Cannabinoid Mixtures Ease Parkinson’s Motor Symptoms in Zebrafish
Researchers ID five compounds that may be potential therapeutic candidates
Gb Sciences has identified a handful of mixtures that contain just enough  cannabinoids — the active compounds of the cannabis plant — to prevent death in lab-grown nerve cells and help lessen motor symptoms in a zebrafish model of Parkinson’s disease.Â
Out of more than 60 mixtures containing varying ratios of three cannabinoids, the researchers pinned down five that may be potential therapeutic candidates for further development.
“Our drug discovery process has identified promising ratio-controlled mixtures of cannabis-inspired compounds for the treatment of Parkinson’s disease, which have proven effective at reducing Parkinsonian motor symptoms in an animal model of the disease,” Andrea Small-Howard, PhD, said in a press release. Small-Howard is president, chief science officer, and director of Gb Sciences.
These mixtures “will be further tested in more advanced animal models to develop new therapeutic options for Parkinson’s patients,” the researchers wrote.
The study, “Identification of minimum essential therapeutic mixtures from cannabis plant extracts by screening in cell and animal models of Parkinson’s disease,” was published in Frontiers in Pharmacology.
In recent years, there has been growing interest in the use of cannabis to treat a range of diseases, including Parkinson’s. But extracts of the cannabis plant contain hundreds of compounds. There are many forms of preparation and some of the products available have unknown composition. This raises concerns about the use of cannabis for medical purposes.
“There is a need to move beyond whole plant extracts and generate safe, reproducible medicines for patients,” the researchers wrote.
With this need in mind, Gb Sciences started building a pipeline of patented mixtures containing well-defined ratios of certain cannabinoids. These mixtures are less complex than the whole plant extracts, making them easier to prepare under quality control standards, yet they retain at least some of the benefits of the whole plant extracts.
Which mixtures were best?
Now, researchers set out to determine which of these mixtures may work best at preventing the death of dopamine-producing nerve cells, whose loss is a hallmark feature of Parkinson’s. They grew nerve cells in the lab and triggered their death by using MPP+, a compound that can mimic the symptoms observed in Parkinson’s disease.
Three mixtures were tested. One contained three minor (usually less-abundant) cannabinoids and one contained terpenes, another type of compound present in cannabis. A third mixture contained a combination of the cannabinoids and the terpenes.
Treating nerve cells with cannabinoids increased their survival by 25%. The terpenes had a more limited effect (4%). But in the mixture combining both the cannabinoids and the terpenes, nerve cell survival was increased to 37%.
When the researchers also added cannabidiol (CBD), a major cannabinoid that is present in large amounts in cannabis, to each mixture, nerve cell survival was increased further up to 62%. A similar observation, albeit less-pronounced, was made when cannabinol (CBN), another major cannabinoid, was added to the mixture.
The dopamine connection
The mixtures also were tested for their ability to help with the production of dopamine. The combination of the cannabinoids and the terpenes led to the largest increase in dopamine (31%), but adding CBD increased its production by an additional 18%. Adding CBN to this mix did not significantly increase dopamine release.
“Taken together, these results demonstrate that the effects of the mixtures cannot be attributed to a single ingredient. On the contrary, it suggests that interactions between the components in the mixtures are critical for the maximal efficacy of the mixture,” the researchers wrote.
Next, the team used a model of Parkinson’s in which larvae of zebrafish are exposed to 6-hydroxydopamine, a compound that is toxic to nerve cells. These zebrafish develop resting tremor, a common motor symptom of Parkinson’s. They also remain inactive most of the time.
An additional series of new mixtures were prepared, each containing combinations of three cannabinoids in equal amounts. Three of these mixtures were found to significantly increase the activity of the zebrafish, which was measured by the total distance traveled over 1.5 hours.
In a next step, the researchers tweaked the ratios of the three cannabinoids in each of the mixtures to find out which worked best. Of 63 variations of the mixtures, five were found to outperform the original equal-amount mixtures. These mixtures “represent the most attractive candidates for therapeutic development,” the researchers concluded.
“This study allows us to continue addressing unmet clinical needs through the development of novel plant-inspired drugs, and positions Gb Sciences as a contributor to the expanding world of novel [Parkinson’s disease] therapeutics,” Small-Horward said.
The company has a dose-ranging study in a rodent model of Parkinson’s underway at the University of Lethbridge in Alberta, Canada, that may be the jump-start for a first-in-human study.
Also underway are pharmacology and toxicology tests to find out whether the cannabinoid-containing mixtures are reasonably safe for a study in humans. With the results of these tests in hand, the company is planning to file an investigational new drug application with the U.S. Food and Drug Administration.
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