Doses of the CB1 receptor blocker rimonabant 30 to 300 times lower than those causing psychiatric side effects in humans normalized brain signaling and cognitive deficits in a mouse model of Fragile X syndrome.
Read this if you follow research on cannabinoid-based treatments for neurological conditions or Fragile X syndrome.
Effective dose was 30-300x lower than the dose that caused psychiatric side effects
What the researchers found
Fragile X syndrome is the most common genetic cause of intellectual disability. Previous research from this group showed that blocking CB1 cannabinoid receptors with rimonabant corrected multiple features of the disease in mice. However, rimonabant was pulled from the market as an obesity drug due to psychiatric side effects at the doses used for weight loss.
This study asked whether much lower doses could still work. The answer was yes. Doses of rimonabant as low as 0.01 mg/kg normalized the memory deficit in Fragile X mice, and 0.1 mg/kg corrected abnormal brain signaling (mGluR-dependent long-term depression). These doses are 30 to 300 times lower than those needed for weight loss and presumably for causing side effects.
Additionally, a "neutral" CB1 antagonist called NESS0327, which blocks the receptor without the inverse agonist activity linked to side effects, also prevented memory deficits in Fragile X mice.
Why it matters
Fragile X syndrome has no approved pharmacological treatment. This study suggests that the endocannabinoid system is a viable therapeutic target and that the dose needed for treating cognitive deficits is far below the dose that caused problems in the obesity trials. This could potentially rehabilitate CB1 receptor targeting as a treatment strategy.
The numbers in context
Rimonabant 0.01 mg/kg normalized cognition (30-300x below weight-loss doses). Rimonabant 0.1 mg/kg normalized mGluR-LTD brain signaling. Weight-loss doses in rodents: 3-10 mg/kg. NESS0327 (neutral antagonist) also effective for cognitive rescue.
How the study worked
Electrophysiological recordings measured mGluR-dependent long-term depression in brain slices from Fragile X knockout mice treated with low-dose rimonabant. Behavioral testing used the novel object recognition task to assess cognitive function. NESS0327 was tested as an alternative neutral antagonist.
What this study cannot tell us
Mouse models of Fragile X syndrome do not fully replicate the human condition. The effective doses were for acute administration; long-term safety at low doses has not been established. Human pharmacokinetics may differ from mice. The neutral antagonist NESS0327 has limited preclinical data.
How to read the evidence
Well-designed preclinical study with multiple outcome measures and a mechanistic alternative (neutral antagonist), but entirely in mice with uncertain clinical translation.
When this study was published
Published in 2016. Clinical translation of CB1-targeting approaches for Fragile X and other neurodevelopmental conditions remains an active area of research.
The bigger picture
The failure of rimonabant as an obesity drug due to psychiatric side effects was a major setback for cannabinoid receptor pharmacology. This study shows that not all therapeutic applications require the high doses that caused problems, potentially reopening a pathway for CB1-targeted medicines in neurological conditions.
Questions still open
- Could very low-dose rimonabant or neutral CB1 antagonists be safely used in Fragile X patients? Would chronic low-dose treatment maintain efficacy without causing psychiatric side effects? Are there other genetic conditions where CB1 targeting might help?
Common questions
What is Fragile X syndrome?
Why was rimonabant pulled from the market if it works here?
Read the original research
Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.
Genes, 7(9)
Citation
Gomis-González, Maria; Busquets-Garcia, Arnau; Matute, Carlos; Maldonado, Rafael; Mato, Susana; Ozaita, Andrés. (2016). Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.. Genes, 7(9). https://doi.org/10.3390/genes7090056
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