Medicinal cannabis is not (yet) reimbursed for the treatment of chronic pain. A recent publication provides more insight into the action of the two main active substances in cannabis, THC and CBD. It turns out that CBD does not affect the action of THC, but high doses do inhibit the breakdown of THC, increasing side effects. An unexpected result for some, showing the importance of clinical pharmacological studies of such agents.

‘Some of the patients with chronic pain syndromes that I see at the LUMC pain clinic, about 10-20% of them, benefit from medicinal cannabis. They now sometimes have to pay as much as €350 a month out of pocket, because medicinal cannabis is not reimbursed because there is insufficient scientific evidence that it is effective. ‘For most of them, that’s a huge amount of money that they can’t actually afford,’ says Prof Geert-Jan Groeneveld, neurologist and clinical pharmacologist and director of Centre for Human Drug Research (CHDR), a Leiden-based foundation that conducts drug research.

Evidence of the efficacy of (substances from) cannabis in chronic pain would mean that patients might be able to get reimbursed for the treatment. Against that background, CHDR conducts research on cannabis, partly from the ZonMw Medicinal Cannabis programme and partly with its own funding. Because CHDR also works on behalf of pharmaceutical companies, it earns money that the foundation can invest in its own research and method development.

Romantic idea
Andriy Gorbenko, physician-researcher at CHDR, is researching cannabis in Groeneveld’s team using the same methodology they would use for a new painkiller. ‘In modern pharmacology, we don’t work with plants, but with active substances,’ Gorbenko says. ‘Some people have the romantic idea that the different substances in a plant like cannabis would enhance each other’s effects, or “balance each other out”, and that plant preparations would therefore be better than isolated active substances. But there is actually no example that this is how it works. That’s why doctors give morphine and not milk juice from the poppy plant, and penicillin instead of a scoop of fungus.’

Since such beliefs about cannabis are still common, the researchers decided to investigate the interaction between THC and CBD, the main two active substances in cannabis. Gorbenko: ‘Besides the terpenes that give cannabis its characteristic smell, these are two substances that could influence each other’s effects. What you often hear is that CBD softens the effects of THC. People would be less likely to suffer from anxiety and get less high thanks to the CBD in cannabis.’

To chart the interaction, the researchers conducted a placebo-controlled crossover study in 37 healthy volunteers. All volunteers came to CHDR five times and received each of five possible combinations over the course of those visits: placebo alone, 9 milligrams of THC plus placebo or 9 milligrams of THC with 10, 30 or 450 milligrams of CBD. Then, using a series of standardised pain tests, they looked at what the different combinations did to pain perception, and the other effects of the administered cocktail were measured using a standardised battery of neurophysiological and neuropsychological tests. In the lower doses, CBD had little to no noticeable effect on the measurements. High-dose CBD (450 milligrams) did not affect the effect of THC in the pain tests, but did lead to more side effects, including anxiety and feeling ‘high’.

An explanation for this phenomenon was also found: with this high dose of CBD, the concentration of THC in the blood was increased and remained elevated for longer, as did the concentration of the active breakdown product 11-OH-THC. Gorbenko: ‘While we were conducting our study, another group published data showing that CBD inhibits a number of CYP enzymes in the liver, slowing down the breakdown of THC and a large number of other pharmacologically active substances’. ‘In any case, what our study shows is that pharmacologically there is no reason to prefer cannabis extract over pure THC,’ says Groeneveld. ‘That whole romantic idea that the plant has added value over the one pharmacologically active substance is just not true. The amount of CBD that occurs naturally In cannabis probably doesn’t do much, but it doesn’t add value and at high concentrations it can even be counterproductive.’

CBD’s influence on the breakdown of other pharmacologically active substances in the liver also puts its ‘efficacy’ in pain and other conditions such as epilepsy in a different light. CHDR is currently investigating to what extent the putative effects of CBD can be explained by CBD affecting the blood concentrations of the other drugs the patient is taking. Gorbenko: ‘CBD oil is freely available at any drugstore. You may assume that it is used by people who have health problems, so who may also be taking other drugs. It could well be that the drug actually causes a dose increase of those other drugs in a complicated way. We’re figuring that out now.’

Psychedelics as drugs
Dr Saco de Visser of FAST, who was involved in this study, stresses the importance of a clinical-pharmacological approach to cannabis and similar products. ‘There is also currently a lot of interest in psychoactive mushrooms and psychedelics, with much research taking place from an exploratory phenomenological approach. That may seem logical from history, but if you really want to use these kinds of drugs as treatment and thus prepare a dossier for market authorisation and/or reimbursement, you just have to take the steps appropriate to clinical pharmacological drug development and understanding how this drug may or may not work for patients. And so then sometimes you come across things that are different from what is always claimed, as this study shows.’

FAST is regularly approached by both private and public parties with therapy development issues. These questions range from showing the way in the regulatory field or making connections between parties to jointly thinking of ways to improve affordability and accessibility of medicines. So we do this at system level, but in a number of areas we also like to do this on the basis of case histories. As an organisation, we like to use our extensive expertise and our broadly branched network to contribute to solutions to support the development of therapies.