Female Mice Developed Greater THC Tolerance Than Males, Especially With HIV | Research

The takeaway

After 90 days of chronic THC, female mice showed greater tolerance to a high THC dose than males, with HIV status adding another layer of complexity to the response.

Cannabis researchers, HIV clinicians, neuroscientists studying sex differences, and people interested in THC tolerance.

Females showed greater THC tolerance after 90 days

What the researchers found

Chronic THC history (90 days) led to tolerance across behavioral measures, reducing THC-induced hypothermia, pain relief, and sedation, especially in females. An acute THC challenge increased anxiety-like behavior specifically in females with chronic THC history. HIV-transgenic mice showed genotype-dependent effects, with high microglial-CCL3 co-occurrence in sex-specific brain regions.

Why it matters

This study reveals important sex differences in THC tolerance development that have clinical implications for both recreational and medical cannabis users. The interaction with HIV status is particularly relevant given that cannabis is commonly used among people living with HIV.

The numbers in context

63 mice total. Chronic THC: 3 mg/kg daily for 90 days. Acute challenge: 10 mg/kg after 7-day washout. Females showed greater tolerance across multiple behavioral measures. HIV genotype affected microglial inflammation in sex-specific brain regions.

How the study worked

HIV-1 Tg26 transgenic and control mice received 3 mg/kg THC or vehicle for 90 days (5 days/week). After a 7-day washout, all received a 10 mg/kg acute THC challenge. Behavioral, neuroinflammatory, and THC metabolite measures were assessed.

What this study cannot tell us

Mouse model, and the Tg26 HIV model does not perfectly replicate human HIV infection. The 90-day chronic exposure may not mirror typical human use patterns. Small sample sizes per group.

How to read the evidence

Well-controlled animal study with HIV model, but small group sizes and typical limitations of mouse-to-human translation.

When this study was published

2026 study.

The bigger picture

Sex differences in cannabis tolerance have been suggested by human studies but are difficult to study rigorously. This controlled animal model confirms that females develop tolerance differently and may experience different consequences of chronic use, especially when combined with HIV.

Questions still open

Should cannabis dosing recommendations differ by sex? Does the anxiety increase in tolerant females translate to human experience?

Common questions

Do women build THC tolerance differently than men?

This mouse study suggests yes. Female mice showed greater tolerance to THC effects after chronic exposure and developed increased anxiety, while males did not show the same pattern.

How does HIV affect the response to THC?

HIV-transgenic mice showed different patterns of brain inflammation after chronic THC, with sex-specific differences in which brain regions were affected.

Read the original research

Effects of acute THC challenge on behavior and neuroinflammation in HIV-1 Tg26 mice vary based on HIV status, chronic THC history, and sex.

Brain, behavior, and immunity, 134, 106476

View on PubMed ↗Publisher’s paper ↗

Citation

Ravula, Havilah P; Yadav-Samudrala, Barkha J; Sawaqed, Laith E; Arciniega, Cristina; Hu, Wenhui; Jiang, Wei; Fitting, Sylvia. (2026). Effects of acute THC challenge on behavior and neuroinflammation in HIV-1 Tg26 mice vary based on HIV status, chronic THC history, and sex.. Brain, behavior, and immunity, 134, 106476. https://doi.org/10.1016/j.bbi.2026.106476