improvement in symptoms that were correlated with cannabinoids, compared with a placebo. However, symptoms positively correlated with cannabinoids did not reach statistical significance in all studies. The review reported that there was an increased risk of short-term adverse effects associated with cannabinoids, some of which were severe. Common among these were dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

The review concluded that, “There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were correlated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were also correlated with an increased risk of short-term adverse effects.”

 
Clinical studies design challenges

Although cannabis compounds are currently used to treat disease or alleviate symptoms for a number of conditions, their efficacy for some specific indications is not altogether clear. This reflects the relative dearth of clinical studies that have been carried out on cannabinoids. Further, there are several design challenges associated with clinical studies that involve THC. One is whether cannabis components beyond THC contribute to its medicinal effects. Another is connected with the ability of studies to provide adequate blinding for psychoactive compounds such as THC. Clinical studies generally are known to show a degree of subjective improvement associated with the additional attention participants in a study are given, and this is compounded when a clinical study outcome measures subjective responses, such as pain and mood, as in the case of THC.
 
Gold standard
 
To be accepted by doctors, supplied by pharmacists and supported by healthcare providers, a medical cannabis product must be standardized and consistent, and display a quality equal to any recognized pharmacological compound. It must have a secure supply chain, possess an appropriate low-risk delivery system, and have minimal adverse effects. Although there are entities working to bring this about, the fact remains that the overwhelming majority of cannabis available today is unregulated, and this provides significant challenges, which include the biochemical variability of one chemovar to another, the possibility of the presence of bacteria and pesticides, and the variation in potency.
 
Nabiximols
 
A significant success of medical cannabis is nabiximols, an oromucosal spray produced from whole cannabis extracts, which is used to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Currently nabiximols is available in 27 countries, is biochemically uniform and provides an easy-to-use, reliable delivery system with immediate onset, allowing a therapeutic window for control of symptoms without intoxication. This suggests a gold standard benchmark, which other cannabis-based medicines will be required to follow.

 
Takeaways
 
There seems to be a clear pathway for medical cannabis to increase in importance in modern pharmacology. Modern technology, which facilitates advanced cultivation and extraction processes appear to be well positioned to facilitate the creation and development of cannabis products to target specific medical needs for maximum relief of a number of chronic conditions.
 
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