Pregabalin and Topiramate Reduced Anxiety and Motor Symptoms During Cannabis Withdrawal in Mice | Research

The takeaway

Both pregabalin and topiramate reduced anxiety-like behavior and motor symptoms during spontaneous cannabinoid withdrawal in mice, while also reversing withdrawal-related gene expression changes in the brain.

Read this if you experience withdrawal symptoms when stopping cannabis and want to know about potential medication options.

Both drugs blocked motor symptoms and reduced anxiety during withdrawal

What the researchers found

Mice made tolerant to the synthetic cannabinoid CP-55,940 showed increased motor activity, rearing, and anxiety-like behavior on days 1 and 3 after cessation. Both pregabalin (40 mg/kg twice daily) and topiramate (50 mg/kg twice daily) blocked the motor signs and significantly reduced anxiety.

At the molecular level, cannabinoid withdrawal decreased tyrosine hydroxylase expression in the reward center and mu-opioid receptor expression in the nucleus accumbens, while increasing CB1 receptor expression. Both drugs reversed the tyrosine hydroxylase and CB1 changes but did not affect the opioid receptor changes.

Why it matters

Cannabis withdrawal, while not life-threatening, includes anxiety, irritability, and sleep disturbance that often drive relapse. Identifying existing medications that can manage these symptoms could improve quit success rates. Both pregabalin and topiramate are already approved for other conditions.

The numbers in context

CP-55,940: 0.5 mg/kg twice daily for 7 days. Pregabalin: 40 mg/kg twice daily. Topiramate: 50 mg/kg twice daily. Both blocked motor signs and reduced anxiety on days 1 and 3. Both reversed TH decrease and CB1 increase in brain. Neither affected mu-opioid receptor changes.

How the study worked

Mice received CP-55,940 (0.5 mg/kg twice daily for 7 days) to induce tolerance. Spontaneous withdrawal was assessed on days 1 and 3 by measuring motor activity, somatic signs, and anxiety-like behavior. Pregabalin or topiramate was administered during days 1-3. Gene expression was measured by qRT-PCR in VTA and nucleus accumbens.

What this study cannot tell us

Animal study using a synthetic cannabinoid (CP-55,940) rather than THC, which may produce different withdrawal profiles. Mouse doses do not directly translate to human doses. Spontaneous withdrawal from 7 days of treatment may not model the withdrawal experienced by chronic human users. The anxiety measures are behavioral proxies, not direct measures of subjective experience.

How to read the evidence

Animal study with behavioral and molecular outcomes; preliminary evidence for repurposing existing medications.

When this study was published

Published in 2013. Clinical trials of these and related medications for cannabis withdrawal have continued.

The bigger picture

Finding that existing, approved medications can manage cannabinoid withdrawal symptoms accelerates the path to clinical application. The gene expression findings provide mechanistic insight into how these drugs work, potentially guiding development of even more targeted treatments.

Questions still open

Would pregabalin or topiramate help human cannabis users manage withdrawal? Are the effective doses safe and tolerable in humans? Would these medications improve quit rates in clinical trials?

Common questions

What is pregabalin and topiramate?

Pregabalin (Lyrica) is approved for nerve pain, fibromyalgia, and epilepsy. Topiramate (Topamax) is approved for epilepsy and migraine prevention. This study found both could reduce anxiety and motor symptoms during cannabis withdrawal in mice, suggesting potential repurposing for cannabis cessation support.

Does cannabis withdrawal cause anxiety?

Yes, in this mouse model, stopping cannabinoid administration produced significant anxiety-like behavior that persisted through day 3 of withdrawal. In humans, anxiety is one of the most commonly reported cannabis withdrawal symptoms and a frequent reason for relapse.

Read the original research

Pregabalin and topiramate regulate behavioural and brain gene transcription changes induced by spontaneous cannabinoid withdrawal in mice.

Addiction biology, 18(2), 252-62

View on PubMed ↗Publisher’s paper ↗

Citation

Aracil-Fernández, Auxiliadora; Almela, Pilar; Manzanares, Jorge. (2013). Pregabalin and topiramate regulate behavioural and brain gene transcription changes induced by spontaneous cannabinoid withdrawal in mice.. Addiction biology, 18(2), 252-62. https://doi.org/10.1111/j.1369-1600.2011.00406.x