THC versus AD

Tetrahydrocannabinol may be neuroprotective against early symptoms of Alzheimer’s disease

Researchers at the Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies have discovered evidence that tetrahydrocannabinol (THC) may be capable of treating early stage Alzheimer’s disease (AD).

David Schubert and team have been researching Alzheimer’s for several years, focusing in particular on two drug candidates – J147 and CNB-001. They already knew that these potent anti-inflammatory molecules have the ability to remove the amyloid that accumulates within cultured human neurons and is thought to be involved in the development of Alzheimer’s. However, they didn’t know the molecular target and the signaling pathways that they activate.

While attempting to answer these questions, they first discovered that the accumulation of intracellular aggregated proteins like amyloid within human neurons caused a very potent inflammatory response, leading to cell death – but that their new AD drug candidate CNB-001 blocked both amyloid accumulation and cell death. Interestingly, the cannabis component, THC, was able to function in a similar way. “We knew that one of our drug candidates weakly bound to the CB1 cannabinoid receptor, but did not expect THC to mimic the clearance of intracellular amyloid as well as it did,” says Schubert. “We know that intraneuronal amyloid appears a long time before extracellular plaques in AD patients [...] so this suggests that they may be useful in treating early stage AD.”

Most of the work involved pharmacological studies with receptor agonists and antagonists to identify the molecular pathways. Oswald Quehenberger, collaborator at UCSD and second author, used high tech LC/MS-MS methods to identify pro and anti-inflammatory eicosanoids. Nanostring technology was used to identify changes in gene expression and Myriad RMB to measure cytokines.

Surprising as the results were, the team were more shocked by the positive reaction to the manuscript. “Unfortunately, because of the great restrictions on the efficient use of marijuana in the medical research field – because of its absurd classification as a Schedule I drug –  there have been no significant clinical trials for marijuana or its component chemicals for AD. I think this is why we’ve had such enormous interest.”

Schubert says there is a need to take the research further. “A simple experiment would be to identify the chemicals that are different between good and bad strains, synthesize or purchase them, run them through our cell culture assays for neurodegeneration and AD, and test the best in animal models of AD,” Schubert says. But, he says, even conducting such straightforward scientific research is difficult in the current climate. “Work like this is tough to do because of the regulatory requirements surrounding marijuana and the difficulty in obtaining the necessary funding. It is very curious that I can easily and legally buy medical marijuana, but cannot have a single leaf legally in the lab without an enormous amount of time and paperwork!”

Reference

  1. A Currais et al, “Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids,” NPJ Aging Mech Dis, 2, 2056-3973 (2016).