Many years ago we showed that there was genetic control of entry of cannabinoids into the brains of mice. We linked the trait back to Swiss mice that arrived into the USA in 1926. There were two males and 5 female white mice that arrived at the Rockerfellow Institute in New York. They gave rise to loads of lab mice. We reckoned that probably one of the males had the gene or lack of gene that determined whether mice get “bombed” if they got a cannabinoid. They should have called them French mice as whilst they were sent from Switzerland they originated from the Curie Institute in Paris. This gene product would keep a CNS excluded cannabinoid from the CNS. The effect was dominant and segregated as a single gene effect, but we could not be 100% sure what it was and so we sat on the information, whilst we went hunting for it or should I say them.
P glycoprotein of ATP (energy)-dependent binding cassette family B one (ABCB1) is a major drug pump that excludes fat soluble molecules from entering the brain and cancer cells. It is found on chromosome 5 and in mice there are two genes (Mdr1a and Mdr1b). In humans, there is one gene (MDR1)
The drug defuses into the brain and is picked up by ABCB1 and it uses energy (ATP) to kick the drug out. This was found in MDR1 mice who get neurological problems and die when they are given ivermectin which is used for killing parasite. It also gives Collie dogs neurological problems. Ivermectin is a nerve toxin and so I was surprised that it was been given during COVID-19 (it didn’t work). I also heard a story of a pot grower who developed neurological problems when the were working in the pot growing facilities. A pest of Pot is a mite so they sometimes spray the plant with ivermectin. I was guessing that this individual lacked the gene that kept marijuana out of the CNS.
For marijuana to cause intoxication. The cannabis has to enter the brain and we reckoned that this worker did not have ABCB1 that was limiting the ivermectin from entering the brain. The gene is lacking in the MDR1 mice is p-glycoprotein. We did not think the main effect was P-glycoprotein and thought we would get a Nature paper if we found the gene that allowed you to get stoned with cannabis. The bosses would have been pleased to say the least. But as I say we were not 100 percent confident about it by eventually we had to publish the paper and implicated one element as ABCC1 which is known as MRP-1 (Multidrug resistance protein one)
Pryce G, Visintin C, Ramagopalan SV, Al-Izki S, De Faveri LE, Nuamah RA, Mein CA, Montpetit A, Hardcastle AJ, Kooij G, de Vries HE, Amor S, Thomas SA, Ledent C, Marsicano G, Lutz B, Thompson AJ, Selwood DL, Giovannoni G, Baker D. Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists. FASEB J. 2014 Jan;28(1):117-30.
The purpose of this study was the generation of central nervous system (CNS)-excluded cannabinoid receptor agonists to test the hypothesis that inhibition of spasticity, due to CNS autoimmunity, could be controlled by affecting neurotransmission within the periphery. Procedures included identification of chemicals and modelling to predict the mode of exclusion; induction and control of spasticity in the ABH mouse model of multiple sclerosis; conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide association study in N2(129×ABH) backcross to map polymorphic cannabinoid drug pump; and sequencing and detection of cannabinoid drug-pump activity in human brain endothelial cell lines. Three drugs (CT3, SAB378 and SAD448) were identified that control spasticity via action on the peripheral nerve CB1 receptor. These were peripherally restricted via drug pumps that limit the CNS side effects (hypothermia) of cannabinoids to increase the therapeutic window. A cannabinoid drug pump is polymorphic and functionally lacking in many laboratory (C57BL/6, 129, CD-1) mice used for transgenesis, pharmacology, and toxicology studies. This phenotype was mapped and controlled by 1-3 genetic loci. ABCC1 within a cluster showing linkage is a cannabinoid CNS-drug pump. Global and conditional CB1 receptor-knockout mice were used as controls. In summary, CNS-excluded CB1 receptor agonists are a novel class of therapeutic agent for spasticity.
So it is interesting that this was reported here in controlling response to nabiximols/sativex
Gemma A, Mauri M, Banfi P, Versino M, Zollo A, Boneschi FM, Marino F, Cosentino M, Ferrari M. ABCB1 polymorphisms are associated with clinical response to nabiximols in patients with multiple sclerosis-related spasticity. J Cannabis Res. 2025.;7(1):72. doi: 10.1186/s42238-025-00333-4.
COI our work
Source: multiple-sclerosis-research.org