The FAAH inhibitor URB597 reduced withdrawal-induced anxiety in nicotine-dependent rats but did not prevent physical withdrawal signs, while brain anandamide levels fluctuated across multiple regions during withdrawal.
Read this if you are interested in the connection between the endocannabinoid system and nicotine addiction.
URB597 reduced withdrawal anxiety but not physical symptoms
What the researchers found
Rats made dependent on nicotine via transdermal patches for 7 days showed both physical and emotional withdrawal symptoms when patches were removed.
Physical (somatic) withdrawal signs appeared at 16 hours and emotional (affective) signs at 34 hours after patch removal. The researchers found that spontaneous nicotine withdrawal was accompanied by significant fluctuations in anandamide (an endocannabinoid) levels across the amygdala, hippocampus, hypothalamus, and prefrontal cortex. Levels of 2-AG, the other major endocannabinoid, were not significantly altered.
The FAAH inhibitor URB597, which boosts anandamide levels, reduced withdrawal-related anxiety at both doses tested (0.1 and 0.3 mg/kg) on two different anxiety measures. However, URB597 did not reduce physical withdrawal signs.
Why it matters
The selective effect of endocannabinoid enhancement on emotional but not physical nicotine withdrawal suggested that boosting the endocannabinoid system could specifically target the anxiety component that often drives relapse.
The numbers in context
Nicotine: 5.2 mg/rat/day for 7 days. Somatic signs at 16 hours, affective signs at 34 hours. URB597 at 0.1 and 0.3 mg/kg reduced anxiety. Anandamide fluctuated in amygdala, hippocampus, hypothalamus, and prefrontal cortex.
How the study worked
Controlled animal study in Wistar rats. Nicotine dependence induced via transdermal patches (5.2 mg/rat/day for 7 days). Withdrawal assessed by somatic signs, anxiety tests (elevated plus maze, shock-probe defensive burying), locomotion, and weight. Brain endocannabinoid levels measured by mass spectrometry. URB597 tested at 0.1 and 0.3 mg/kg i.p.
What this study cannot tell us
Animal model using transdermal nicotine delivery that may differ from human smoking. Only one week of dependence induction. Brain endocannabinoid measurements were at specific time points. Translation to human smoking cessation uncertain.
How to read the evidence
Well-controlled animal study with multiple behavioral tests and neurochemical measurements, but limited to rodent models.
When this study was published
Published in 2011. Research on endocannabinoid-based smoking cessation approaches has continued.
The bigger picture
This research connected the endocannabinoid system specifically to the emotional aspects of nicotine withdrawal, suggesting that FAAH inhibitors could complement existing smoking cessation treatments by targeting withdrawal anxiety.
Questions still open
- Could FAAH inhibitors help people quit smoking by reducing withdrawal anxiety? Would combining endocannabinoid enhancement with nicotine replacement be more effective than either alone?
Common questions
Could the endocannabinoid system help people quit smoking?
Does nicotine withdrawal affect the endocannabinoid system?
Read the original research
Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition.
PloS one, 6(11), e28142
Citation
Cippitelli, Andrea; Astarita, Giuseppe; Duranti, Andrea; Caprioli, Giovanni; Ubaldi, Massimo; Stopponi, Serena; Kallupi, Marsida; Sagratini, Gianni; Rodrìguez de Fonseca, Fernando; Piomelli, Daniele; Ciccocioppo, Roberto. (2011). Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition.. PloS one, 6(11), e28142. https://doi.org/10.1371/journal.pone.0028142
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