On Wednesday morning I attended the session “Novel therapeutic uses of cannabinoids” chaired by Prof Jan Ramaekers (Maastrict). Over recent years the therapeutic use of cannabis have gained increasing interest but there is a lack of clinical data to support whether cannabis/cannabinoids are effect for many disorders, and yet increasingly, cannabis based medicines can be prescribed by physicians. In the UK recently, the change in the law has allowed for cannabis prescriptions, but the number of these issued is woefully low. So therefore this symposium gave an overview of the novel treatment indications for cannabinoids for which there is clinical evidence, and importantly why they work.
Professor Roger Pertwee (Aberdeen) gave an overview of the pharmacological actions and potential indications based on cellular and preclinical research. The cannabis plant is a unique source of “phytocannabinoids” such as THC, CBD and CBG. There are at least 120 cannabinoids and at least 445 other compounds in the cannabis plant. Some cannabinoids have been approved for medical used since the 1980’s including THC, dronabinol and marinol, mostly used for their antiemetic and appetite stimulants. More recently there has been Sativex (GW pharmaceuticals) which is plant-derived and is licenced for Multiple Sclerosis. THC has a unique fingerprint where it acts as a CB1 and CB2 agonist and at higher concentrations at other targets. CBD as a medication has been approved for childhood epilepsies as the drug Epidiolex (GW pharmaceuticals). Pertwee warned against the use of high street CBD due to lack of quality. Interesting many cannabinoids have opposite effects at the same receptors and gives the example of how CBD enhances 5HT1a but CBG has the opposite effect at the same receptor site. Since CBD acts at 5HT1a it has several uses in chemotherapy induced nausea and vomiting. He notes the bell shaped curve with CBD with recent data showing it works at 300mg better than 150 or 600mg.
Pertwee and colleagues have also looked at CBDA which is more potent than CBD but isn’t druggable, so they developed HU580, which is druggable. HU580 enhances 5HT1a in vivo and in vitro and is a stable molecule with potent anti-anxiety effects.
THCV (discovered by Pertwee and colleagues in the 1960s) is an interesting cannabinoid because it blocks CB1 and activates CB2 at the same time, and seems to be effective in kidney damage and nicotine dependence but not cocaine dependence, in rats.
Cannabinoids are lipid soluble. Water-soluble molecules would have different indications and he reports on a THC Pro-Drug that when applied directly to the eyes of rabbits, reduces glaucoma, via a reduction in eye pressure.
He also reported on the use of drugs that modulate the endocannabinoid system. Endocannabinoids act in an “autoprotective way”. Recently there was an interesting story about a lady in Scotland who did not have the FAAH gene which means she has a high level of anandamide because she cannot metabolise it (as FAAH metabolises anandamide). This also means she doesn’t really feel pain, such that drugs targeting this system may have an effect on pain.
Roger then moved on to discuss positive and negative allosteric modulators that mean that endocannabinoids can better bind to the CB1 receptor strengthening the receptor.
Roger was recently awarded the lifetime achievement award at the International Cannabinoid Research Society – congratulations Roger!
Professor Müller-Vahl from Hanover started with the idea that clinical trials are really difficult to conduct and we are moving in the right direction with them, as such she has many conflicts of interest as she consults for companies. She reports of the effects of cannabinoids in Tourette’s syndrome which is characterised by tics (motor and vocal), is neurodevelopmental in nature and to be diagnosed, one needs to have tics for at least a year. However it’s highly comorbid with sleep disorder, ADHD and OCD as well as depression and anxiety. Her work is conducted in Germany where she can prescribe cannabinoids as a whole plant (full spectrum), as well as a whole host of synthetic and pure cannabinoids. In Germany there are 26 varieties which can be prescribed which vary in THC (1-25%) and CBD (1-12%).
Some case studies (200 patients) have supported cannabis, in its many forms) in the improvement of tics and associated co-morbidities which supported an RCT where she found a reduction in tics (back in 2002). However there are adverse effects with cannabinoids which need to be managed (Whiting et al. 2015) and pure THC is less effective, less tolerated then cannabis extracts. Interestingly in those with Tourette’s, neuropsychological tests after cannabis showed no change, and aligned with this case studies have shown that cannabis helped with visual perception in Tourette’s. So although there may be side effects, it really depends what the baseline is.
Why does cannabis work in Tourette’s? The underlying mechanism is not known and she discussed some of the hypotheses around this (dysfunction of cortico-striato-thalamic networks and the dopaminergic system; especially the dysfunction between tonic and phasic dopamine in the basal ganglia where there are high numbers of CB1 receptors).
She had hypothesised that those with Tourette’s had an endocannabinoid deficiency. But when she measured the levels of endocannabinoids in the cerebrospinal fluid (a measure of central endocannabinoids) she found an increase in 2AG. Is this a compensatory mechanism?
A recent drug has been developed called ABX1431 which increases 2ag in Tourette’s. A small clinical trial showed there was strong target engagement, increasing plasma levels of 2-AG, and a significantly reduction in tics. People with Tourette’s report a strong urge to tic and this drug also reduced the urge. It was also well tolerated wit no serious adverse effects so a follow up multi-centre trial is occurring. We will wait and see.
Dr Benjamin Whalley (GW Pharmaceutical Ltd) reported on the evolution of cannabidiol in epilepsy. GW have developed Epidiolex, a plant-derived, highly-purified form of CBD. He notes the poor bioavailability of CBD, the significant effects of food and the metabolism of CBD. He gives an overview of the preclinical and clinical pipeline, which happened in about 6 years from the first patient to FDA approval, with about 1700 patients. This was because of FDA compassionate use programme.
CBD seems to have a broad spectrum of action in antiepileptic models, inconsistent with other anti-epileptic drugs). To understand the mechanism they have used genetic knock out models of dravets symdrome (SCN1A (+/- mice). CBD improved survival rates, ameliorated anxiety, autism-like behaviour and anhedonia. He notes the main limitation to this work is that it’s unclear if this is the action of CBD or the action of a reduction in epilepsy.
He also discussed work on an orphan G protein coupled receptor GPR55 which some a calling a new cannabinoid receptor but it’s still categorised as orphan receptor. The ligand for it is called LP1, and this may be the mechanism through which CBD works with evidence coming from cellular and animal research.
Another mechanism is via ENT1 which is the transformer for adenosine. CBD produces a reduction in ENT1 and increases adenosine, so this is another mechanism by which CBD may be working in epilepsy.
In regards to the clinical trials, CBD at clinically therapeutic doses does have side effects but they are manageable.
Finally Dr Ruth Cooper (London) discusses the first trial of cannabinoids, particular Sativex (GW, 1:1 THC:CBD), for the treatment of tatention-deficit/hyperactivity disorder (ADHD)
ADHD characterised by hyperactivity and impulsivity, it can have clinical significant effects in job/academic performance. It is often treatment with stimulant drugs such as Ritalin. Patients with ADHD report using cannabis for self-medication, reporting that it helps them think clearer, and improves attention.
But there is little empirical evidence and a few analyses of online forums and a few case studies did show a signal that it could be useful for ADHD. The trigger really was a patient who asked for cannabis and was prescribed it for a month before the NHS stopped maybe for the drug.
The study involved 30 unmediated adults with ADHD who were titrated on to Sativex/Placebo for 2 week and used the drug for 4 weeks in a randomised double blind trial. They saw small improvement in hyperactivity/impulsivity, no significant adverse effects, as well as trend improvements in attention and emotional lability and cognitive performance. The drug was well tolerated and patients reported improved focus, concentration and calmness although some said it was too sedative. Certainly an active control would be needed as participants guessed which drug they were on and this study was underpowered to detect real effects, with at least 100 per arm necessary.
Overall, it looks like we are slowly starting to understand the effects of cannabinoids and where they might be clinically effective but there are many issues in regarding to dosing, cannabinoid concentrations and route of administration. Clinical trials are underway.