Cannabis health products are everywhere – but do they live up to the hype?
T his has been the year medical cannabis hit the mainstream. The government has announced that it is relaxing laws on when cannabis medicines can be prescribed by doctors, following high-profile cases such as that of Billy Caldwell, the 13-year-old boy hospitalised by his epileptic seizures after he was denied legal access to the cannabis oil that helps control them. Meanwhile a new generation of cannabis medicines has shown great promise (both anecdotally and in early clinical trials) in treating a range of ills from anxiety, psychosis and epilepsy to pain, inflammation and acne. And you don’t have to get stoned to reap the health benefits.
Caldwell’s medicine was illegal because it contained THC, the psychoactive compound that smoking weed socks you with. However, the new treatments under development use a less mind-bending cannabinoid known as CBD (or cannabidiol).
Natural, legal and with no major side effects (so far), CBD is a marketer’s dream. Hemp-based health products are launching left, right and centre, cashing in while the research is in its first flush of hazy potential. As well as ingestible CBD (also sold as hemp or cannabis oils or capsules) the compound has become a buzzword among upmarket skincare brands such as CBD of London. Predictably, Gwyneth Paltrow is a proponent of the trend, and has said that taking CBD oil helps her through hard times: “It doesn’t make you stoned or anything, just a little relaxed,” she told one beauty website.
Meanwhile, so-called wellness drinks infused with CBD are gaining traction. The UK’s first has been launched by Botanic Lab, promoted as “Dutch courage with a difference”. Drinks giants Coca-Cola, Molson Coors Brewing Company and Diageo are all considering launching their own versions, while UK craft breweries such as Green Times Brewing (formerly Cloud 9 Brewing) and Stockton Brewing Company are offering cannabis-oil laced beers, and mixologists are spiking their cocktails with CBD mellowness. The fancy marshmallow maker, The Marshmallowist, has added CBD-oil flavour to its menu, promising that “you feel the effects immediately upon eating”, without specifying what those effects might be.
Cannabis and grapefruit marshmallows from The Marshmallowist
While THC can make you feel edgy, CBD does the opposite. In fact, when used together, CBD can temper the negative effects of THC. Unsurprisingly, there isn’t much CBD in recreational cannabis strains such as purple haze or wild afghan; it is far richer in hemp plants.
Whether any of these CBD products will do anyone any good (or bad) is moot. “Cannabidiol is the hottest new medicine in mental health because the proper clinical trials do suggest it has clinical effects,” says Philip McGuire, professor of psychiatry and cognitive neuroscience at King’s College London. “It is the No 1 new treatment we’re interested in. But although there’s tons of stuff in the news about it, there’s still not that much evidence.” Large, long-term studies are needed; a 2017 review paper into the safety profile of CBD concluded that “important toxicological parameters are yet to be studied; for example, if CBD has an effect on hormones”.
McGuire doesn’t advise buying CBD products. You need to differentiate, he says, between the extremely high doses of pharmaceutical-grade pure CBD that participants in the handful of successful studies were given and the dietary supplements available over the counter or online. “These may contain quite small amounts of CBD that might not have large enough concentrations to have any effects,” he says. “It’s the difference between a nutraceutical and a pharmaceutical.” These supplements aren’t allowed to make claims of any effects. “If you’re making creams or sports drinks with CBD, you can say anything you like as long as you don’t say it will do such and such,” he says.
Two cannabis-based pharmaceutical drugs, manufactured in the UK, are licensed for prescription but only for very specific uses. Sativex has been available in the UK since 2010 and uses THC and CBD to treat spasticity in multiple sclerosis. And a new CBD-only drug, Epidiolex, was approved in June in the US to treat rare childhood epilepsies, with a similar decision expected imminently for Europe and the UK.
Another concern with non-pharmaceutical products, says McGuire, “is that people try them and find, ‘Oh, it doesn’t seem to work.’ Or they get side-effects from some other ingredient, because, if you buy an oil or cannabis product, it’s going to contain all kinds of other things which may have different effects.”
You only have to read the reviews under a CBD product on the Holland & Barrett website to see the extent to which anecdotal reports cannot be trusted. More than 100 customers gave Jacob Hooy CBD+ Oil five stars, with a few saying they always noticed if they missed a dose (presumably this made them less relaxed, although they did not reveal what they were taking it for), while 93 people gave it one star, saying it did nothing, or was too weak. One couple even said it gave them palpitations and a sleepless night. All these people had different conditions, expectations and situations. “And,” says McGuire, “you have to remember that anything can have a placebo effect.” While it looks unlikely that the recommended doses of these products will do any harm, McGuire’s guess is that doses are so small “that it’s like homeopathy – it’s not going to do anything at all”.
McGuire published his own study in August, in which CBD was shown to reduce psychotic episodes in people with schizophrenia. The daily dose was 1,000mg of pure CBD. And a study in which CBD seemed to ease anxiety, published in Nature in 2011, administered a single dose of 600mg, an hour and a half before giving participants a public speaking task. These larger doses contrast with that found in, say, Botanical Labs’ CBD drink. Rebekah Hall, the company’s founder, says her drink is for recreational rather than medicinal purposes and “the amount of CBD per batch is constant and precise, at 2mg per bottle”. A daily dose of two hemp capsules made by Nature’s Plus offers 15mg of mixed “plant cannabinoids” without a specific CBD count.
One of the strongest nutraceutical CBD oils is called Charlotte’s Web, with a 50mg dose. Charlotte’s Web is produced in Colorado by the Stanley Brothers, and named after Charlotte Figi, a girl who became famous in the US after her frequent seizures, brought on by the rare Dravet syndrome, were greatly reduced when she started taking CBD oil aged five. The company makes THC products too and is extremely successful, having just offered shares on the Canadian securities exchange, raising about $100m.
“Among the many benefits that Charlotte’s Web customers experience are: a sense of calm and focus; relief from everyday stresses; help in recovery from exercise-induced inflammation; and support for healthy sleep cycles,” says co-founder Jesse Stanley. But he is obliged to point out that the product is a dietary supplement, and no clinical claims can be made for it.
He emphasises that the company’s products are “whole-plant extracts that include a variety of phytochemicals, not just CBD. These beneficial compounds include a range of phytocannabinoids, terpenes and flavonoids that work together.” This isn’t necessarily seen as a positive by researchers, with McGuire saying: “They muddy the water.” However, Sativex is also a plant extract containing other cannabinoids and substances. David Potter, chief botanist at GW Pharmaceuticals, which makes the drug, says the evidence at the time the drug was developed “suggested there was a synergy between these active ingredients”.
The truth is that no one knows precisely what any of these molecules are doing to us. It is a case of finding the effects first and working backwards to understand the mechanisms. “There are a number of possible transmitter systems that CBD could act on,” says McGuire. “And it’s not 100% clear which ones are critical for anxiety, or psychosis or schizophrenia. But [the antipsychotic effect] is a different mechanism from existing treatments, which is a big deal because existing treatments aren’t working.”
This article was amended on 19 October 2018. An earlier version referred to a beer from Cloud 9 Brewing. The brewery changed its name to Green Times Brewing in September. This has been corrected.
The Biology and Potential Therapeutic Effects of Cannabidiol
“Cannabidiol: Barriers to Research and Potential Medical Benefits”
Mr. Chairman, Ms. Chairwoman, and Members of the Senate Drug Caucus, thank you for inviting the National Institute on Drug Abuse (NIDA), a component of the National Institutes of Health (NIH), to participate in this hearing to share what we know about the biology and the potential therapeutic effects of cannabidiol (CBD), one of the main active chemical compounds found in marijuana. In light of the rapidly evolving interest in the potential use of marijuana and its derivative compounds for medical purposes, it is important to take stock of what we know and do not know about the therapeutic potential of CBD.
To date, 23 states and the District of Columbia have passed laws allowing marijuana to be used for a variety of medical conditions. Fifteen additional states have enacted laws intended to allow access to CBD oil and/or high-CBD strains of marijuana. Interest in the potential therapeutic effects of CBD has been growing rapidly, partially in response to media attention surrounding the use of CBD oil in young children with intractable seizure disorders including Dravet syndrome and Lennox-Gastaut syndrome. While there are promising preliminary data, the scientific literature is currently insufficient to either prove or disprove the efficacy and safety of CBD in patients with epilepsy. i and further clinical evaluation is warranted. In addition to epilepsy, the therapeutic potential of CBD is currently being explored for a number of indications including anxiety disorders, substance use disorders, schizophrenia, cancer, pain, inflammatory diseases and others. My testimony will provide an overview of what the science tells us about the therapeutic potential of CBD and of the ongoing research supported by NIH in this area.
CBD Biology and Therapeutic Rationale
CBD is one of more than 80 active cannabinoid chemicals in the marijuana plant. ii Unlike the main psychoactive cannabinoid in marijuana, tetrahydrocannabinol (THC), CBD does not produce euphoria or intoxication. iii,iv,v Cannabinoids have their effect mainly by interacting with specific receptors on cells in the brain and body: the CB1 receptor, found on neurons and glial cells in various parts of the brain, and the CB2 receptor, found mainly in the body’s immune system. The euphoric effects of THC are caused by its activation of CB1 receptors. CBD has a very low affinity for these receptors (100 fold less than THC) and when it binds it produces little to no effect. There is also growing evidence that CBD acts on other brain signaling systems, and that these actions may be important contributors to its therapeutic effects. ii
Preclinical and Clinical Evidence
Rigorous clinical studies are still needed to evaluate the clinical potential of CBD for specific conditions. i However, pre-clinical research (including both cell culture and animal models) has shown CBD to have a range of effects that may be therapeutically useful, including anti-seizure, antioxidant, neuroprotective, anti-inflammatory, analgesic, anti-tumor, anti-psychotic, and anti-anxiety properties.
A number of studies over the last two decades or more have reported that CBD has anti-seizure activity, reducing the severity of seizures in animal models. vi,vii In addition, there have been a number of case studies and anecdotal reports suggesting that CBD may be effective in treating children with drug-resistant epilepsy. viii,ix,x However, there have only been a few small randomized clinical trials examining the efficacy of CBD as a treatment for epilepsy; the total number of subjects enrolled in these studies was 48. Three of the four studies reported positive results, including decreased frequency of seizures. However, the studies suffered from significant design flaws, including failure to fully quantify baseline seizure frequency, inadequate statistical analysis, and a lack of sufficient detail to adequately evaluate and interpret the findings. viii Therefore, the currently available information is insufficient to draw firm conclusions regarding the efficacy of CBD as a treatment for epilepsy; a recent Cochrane review concluded, there is a need for “a series of properly designed, high quality, and adequately powered trials.” xi
NIDA is currently collaborating with the National Institute on Neurological Disorders and Stroke to evaluate CBD in animal models of epilepsy in order to understand the underlying mechanisms and optimize the conditions under which CBD may treat seizure disorders, and determine whether it works synergistically with other anti-seizure medications. In addition, clinical trials are currently underway by GW Pharmaceuticals, testing the efficacy of Epidiolex, a purified CBD extract, for treatment of pediatric epilepsy.
Neuroprotective and Anti-Inflammatory Effects
CBD has also been shown to have neuroprotective properties in cell cultures as well as in animal models of several neurodegenerative diseases, including Alzheimer’s, xii,xiii,xiv stroke, xv glutamate toxicity, xvi multiple sclerosis (MS), xvii Parkinson’s disease, xviii and neurodegeneration caused by alcohol abuse. xix Nabiximols (trade name Sativex), which contains THC and CBD in roughly equal proportions, has been approved throughout most of Europe and in a number of other countries for the treatment of spasticity associated with MS. It has not been approved in the United States, but clinical trials are ongoing, and two recent studies reported that nabiximols reduced the severity of spasticity in MS patients. xx,xxi There have been limited clinical trials to assess the potential efficacy of CBD for the other indications highlighted; however, a recent small double-blind trial in patients with Parkinson’s disease found the CBD improved quality-of-life scores. xxii
There have been multiple clinical trials demonstrating the efficacy of nabiximols on central and peripheral neuropathic pain, rheumatoid arthritis, and cancer pain. xxiii In addition, nabiximols is currently approved in Canada for the treatment of central neuropathic pain in MS and cancer pain unresponsive to opioid therapy. However, the current evidence suggests that the analgesia is mediated by THC and it is unclear whether CBD contributes to the therapeutic effects. xxiv THC alone has been shown to reduce pain; xxv,xxvi we are unaware of clinical studies that have explored the efficacy of CBD alone on pain. However, the anti-inflammatory properties of CBD (discussed above) could be predicted to play a role in the analgesic effects of nabiximols. Recent research has also suggested that cannabinoids and opioids have different mechanisms for reducing pain and that their effects may be additive, which suggests that combination therapies may be developed that may have reduced risks compared to current opioid therapies. However, this work is very preliminary. xxvii
In addition to the research on the use of cannabinoids in palliative treatments for cancer—reducing pain and nausea and in increasing appetite—there are also several pre-clinical reports showing anti-tumor effects of CBD in cell culture and in animal models. xxviii These studies have found reduced cell viability, increased cancer cell death, decreased tumor growth, and inhibition of metastasis (reviewed in McAllister et al, 2015). xxix These effects may be due to the antioxidant and anti-inflammatory effects of CBD; xxx however these findings have not yet been explored in human patients. There are multiple industry sponsored clinical trials underway to begin to test the efficacy of CBD in human cancer patients.
Marijuana can produce acute psychotic episodes at high doses, and several studies have linked marijuana use to increased risk for chronic psychosis in individuals with specific genetic risk factors. Research suggests that these effects are mediated by THC, and it has been suggested that CBD may mitigate these effects. xxxi There have been a few small-scale clinical trials in which patients with psychotic symptoms were treated with CBD, including case reports of patients with schizophrenia that reported conflicting results; a small case study in patients with Parkinson’s disease with psychosis, which reported positive results; and one small randomized clinical trial reporting clinical improvement in patients with schizophrenia treated with CBD. xxxii Large randomized clinical trials would be needed to fully evaluate the therapeutic potential of CBD for patients with schizophrenia and other forms of psychosis.
CBD has shown therapeutic efficacy in a range of animal models of anxiety and stress, reducing both behavioral and physiological (e.g., heart rate) measures of stress and anxiety. xxxiii,xxxiv In addition, CBD has shown efficacy in small human laboratory and clinical trials. CBD reduced anxiety in patients with social anxiety subjected to a stressful public speaking task. xxxv In a laboratory protocol designed to model post-traumatic stress disorders, CBD improved “consolidation of extinction learning”, in other words, forgetting of traumatic memories. xxxvi The anxiety-reducing effects of CBD appear to be mediated by alterations in serotonin receptor 1a signaling, although the precise mechanism remains to be elucidated and more research is needed. xxxvii
Efficacy for Treating Substance Use Disorders
Early preclinical findings also suggest that CBD may have therapeutic value as a treatment of substance use disorders. CBD reduced the rewarding effects of morphine xxxviii and reduced cue-induced heroin seeking xxxix in animal models. A few small clinical trials have examined CBD and/or nabiximols (THC/CBD) for the treatment of substance use disorders; however, the available data are not sufficient to draw conclusions. NIDA is supporting multiple ongoing clinical trials in this area.
Safety of CBD
For reasons discussed previously, despite its molecular similarity to THC, CBD only interacts with cannabinoid receptors weakly at very high doses (100 times that of THC), xl and the alterations in thinking and perception caused by THC are not observed with CBD. iii.iv,v The different pharmacological properties of CBD give it a different safety profile from THC.
A review of 25 studies on the safety and efficacy of CBD did not identify significant side effects across a wide range of dosages, including acute and chronic dose regimens, using various modes of administration. xli CBD is present in nabiximols which, as noted earlier, is approved throughout most of Europe and in other countries. Because of this, there is extensive information available with regard to its metabolism, toxicology, and safety. However, additional safety testing among specific patient populations may be warranted should an application be made to the Food and Drug Administration.
Research Opportunities and Challenges
This is a critical area for new research. While there is preliminary evidence that CBD may have therapeutic value for a number of conditions, we need to be careful to not get ahead of the evidence. Ninety-five percent of drugs that move from promising preclinical findings to clinical research do not make it to market. The recently announced elimination of the PHS review of non-federally funded research protocols involving marijuana is an important first step to enhance conducting research on marijuana and its components such as CBD. Still, it is important to try to understand the reasons for the lack of well-controlled clinical trials of CBD including: the regulatory requirements associated with doing research with Schedule I substances, including a requirement to demonstrate institutional review board approval; and the lack of CBD that has been produced under the guidance of Current Good Manufacturing Processes (cGMP) – required for testing in human clinical trials – available for researchers. Furthermore, the opportunity to gather important information on clinical outcomes through practical (non-randomized) trials for patients using CBD products available in state marijuana dispensaries is complicated by the variable quality and purity of CBD from these sources.
Ongoing CBD Research
The NIH recognizes the need for additional research on the therapeutic effects of CBD and other cannabinoids, and supports ongoing efforts to reduce barriers to research in this area. NIH is currently supporting a number of studies on the therapeutic effects as well as the health risks of cannabinoids. These include studies of the therapeutic value of CBD for:
- Treatment of substance use disorders (opioids, alcohol, cannabis, methamphetamine)
- Attenuation of the cognitive deficits caused by THC
- Neuropathic pain due to spinal cord injury
- Mitigating the impact of cannabis use on risk for schizophrenia
- Examination of the potential of CBD as an antiepileptic treatment
It is important to note that NIDA’s mission is focused on drug abuse; studies related to the therapeutic effects of CBD in other areas would be funded by the Institute or Center responsible for that program area. For example, studies related to epilepsy will likely be funded by the National Institute of Neurological Disorders and Stroke or by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, while studies related to schizophrenia will likely be funded by the National Institute on Mental Health.
There is significant preliminary research supporting the potential therapeutic value of CBD, and while it is not yet sufficient to support drug approval, it highlights the need for rigorous clinical research in this area. There are barriers that should be addressed to facilitate more research in this area. We appreciate the opportunity to testify on the potential use of CBD for therapeutic purposes. Thank you again for inviting me here today, and I look forward to any questions you may have.