Lithium did not improve overall cannabis withdrawal symptoms compared to placebo | Research

The takeaway

Despite a strong preclinical rationale, lithium did not significantly reduce overall cannabis withdrawal severity compared to placebo in an inpatient trial, though it helped with appetite loss, stomach aches, and nightmares.

Read this if you are interested in medication approaches to managing cannabis withdrawal.

Lithium failed to reduce overall withdrawal but helped with appetite, GI symptoms, and dreams

What the researchers found

In a double-blind RCT, 38 cannabis-dependent adults were randomized to lithium (500 mg twice daily) or placebo for 8 days of inpatient withdrawal. Lithium did not significantly affect total withdrawal severity scores compared to placebo.

However, lithium did significantly reduce three individual symptoms: loss of appetite, stomach aches, and nightmares/strange dreams. No significant differences were found in treatment retention or adverse events between groups.

Contrary to the preclinical hypothesis, lithium did not increase plasma oxytocin levels, the proposed mechanism by which it might reduce withdrawal. Both groups showed reduced cannabis use and improved outcomes at 30 and 90-day follow-up.

Why it matters

Negative trials are informative. Despite a compelling rationale from animal studies showing lithium reduces cannabinoid withdrawal through oxytocin release, the human trial did not confirm the overall benefit. This illustrates the gap between preclinical promise and clinical reality.

The numbers in context

38 participants. Lithium 500 mg twice daily vs. placebo for 8 days. No significant difference in total withdrawal scores. Significant improvement in appetite loss, stomach aches, and nightmares. No increase in plasma oxytocin. Both groups improved at 30 and 90-day follow-up.

How the study worked

Double-blind, placebo-controlled randomized trial. 38 treatment-seeking cannabis-dependent adults were randomized to lithium 500 mg or placebo twice daily during an 8-day inpatient admission. Withdrawal severity, cannabinoid levels, and oxytocin levels were measured. Follow-up at 14, 30, and 90 days post-discharge.

What this study cannot tell us

Small sample of 38 participants. The 8-day treatment period was relatively short. Only one dose level was tested. The proposed oxytocin mechanism was not supported. The inpatient setting may differ from outpatient reality.

How to read the evidence

Double-blind placebo-controlled RCT, though underpowered with only 38 participants.

When this study was published

Published in 2014.

The bigger picture

The search for medications to treat cannabis withdrawal continues. While lithium did not prove effective overall, the finding that it helped with specific symptoms (appetite, GI complaints, dreams) suggests withdrawal is not a monolithic syndrome but a collection of distinct symptom domains that may require targeted approaches.

Questions still open

Would higher doses of lithium be more effective? Would targeting individual withdrawal symptoms with specific medications be more successful than seeking a single withdrawal treatment? Why did lithium not increase oxytocin levels as predicted by animal data?

Common questions

Can lithium help with cannabis withdrawal?

This trial found that lithium did not significantly reduce overall withdrawal severity compared to placebo. However, it did help with specific symptoms: appetite loss, stomach aches, and nightmares.

Is there any medication approved for cannabis withdrawal?

No medication was approved for cannabis withdrawal at the time of this study, and none has been approved since. The search for effective pharmacological treatments continues.

Read the original research

Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting.

Psychopharmacology, 231(24), 4623-36

View on PubMed ↗Publisher’s paper ↗

Citation

Johnston, Jennifer; Lintzeris, Nicholas; Allsop, David J; Suraev, Anastasia; Booth, Jessica; Carson, Dean S; Helliwell, David; Winstock, Adam; McGregor, Iain S. (2014). Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting.. Psychopharmacology, 231(24), 4623-36. https://doi.org/10.1007/s00213-014-3611-5