Published May 18 in Cell Reports Medicine, the study results need to be confirmed in clinical trials to see if beta-sitosterol could help relieve anxiety in humans.

Developing antianxiety drugs is challenging, because the brain circuits for anxiety are closely related to those responsible for memory, awareness and other functions vital for handling danger. Scientists try to find compounds that selectively suppress anxiety without causing unwanted side effects.

Several years ago, Prof. Mike Fainzilber’s biomolecular sciences lab at Weizmann discovered that in stressful situations, mice lacking the protein importin alpha-five showed less anxiety than the control mice. The calmer mice were found to have about 120 genes with a characteristic pattern of expression in the hippocampus, one of the brain regions that regulate anxiety.

In the new study, Fainzilber lab senior intern Nicolas Panayotis led a search of an international genomic database for existing drugs or other compounds that might mimic the same gene expression signature.

He identified five candidates and tested their effects on behavior in mice. That was how the researchers zeroed in on beta-sitosterol, a plant substance now sold as a dietary supplement intended mainly to reduce cholesterol levels.

No side effects

In a series of behavioral experiments, mice given beta-sitosterol showed much less anxiety than the control group.

They were, for example, less fearful than the controls when placed in an illuminated enclosure, daring to walk into its brightly lit center, whereas the control mice stayed on the darker periphery, avoiding the stress of the bright light.

Moreover, the mice receiving beta-sitosterol did not exhibit any of the side effects that might be expected from antianxiety medications – their locomotion was not impaired, and they did not refrain from exploring novel stimuli.

Then the researchers gave the mice beta-sitosterol in combination with fluoxetine, a selective serotonin reuptake inhibitor (SSRI) sold under the brand name Prozac.

The combination had a synergistic effect: Both beta-sitosterol and fluoxetine reduced anxiety at lower doses when given together, compared with the doses needed to produce the same effect when they were administered separately.

“One of the major problems with existing antianxiety medications is that they produce side effects, so if beta-sitosterol could help cut down the dosage of such medications, it might potentially also reduce the unwanted side effects,” Panayotis said.

Plant-derived

A great advantage of beta-sitosterol is that it is naturally present in a variety of edible plants, and it is thought to be safe, as it has been marketed for years as a nutraceutical.

The substance is found in particularly large concentrations in avocados, but also in pistachios, almonds and other nuts, as well as in canola oil and in various grains and cereals.

However, this does not mean that simply eating avocado can induce a calming effect. “You’d need to eat avocado day and night to get the right dose – and you would be more likely to develop digestive problems than relieve your anxiety,” Panayotis said.

The precise mechanism of beta-sitosterol’s effect on anxiety remains to be revealed, but the scientists did find that the expression of several genes known to be activated in stressful situations was reduced in mice given the supplement.

They also found that these mice had changes in the levels of certain metabolites and neurotransmitters in brain areas involved in anxiety.

Since the study focused on brain regions and neural pathways that are involved in regulating anxiety in both mice and humans, the researchers are optimistic that the findings will apply to humans as well.

“There’s a need for a clinical trial to test the use of beta-sitosterol for reducing anxiety in humans. Until then, we recommend that people consult their physicians before taking the supplement for this purpose,” Fainzilber said.

Researchers included Philip Freund and Letizia Marvaldi of the Biomolecular Sciences Department; Tali Shalit of the Nancy and Stephen Grand Israel National Center for Personalized Medicine; Alexander Brandis and Tevie Mehlman of the Life Sciences Core Facilities Department; and Michael Tsoory of the Veterinary Resources Department.