Pharma Gets Help Developing Cannabis Drugs

The pharmaceutical industry process to test potential medicines has mostly failed to develop cannabinoid medicines. That’s all the more remarkable because the cannabis plant irrefutably produces profound and desirable medical and recreational effects, and does it so safely that millions of people regularly self-medicate in nearly every country in the world. And the raw plant material, the biomass found in female marijuana plants, grows like a weed so it shouldn’t be difficult to find a source of raw material.

Leaving the confusing and draconian marijuana research laws aside, one lab at the Leiden Institute for Chemistry may have opened the clogged cannabis research pathway. In an article in Nature Communications these researchers set out ‘gold standards’ for the use of reference substances, to improve tests for synthetic cannabis.

Many of the clinical trials with synthetic cannabis have failed, with no measurable effect being recorded in patients. One of the causes of these failures can be found in the pre-clinical lab, during testing with animals. Substances are often used in these tests whose biochemical and molecular-pharmaceutical effects have never been properly characterized. As a result, there have been a lot of contradictory publications on research findings, the results of which cannot be reproduced. This is having a major effect on the allocation of research funding, the use of animal testing and the exposure of patients to non-active substances.

You may wonder why pharmaceutical scientists want to use synthetic cannabinoid molecules when easy-to-grow plants produce hundreds of readily available ingredients. It’s for several reasons:

  1. It’s difficult to obtain patents on naturally occuring drug ingredients.
  2. Growing plants are a haphazard way to secure a reliable / consistant source of raw material for drug testing that must meet stringent Good Manufacturing Practices [GMP].
  3. FDA and other regulatory agencies practically insist that a drug contain only one active ingredient, and the marijuana plant contains hundreds of potentially active ingredients.

The 18 most commonly used reference substances, including the psychoactive ingredient in marijuana, Δ9-THC were examined by Marjolein Soethoudt, a PhD candidate in Van der Stelt’s research group. This was done in collaboration with 12 international academic groups, the National Institute of Health (US) and Hoffman-LaRoche Pharmaceuticals. The molecular pharmacological characteristics of the substances were tested under standardised conditions in 36 different tests. The research led to three molecules, potential ‘gold standards’ that should give an impetus to developing new painkillers and anti-inflammatories because they shouldn’t make people ‘high’, but will have other desirable medical effects, and are probably non-toxic at expected dosage levels.

The three ‘gold standards’ are molecules that are highly selective in activating only the CB2 receptor and ignoring the CB1 receptor. These three gold standards also appeared to cause the fewest side-effects, nor did they give the mice ‘a high’. Earlier studies have shown that these substances do have an analgesic and anti-inflammatory effect. The researchers advise that these three gold standards should be used in future research to develop new medicines that activate the cannabinoid CB2 receptor.

The author’s state: “We reached a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.”

The full publication can be found at:

Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity. Marjolein Soethoudt, Uwe Grether, Jürgen Fingerle, Travis W. Grim, Filomena Fezza, Luciano de Petrocellis, Christoph Ullmer, Benno Rothenhäusler, Camille Perret, Noortje van Gils, David Finlay, Christa MacDonald, Andrea Chicca, Marianela Dalghi Gens, Jordyn Stuart, Henk de Vries, Nicolina Mastrangelo, Lizi Xia, Georgios Alachouzos, Marc P. Baggelaar, Andrea Martella, Elliot D. Mock, Hui Deng, Laura H. Heitman, Mark Connor, Vincenzo Di Marzo, Jürg Gertsch, Aron H. Lichtman, Mauro Maccarrone, Pal Pacher, Michelle Glass, Mario van der Stelt. Nature Communications, 2017; 8: 13958 DOI: 10.1038/ncomms13958