All tested cannabinoids (THC, anandamide, WIN55,212-2, AM251, and CBD) inhibited mitochondrial energy production complexes II/III and IV in brain tissue, through a mechanism independent of cannabinoid receptors.
Read this if you are interested in how cannabinoids affect brain cells at the molecular level beyond receptor activation.
All cannabinoids inhibited mitochondrial complexes II/III and IV via non-receptor mechanism
What the researchers found
Researchers tested how five different cannabinoids affect the energy-producing machinery (electron transport chain) inside brain cell mitochondria.
All five compounds, whether receptor agonists (THC, anandamide, WIN55,212-2), an antagonist (AM251), or CBD, inhibited complexes II/III and IV of the mitochondrial respiratory chain at micromolar concentrations. This common effect occurred regardless of whether the compound activated or blocked cannabinoid receptors, indicating a non-receptor mechanism.
Anandamide uniquely stimulated complex I activity, which may explain some of the distinct physiological effects of this endocannabinoid compared to plant-derived or synthetic cannabinoids. THC and AM251 also decreased citrate synthase activity.
Why it matters
Mitochondria produce the energy cells need to function. The finding that cannabinoids directly impair mitochondrial energy production, independent of receptor activation, reveals a fundamental cellular mechanism that could explain some cognitive and neural effects of cannabis.
The numbers in context
Five cannabinoids tested: THC, anandamide, WIN55,212-2, AM251, CBD; all inhibited complexes II/III and IV; anandamide stimulated complex I; THC and AM251 decreased citrate synthase
How the study worked
In vitro study measuring individual mitochondrial respiratory chain complex (I, II/III, IV) and citrate synthase activities in crude mitochondrial fractions from pig brain after exposure to five cannabinoids.
What this study cannot tell us
In vitro study using isolated mitochondria. Concentrations used (micromolar) may not reflect brain concentrations during typical cannabis use. Pig brain tissue may not perfectly represent human mitochondria. Acute exposure only.
How to read the evidence
In vitro biochemistry study on isolated mitochondria. Reveals a mechanism but clinical significance depends on whether these concentrations are reached in living brain tissue.
When this study was published
Published in 2015. Cannabinoid effects on mitochondria remain an active research area.
The bigger picture
If cannabinoids impair brain cell energy production through a non-receptor mechanism, this effect would be difficult to avoid with receptor-selective drugs and represents a fundamental limitation of cannabinoid-based therapeutics at higher doses.
Questions still open
- Do these mitochondrial effects occur at concentrations achieved during normal cannabis use? Could chronic mitochondrial impairment contribute to cognitive effects of long-term cannabis use? Would lower, therapeutic doses also affect mitochondria?
Common questions
Do cannabinoids affect brain cell energy?
Does this mean CBD is harmful to brain cells?
Read the original research
Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria.
Journal of molecular neuroscience : MN, 56(4), 926-931
Citation
Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk. (2015). Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria.. Journal of molecular neuroscience : MN, 56(4), 926-931. https://doi.org/10.1007/s12031-015-0545-2
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