Found in Translation

Where – and how – do you focus your research?

After decades  of research, there’s still more knowledge being gained in terms of the neurobiology and pharmacology of the endocannabinoid system. At the same time, we know that people are using the cannabis plant in many different ways; for example, extracting and trying cannabinoids that we didn’t even think about five years ago. There appear to be almost endless possibilities in connecting what we know from the animal literature about the pharmacology of cannabis-based compounds with what we know about how people are using the plant. And my area of expertise, in simple terms, is designing and running controlled human studies to try and integrate these two streams of information. 

For example, we hear time and time again that people are using cannabis and cannabis based products for pain – and that they’re able to reduce their opioid use over time. But we also know that those surveys are done with a select group of people, where there may be some expectancy effect – a placebo effect. Nevertheless, it gives us a good reason to search for specific signals in the animal literature. And the same is true vice versa. There’s so much to learn about cannabis and its effects – and seeking signals at opposite ends of the spectrum gives us a strong starting position.

How did you find yourself heading up a cannabis research initiative?

In my earlier days, I was interested in music and physics, so I actually went to college wanting to become an acoustical engineer – so very different to where I ended up! But along my academic journey I became fascinated by how exogenous substances – especially drugs – interact chemically with the brain to elicit changes in mood and perspective. Unsurprisingly, my interest led to a deeper focus on psychoactive drugs – so I started studying opioids and other psychoactive drugs, such as cocaine. But it wasn’t until around seven years later in 2007 that I started working with Meg Haney (who went on to become my mentor) and began exploring the effects of cannabis and cannabinoids. 

Getting into the field at that time was particularly interesting because it felt so wide open – in fact, it was striking to me how little work had been done. In large part, the barriers and obstacles to research were at fault, but I suddenly found myself in a laboratory and a collaborative environment where the work was possible – and it seemed there were so many questions that needed to be answered. That’s a great place to be as a scientist! Moreover, there were also some really nice overlaps between the cannabinoid system and the opioid system I’d been studying, and so I also became interested in the interaction between the two – a direction of research I'm still pursuing 12 years later.

In short, it was really exciting when I entered the field – and, in truth, it still is really exciting.

And what are today’s big unanswered questions in cannabis research?

Well, what do we know? We know that the actions of cannabis on the brain and body depend on the chemical constituents of the plant. We also know that the action depends on how people administer it – and how often. We know the action is dose dependent. And we know that it’s dependent on age, sex, physiology, and perhaps even genetics.

In other words: cannabis is not one thing – it’s a million different things, and people are not all the same. At a very fundamental level, those two aspects still need a great deal of unraveling. I know that’s not one big question, and it’s certainly not a single answer!

Our knowledge of THC is solid and growing. We know that many of the intoxicating and (potential) therapeutic effects of cannabis are due to the THC concentration in the plant. And we’re starting to learn more about some of the other constituents that were not typically found in high concentrations in the cannabis plant. Cannabis is now being bred with higher concentrations of other cannabinoids – CBD being the most well known. And so our knowledge there is also growing. We can say with fair certainty that CBD is not intoxicating (at least I have not seen data) and that it doesn’t have abuse potential like THC. CBD has proven therapeutic effects for certain indications, but people appear to be taking CBD for hundreds of other reasons. Many assumptions are being made about CBD’s anti-inflammatory and other potential therapeutic effects in humans based on the animal literature – but without the all important translational research. 

Consider anxiety, sleep, and pain – the primary reasons people are using CBD – placebo-controlled studies are lacking. At the same time, going back to my previous point about signals in the population, is there likely to be so much smoke without fire? For that reason, anxiety, pain, and sleep represent low-hanging fruits for translational science questions. In my opinion, CBD research is still in its infancy – but there are plenty of clinical trials ongoing, so I suspect we’re going to be learning a lot more in the next couple of years…

You’ve mentioned THC and CBD; what about other minor constituents?

Again, based on preclinical studies there are certainly signals that many of these compounds have potential therapeutic effects with little psycho activity (or at least very little intoxicating effects). In our laboratory, we’re exploring minor cannabinoids and other constituents, such as terpenes, to figure out if the signals in the animal literature translate to humans. You’re probably seeing a theme develop here!

We’re also interested in the concept that the chemicals in the cannabis plant can work together to optimize the therapeutic effect and minimize adverse effects – popularly known as the entourage effect. It’s certainly an enticing hypothesis – and one that can be tested methodically in the laboratory. What happens when you add these chemicals together? We want to find out – in controlled studies. For example, could we reduce the required dose of THC by adding other chemicals and thus reduce the intoxication or memory impairing effects, while boosting its potential pain relieving effects? You may have heard of the opioid sparing effects of cannabinoids – but what if minor cannabinoids (and other chemical constituents) had THC sparing effects?

When it comes to medicinal cannabis, the science often lags behind perceptions and actual use of the drug – how do you feel about that as a scientist?

Good question. I think it puts us scientists in a tough spot. Public policy and public perceptions shift quickly – and the industry rapidly grows in new ways to capture the market. But, all too often, these views, trends, and decisions are not good indicators of where the science is at. And it’s hard to explain to people that science can be slow. While the rest of the globe is going through this real-life experiment, figuring out what’s working for them (or what’s not working for them), the science takes a long time to catch up. There may be a hot trend – CBG or delta-8-THC in the US right now – and we’ll put in a grant, get funding a year later, start a randomized control trial, and begin collecting and analyzing data just as the next trend emerges...

That’s probably frustrating from the lay public’s perspective, and it’s definitely frustrating as an educator and as a scientist. On the other hand – and despite the lag – it is at least gratifying to share robust data (for example, what CBG or delta-8-THC actually does) with people who could have not gained the evidence from any other source.

You touched upon your role (and frustration) as an educator...

When it comes to medical school curriculums in the US (and probably elsewhere), the endocannabinoid system  – as well as cannabis and cannabinoids in general – aren’t really covered at all at most universities. And that’s a problem we’re striving to fix at UCLA. We offer a course to undergraduate and graduate students, and we offer seminars to medical students, residents, and fellows. We’re trying very hard not just to expand research in this area, but also to expand the knowledge within the university setting and beyond. Considering that people increasingly turn to the internet for knowledge and information, it’s really important that scientists, researchers, and physicians in the field are able to communicate directly with the public, with students, and with medical professionals to highlight what the evidence does and does not say.

What research are you most proud of?

As a behavioral pharmacologist, what excites me most is when our results show a positive translation from preclinical models to humans, which doesn’t happen all the time – far from it. And so it was very gratifying when we showed a strong sex-dependent effect of cannabis in humans – a wonderful reflection of what we observed in the animal literature. We also demonstrated the aforementioned opioid sparing effect of THC in humans; we showed that when you combine THC and an opioid at doses that would not typically produce pain relief on their own, you get significant pain relief. And we’re still digging into these areas.

What’s the research funding landscape like – and who do you turn to for support?

Certainly, the cannabis industry is large and growing. But it’s actually very difficult to get funding for scientific studies – in the US and across the globe. Fortunately, there’s a very strong network of researchers who are either collaborating or sharing information, and that helps drive all this research forwards.

There are excellent researchers across Europe, Australia (see page 12), and Israel, who have really pushed our field forward. For me, in the US, where we’re dealing with a unique set of regulatory obstacles, developing close collaborations is really important. And that’s why I still maintain close contact with Columbia University, where I stayed for about 13 years. Ryan Vandrey at Johns Hopkins has also been a tremendous source of collaborative energy. Closer to home, I work with Daniele Piomelli – a neuroscientist and scientific pioneer in the endocannabinoid system at the University of California, Irvine. There are many other influential people, groups, and institutions that have been instrumental in forwarding cannabis and cannabinoid science – it’s an incredible network of talented scientists. 

I will also say that the National Institutes of Health have been enormously helpful. Traditionally, they didn’t fund therapeutic effects of cannabis and cannabinoids, but they have begun earmarking funds for this specific purpose. And they are genuinely interested in researchers finding success because they know how difficult it is.

Where would you like to see the field 10 years from now?

We’re already on the path. We have ample data from survey reports, anecdotal reports, and observational studies – and they are important in helping us identify what patients are self reporting to be potentially effective. But we need to move on from those published data, integrating the findings into the well designed randomized control studies, where we can probe – in detail and with scientific rigor – specific cannabinoids and cannabis constituents (either isolated or combined) for specific indications. That’s what we – and several other groups – are working towards. 

Over the next 5–10 years, I think we’re going to see a boom with respect to the data that will be available across different indications. And I’m really excited for that!