Methamphetamine Brain Damage Increased Endocannabinoid Levels and Alcohol Drinking in Mice | Research

The takeaway

Meth-induced brain damage raised 2-AG endocannabinoid levels in the limbic forebrain and increased alcohol consumption in mice, effects that were blocked by a CB1 receptor antagonist.

Read this if you are interested in why stimulant users often develop problems with alcohol.

Meth damage increased endocannabinoid 2-AG levels and alcohol drinking; CB1 blocker prevented this

What the researchers found

Mice exposed to a neurotoxic methamphetamine regimen showed increased alcohol consumption and preference seven days later.

Biochemical analysis of the limbic forebrain revealed that while CB1 receptor density and activity were unchanged, 2-AG (endocannabinoid) levels were significantly elevated. This increase was associated with reduced MAGL (the enzyme that breaks down 2-AG) activity.

As expected, dopamine levels and dopamine transporter density were decreased (reflecting meth neurotoxicity).

The CB1 receptor antagonist AM251 prevented the meth-induced increase in alcohol consumption. Conversely, a MAGL inhibitor (which raises 2-AG) increased alcohol consumption in both meth-treated and control mice.

This suggested that increased endocannabinoid tone following meth neurotoxicity drives increased alcohol seeking.

Why it matters

This study identified an endocannabinoid mechanism linking methamphetamine neurotoxicity to increased alcohol consumption, suggesting that meth use could change brain chemistry in ways that promote polysubstance use.

The numbers in context

Meth: 4 mg/kg x 4 doses. 7 days later: increased 2-AG, decreased MAGL activity, decreased dopamine, decreased dopamine transporters. CB1 receptor density/activity unchanged. AM251 blocked increased drinking. MAGL inhibitor increased drinking.

How the study worked

Mice received neurotoxic methamphetamine (4 mg/kg x 4, 2 hours apart) and were tested for alcohol consumption 7 days later with increasing ethanol concentrations (3-20%). Limbic forebrain was analyzed for CB1 density/activity, 2-AG levels, MAGL activity, dopamine levels, and dopamine transporter density. CB1 antagonist and MAGL inhibitor were tested for effects on drinking.

What this study cannot tell us

Animal model using a specific neurotoxic meth protocol. Human meth use patterns differ. The 7-day timepoint may not reflect longer-term changes. Alcohol preference in mice may not directly model human alcohol-seeking behavior.

How to read the evidence

Preclinical study with pharmacological confirmation of the mechanism. Limited to animal models and a specific meth protocol.

When this study was published

Published in 2010. The role of the endocannabinoid system in polysubstance use has continued to be investigated.

The bigger picture

Polysubstance use is common but poorly understood mechanistically. This study provided a concrete biological pathway through which damage from one drug (meth) could increase use of another (alcohol) via the endocannabinoid system.

Questions still open

Could endocannabinoid system modulation reduce alcohol craving in meth users? Does this mechanism apply to cannabis co-use as well? Would FAAH inhibition have different effects than MAGL inhibition on alcohol drinking?

Common questions

Why would meth damage increase alcohol drinking?

Meth damages dopamine neurons, creating a low-dopamine state. The brain may compensate by increasing endocannabinoid (2-AG) signaling, which promotes reward-seeking behavior including alcohol consumption.

Could this mechanism apply to humans?

The link between meth use and increased alcohol problems has been observed in humans, and the endocannabinoid mechanism identified here is plausible. However, human polysubstance use involves many additional psychological and social factors beyond this specific biological pathway.

Read the original research

Involvement of 2-arachidonoyl glycerol in the increased consumption of and preference for ethanol of mice treated with neurotoxic doses of methamphetamine.

British journal of pharmacology, 160(3), 772-83

View on PubMed ↗Publisher’s paper ↗

Citation

Gutierrez-Lopez, M D; Llopis, N; Feng, S; Barrett, D A; O'Shea, E; Colado, M I. (2010). Involvement of 2-arachidonoyl glycerol in the increased consumption of and preference for ethanol of mice treated with neurotoxic doses of methamphetamine.. British journal of pharmacology, 160(3), 772-83. https://doi.org/10.1111/j.1476-5381.2010.00720.x