File: Ashwagandha (Withania somnifera)

Bipolar Disorder
Cognitive Dysfunction

HC 021452-498

Date: June 13, 2014

RE: Ashwagandha Improves Verbal Working Memory in People with Bipolar Disorder

Chengappa KNR, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R. Randomized placebo-
controlled adjunctive study of an extract of Withania somnifera for cognitive dysfunction in
bipolar disorder. J Clin Psychiatry. 2013;74(11):1076-1083.

People with bipolar disorder (BD) often have cognitive impairments that persist during
periods of euthymic mood (i.e., not manic or depressed). Ashwagandha (Withania somnifera)
is used in Ayurvedic medicine as an adaptogen to increase the body's ability to adapt to
stress and resist disease. Withania somnifera extract (WSE) contains several classes of
neurologically bioactive constituents which have been shown to reverse memory deficits and
improve cognition in animal models. The purpose of this randomized, placebo-controlled,
double-blind study (trial NCT00761761 registered at clinicaltrials.gov) was to evaluate the
effect of adjunct WSE treatment on cognitive function in patients with bipolar disorder who
were currently stable.

Outpatients (n = 60, aged 18-65 years) with a diagnosis of bipolar I, II, or not otherwise
specified (NOS) disorder participated in this study conducted at Western Psychiatric Institute
and Clinic-University of Pittsburgh Medical Center; Pittsburgh, Pennsylvania. Included
patients had to have a Young Mania Rating Scale (YMRS) and Montgomery-Asberg
Depression Rating Scale (MADRS) score of < 10 for at least 4 weeks, and their main mood-
stabilizing medication use at a stable dose for at least 4 weeks. Patients were excluded if
they had other neurologic disorders; unstable medical conditions or mental status; allergy or
adverse reactions to ashwagandha; were taking cholinesterase inhibitors, St. John's wort
(Hypericum perforatum), or omega-3 fish oil; pregnant or breast feeding.

The study used an approved investigational new drug (IND), the standardized WSE
Sensoril

(Natreon Inc.; New Brunswick, New Jersey). Produced using a standardized

aqueous extraction process, the WSE was concentrated to contain a minimum of 8%
withanolides, 32% oligosaccharides, and 2% Withaferin A, and filled in 250 mg hard gel
capsules. The placebo capsules containing inert excipients were placed in a container with
cloth sachets containing WSE for several days to imbue them with the same scent as the
active capsules.

Patients received either placebo or WSE for 8 weeks; for the first week they received 250
mg/day, and then 500 mg/day for the remainder of the study. The patients' regular mood-
P.O. Box 144345 Austin, TX 78714-4345 512.926.4900 Fax: 512.926.2345 www.herbalgram.org
HerbClip

Laura Bystrom, PhD Mariann Garner-Wizard Shari Henson
Amy Keller, PhD Cheryl McCutchan, PhD Heather S Oliff, PhD

ExecutiveEditor Mark Blumenthal Managing Editor Lori Glenn
Consulting Editors Dennis Awang, PhD, Thomas Brendler, Francis Brinker, ND, Allison McCutcheon, PhD, Risa Schulman, PhD
Assistant Editor Tamarind Reaves
stabilizer was continued unchanged. The following cognitive tests were administered at
baseline and at 8 weeks: Set Shifting Test, Strategic Target Detection Test, Flanker Test,
Auditory Digit Span, Word List Memory, and Finger Tapping tests. These tests evaluated
executive functions, processing speed, attention, working memory, memory, and
psychomotor speed. Social cognition was assessed with the Penn Emotional Acuity Test.
Psychopathology was assessed with the YMRS, MADRS, and Hamilton Anxiety Rating
Scale (HARS).

At baseline, the groups were similar. The mean YMRS, MADRS, and HARS scores
confirmed that the population was stable and "normal" (not manic or depressive) during the
study. Two patients taking WSE had the dose decreased to 250 mg/day because of
complaints of vivid dreams (n = 1) and sleepiness (n = 1). One patient in the placebo group
also had a decrease in dose because of complaints of vivid dreams. There was no significant
difference between groups in the frequency of adverse events. All adverse events were mild
and transient. There were no significant changes in laboratory parameters, respiratory rate,
pulse, blood pressure, or body weight. Based on pill counts, compliance ranged from 82.9%
to 100%, with no significant difference between groups.

After 4 weeks, there were no significant changes in any of the test results. After 8 weeks, the
WSE group had significant improvements over the placebo group on the mean digit span
backward test (Auditory Digit Span, P = 0.035), neutral mean response time (Flanker Test, P
= 0.033), and the mean social cognition response rating (Penn Emotional Acuity Test, P =
0.045). There were no significant differences between groups for the other 4 tests. The time
effect suggests that a longer treatment duration might produce more substantial and possibly
also a greater range of improvements. On the Functioning Assessment Short Test (FAST),
the WSE group showed significant improvements in the cognitive domain only (P0.041),
while the placebo group scores did not change in any of the 6 FAST domains.

The authors conclude that WSE improves verbal working memory in patients with bipolar
disorder in a euthymic state. The authors acknowledge that the findings do not support their
initial hypothesis; they anticipated greater cognitive benefits. There are many possible
reasons for the findings. The duration of the study may not have been long enough, the
effect may be different in a symptomatic population, and a different extract may have
different results. In addition, the effective upper and lower dosage limits for the WSE have
not been determined, and its effects may differ among sub-populations (depending upon
type of drug therapy, type of bipolar disorder, patient age, etc.). Finally, the authors observe
that the use of performance-based cognitive measures rather than self-reports may be more
optimal. Further research assessing the impact of these variables is warranted to more
accurately determine the effect of WSE on cognition in people with bipolar disorder.

Heather S. Oliff, PhD

The American Botanical Council has chosen not to include the original article.


The American Botanical Council provides this review as an educational service. By providing this service, ABC does not warrant
that the data is accurate and correct, nor does distribution of the article constitute any endorsement of the information contained or of
the views of the authors.

ABC does not authorize the copying or use of the original articles. Reproduction of the reviews is allowed on a limited basis for
students, colleagues, employees and/or members. Other uses and distribution require prior approval from ABC.