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Research & Development Medical research, Pharmaceutical, Pain

A Deep Dive Into Cannabinoid Pharmacology

What was your entry point into cannabis research?

I studied biochemistry at Oxford University in the 1960s. During my studies, I had the opportunity to work with the British Army Royal Engineers, which included an army diving course. As part of the safety training, I learned about “rapture of the deep” (also known as inert gas narcosis), a phenomenon in which breathable gases like nitrogen cause feelings of drunkenness when descending below 30 m. I was fascinated by the idea that the very air we breathe could have such a potent effect and sought out a PhD on the subject with a prominent pharmacology professor at Oxford, William Paton.

After my PhD, Professor Paton offered me a postdoc position exploring the pharmacological actions of some of the main cannabinoids and developing standard tests to measure their effects. We extracted our cannabinoids from bottles of a dark green liquid called “tincture of cannabis,” still legally sold as a medicine in Britain at that time.

A few years later and newly married, I decided I needed a permanent job and in 1974 I took a lectureship at the University of Aberdeen in Scotland, where I have continued studying cannabinoids ever since.

You are co-discoverer of the first-known endocannabinoid, anandamide – how did that come about?

It was the early 1990s – the CB1 receptor had recently been discovered and several labs were racing to find the mystery endogenous molecule(s) that would bind to it.

My lab had developed an in vitro assay for cannabinoids, based on a similar assay for opioids. We placed the mouse vas deferens, which contains nerve and muscle fibers, in an organ bath and electrically stimulated the nerves to release contractile neurotransmitters; by measuring the resulting contractions of the smooth muscle, we could test the effect of various substances on nerve function. The nerve tissue contains CB1 receptors and, when activated (by adding a psychoactive cannabinoid), they block the release of the contractile transmitters and reduce muscle contractions.

Raphael Mechoulam had isolated a candidate endocannabinoid from pig brain, which he mailed over to me (in a regular envelope – those were different times!). Our assay confirmed that this compound was indeed a ligand for CB1, and the first endogenous cannabinoid to be discovered – a huge breakthrough that breathed new life into the field.

A conversation between William Devane, Raphael, and me led us to name the molecule anandamide – ananda is Sanskrit for “bliss or happiness.”

An exciting discovery – one of many in your career! What have been some other highlights?

A particularly rewarding experience was working with multiple sclerosis (MS) patients. During the 1990s, a woman with MS wrote an anonymous article describing how she self-medicated with cannabis to control her symptoms. I got in touch with her and she connected me to a whole community of MS patients using cannabis in the UK and the USA.

I worked with colleagues in the USA to distribute questionnaires to these patients and we found that their experiences with cannabis were very similar. I believe the resulting paper was a factor behind GW Pharma’s decision to pursue research on cannabinoids in MS, which ultimately led to an approved cannabis-based medication, Sativex.

An exciting pharmacological advance came in the mid-2010s when we discovered an important allosteric binding site – a promising drug target – on the CB1 receptor. Allosteric binding sites allow regulation of the receptor. By introducing molecules that bind to this allosteric site and change the conformation of the receptor, we can enhance or weaken its responses to cannabinoids.

We went on to show that a drug targeting this allosteric site acts as a painkiller in mice – presumably by amplifying the response to the body’s endogenous cannabinoids. This makes sense in the context of what we now know about the endocannabinoid system. For example, there is a woman in Scotland with a rare genetic mutation giving her twice the normal level of anandamide – the result is that she feels very little pain, stress, or anxiety.

Were you ever worried about the stigma of working with cannabis?

Not really. When I started in this field, my supervisor was a very well respected scientist who eventually received a knighthood, and it was clear we were focusing on the mode of action of cannabinoids, not on recreational cannabis. These days, I need an annual Home Office license and a regular criminal record check to possess certain compounds, but it’s not a big barrier, just an inconvenience.

What has kept you working on cannabinoids for over 50 years?

Partly the fact that there was (and is) so much to be learned, and partly the therapeutic importance. For instance, we still don’t know the whole story for plant cannabinoids – there are over 120 of them in the plant, with more discovered each year. That makes it a complicated plant to study but also a treasure chest of potential medicines.

How important is collaboration in your work?

I’ve always been someone who likes to collaborate with other labs and I never felt I should (or could) do everything myself. By working with people who have different skills to my own, we gain greater insight than any of us could do alone – you could describe it as an entourage effect!

I am one of the founders of the International Cannabinoid Research Society (ICRS), and we have succeeded in creating meetings with a very friendly atmosphere – I have formed some of my best collaborations there. Sadly, this year’s event has been canceled due to COVID-19, but there is information about recorded presentations and the 2022 meeting at bit.ly/2RYGxS5.

What’s next for you?

I’m carrying on my research into allosteric modulators and currently working with a medicinal chemist to explore allosteric modulation of the cannabinoid CB2 receptor. I’m 77 now but I still come into the lab every day, and was traveling regularly to conferences until COVID-19 struck – I often remind myself that my longtime friend and collaborator Raphael Mechoulam is still active in research and he will be 90 this year!

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