Ask an Expert: Dr. Ali Salahpour Discusses New Cannabinoid-based Strategies to Enhance L-DOPA Therapy and delay dyskinesia
Dr. Ali Salahpour obtained his B.Sc (1996) and PhD (2002) at the University of Montreal. He then was a post-doctoral fellow at Duke University (2002-2009), where he focused on dopamine neurotransmission. He started his independent career in 2009 in the Department of Pharmacology and Toxicology at the University of Toronto (UofT). In 2023, he was appointed Chair of the Department of Pharmacology and Toxicology at UofT. Research in his lab is focused on dopamine neurotransmission with major emphasis on Parkinson’s and Parkinson’s-related diseases.
The research discussed below was co-funded through a partnership between Parkinson Society British Columbia and the Parkinson Canada Research Program for a total of $75,000 over 2 years.
Can you tell us a little bit about your latest study, titled ‘Cannabinoid compounds to augment L-DOPA treatment and prevent L-DOPA induced dyskinesia’?
For many years our lab has been interested in two aspects of Parkinson’s disease. Firstly, we have been interested in the role of oxidative stress and how this could represent a vulnerability for degeneration of dopamine neurons, which is one of the main hallmarks of Parkinson’s disease. Secondly, we have been interested in identifying new drugs that could improve motor symptoms mostly by enhancing levodopa (L-DOPA) responses.
What inspired you to look at cannabis compounds for Parkinson’s?
My colleague, Dr. Ruth Ross, is a cannabis expert. Over the last five to eight years, we have collaborated with her towards finding drugs that act via the cannabinoid system for reducing psychosis observed in schizophrenia, which results mainly from excess dopamine function.
We successfully found some cannabis drugs that can potentially improve psychosis in schizophrenia, and published those results several years ago. At that time, Dr. Ross also asked me whether we could consider the reverse and find compounds that would enhance dopamine actions, which would be very beneficial in Parkinson’s.
Interestingly, Dr. Ross’ lab already had some preliminary observations that this might work. Since our lab had the expertise in Parkinson’s animal models, we started a new collaboration towards finding compounds that act on the cannabinoid system that could improve L-DOPA responses.
What have you learned about levodopa-induced dyskinesia (LID) through your study?
Our study, per se, is not focused on investigating the pathophysiology of levodopa-induced dyskinesia. We know from many years of work in the field that LID development is linked to the dose and duration of L-DOPA usage, meaning that higher doses and longer duration of L-DOPA treatment are associated with higher LID development.
As such, it has been known for a long time that drugs that could enhance L-DOPA response or reduce the dose of L-DOPA could potentially delay the onset of LID, simply by reducing the doses of L-DOPA. I’m happy to report that two of the cannabinoid drugs we have identified can improve motor symptoms in mice, where we can get the same level of motor improvement with half the dose of L-DOPA when combining it with our cannabinoid compounds.
This is quite exciting because it might be possible to achieve similar motor symptom relief in patients by combining the cannabinoid drug and half the regular dose of L-DOPA. In theory, this could delay development of LID simply because the patients will be using lower doses of L-DOPA. Of course, these are studies in mice, and we need to corroborate our observations in other models, but these are quite exciting and encouraging results.
Have any results surprised you? If so, what?
I have to admit that I was surprised by how much we could enhance L-DOPA response in our model. I originally thought that we might be able to find a drug that gives us a 20% enhancement, for example, but the results we get with our cannabinoid compounds are much higher and, as I said, we can see the same benefit on motor activity with half the dose of L-DOPA. Essentially, we are doubling the effect of L-DOPA, and this is quite surprising to me. I haven’t seen many drugs that can increase L-DOPA activity to this level.
Please explain the relationship between the cannabinoid system and dopamine. How do they impact each other?
This is a great question and not as simple as it sounds. The best and easiest way I can answer this is to say that the cannabinoid system can modulate the dopamine system and, depending on how we affect the cannabinoid system, we can either increase or decrease dopamine function.
As I mentioned earlier, we have data showing that some cannabinoid-modulating compounds that decrease endogenous (produced naturally within the body) cannabinoid activity can decrease dopamine function and could be useful for schizophrenia or bipolar disorder, both of which are associated with increased dopamine function.
And now, we have data that by increasing endogenous cannabinoid function, we can increase dopamine function and L-DOPA response. So, in essence, the cannabinoid system can act as a break or ‘accelerator’ of the dopamine system, depending on whether we increase or decrease the cannabinoid system activity.
Could this research eventually lead to new treatments for Parkinson’s? If so, how long might that take?
One exciting part of our project is that one of the drugs we are testing, ABX 1431, is already in clinical trials for Tourette syndrome, which means that the compound has good safety and can be used for clinical use in humans. This helps us overcome a major hurdle in drug development.
The next limiting step for us is to test this compound for Parkinson’s disease in one or two other preclinical animal models. If those results are also promising, then a pilot clinical study could be considered. Having said that, we all know that drug discovery has a lot of uncertainty, and many drugs that work in mice unfortunately don’t show clinical benefits in humans.
Nonetheless, I remain quite optimistic about the prospect of ABX 1431, but before proving the efficacy of this compound in a couple of other models, it is hard to know whether it can potentially translate to humans or not.
Are there any risks or concerns with combining L-DOPA and cannabinoid-based drugs?
I’m not a clinician, but from my understanding, enhancing L-DOPA too much could lead to some undesired side effects, such as anxiety, excess libido, and even perhaps hallucinations, which are related to increased dopamine signaling.
As such, it would be important to properly titer the dosing for the combined regimen (cannabinoid + L-DOPA) in order to get maximal motor relief with no or limited side effects associated with too much dopamine transmission.
How might these findings change the way doctors treat Parkinson’s in the future?
If ABX 1431 is indeed able to increase L-DOPA response in humans, it would become an additional pharmacotherapy available for physicians to consider for their patients. I essentially think that the treatment of patients would remain the same, but now doctors would have an additional drug therapy that they could use.
What are you most excited or hopeful about going forward?
There is a lot of exciting research in the field of Parkinson’s disease, from new drug treatments (like our study), to neuroprotective treatments, to cell replacement therapies – to just name a few. Science is continuously making strides, and standard of care and therapies are improving each year.
So, what excites me the most for Parkinson’s (but really, for all diseases), is that we are continuously finding better and newer therapies, which have great and meaningful impact on the patients and their quality of life. I’m therefore very optimistic that we will continue to see new improvements and treatments that will be great for patients.
Anything else you would like to add?
I think it is important for me to mention the importance of Parkinson Society BC and Parkinson Canada, and their crucial role for the community, but also for scientists. I have been the recipient of two grants from the Parkinson Canada Research Program, which were the seed funds to get our projects going early on, where traditional routes of funding (for example, CIHR - Canadian Institutes of Health Research) would have not been possible.
For this project, the funds we received from the partnership between Parkinson Society BC and the Parkinson Canada Research Program allowed us to get critical preliminary results, which we then used to get a five-year, $1 million grant from CIHR. This is a great return on investment where a small grant from the Parkinson Canada Research Program ($50-100K) can turn into a much bigger ($1 million or so) grant from CIHR.
Therefore, the funding from the partnership between Parkinson Society BC and the Parkinson Canada Research Program is crucial to help the scientific community, and is made possible with the help of volunteers, fundraisers, and the broader Parkinson’s community. All these efforts are truly helping and contributing to moving the scientific field around Parkinson’s disease forward, which, as I said earlier, will ultimately lead to better treatments and quality of life for Parkinson’s disease patients.
This content was published in the Fall 2025 edition of our quarterly magazine, Viewpoints. The content was accurate as of this publication date.