Efficacy of open-label placebos for premenstrual syndrome: a randomised  controlled trial

Antje Frey Nascimento; Jens Gaab; Bojana Degen; Mareike Rytz; Anja Holder; Dilan Sezer; Sarah Buergler; Andrea H Meyer; Irving Kirsch; Joe Kossowsky; Cosima Locher

doi:10.1136/bmjebm-2024-112875

Menstrual Cycle · Premenstrual Disorders

Efficacy of open-label placebos for premenstrual syndrome: a randomised controlled trial

Frey Nascimento A, Gaab J, Degen B, Rytz M, Holder A, Sezer D, Buergler S, Meyer AH, Kirsch I, Kossowsky J, Locher C

Published March 25, 2025 BMJ Evidence-based Medicine, 30(5), 295-304

DOI 10.1136/bmjebm-2024-112875 PMID 40132912 PMC PMC12573394

RRM Academy Synopsis

Open-label placebos with an explanation lowered PMS symptoms

In a Swiss randomized trial of 150 women with PMS or premenstrual dysphoric disorder, open-label placebos with a treatment rationale lowered symptom intensity more than treatment as usual. Women in both placebo groups knew the pills were placebos. Placebos without a treatment rationale did not differ from treatment as usual on the main outcomes at the third cycle.

Key Findings

Symptom intensity at the third cycle was lower with a treatment rationale than with treatment as usual (d=0.90, 95% CI 0.39 to 1.41) or without one (d=0.55, 95% CI 0.04 to 1.06).
Open-label placebos without a treatment rationale did not differ from treatment as usual on symptom intensity (d=0.35, 95% CI –0.16 to 0.86) or interference (d=0.06, 95% CI –0.41 to 0.53).
Interference at the third cycle was lower with a treatment rationale than with treatment as usual (d=0.55, 95% CI 0.08 to 1.01) and than without one (d=0.48, 95% CI 0.01 to 0.96).
Observed symptom intensity fell 79.3% with a treatment rationale, 50.4% without one, and 33.0% with treatment as usual, from the first to the third cycle.
Four non-serious adverse events were reported, one in the group without a treatment rationale and three in the group with one. Adherence averaged 93.18%.

Interpretation

This randomized controlled trial compared three groups of 50 women and analyzed all 150 as randomized (intention-to-treat). Participants knew their group. Outcomes came from daily symptom diaries that the women completed themselves, across three cycles. The study was advertised as a side-effect free intervention, and the authors note that it may have drawn women open to unconventional treatments. The women averaged 25.3 years of age. The authors report that results adjusted for multiple testing differed slightly. They state that pragmatic non-inferiority trials comparing open-label placebos with established first-line treatments are needed.

RRM Context

PMS symptoms cluster in the luteal phase, the part of the cycle after ovulation. The authors list SSRIs and hormonal agents such as oral contraceptives (suppressive medications) as first-line therapies. They state that the cause of PMS is not yet fully understood. Restorative reproductive medicine treats premenstrual symptoms as information about the ovulatory cycle and looks for the underlying cause. The authors describe prospective symptom assessment as the gold standard for PMS diagnosis.

Our editorial summary of this paper, not the article's abstract.

Abstract

Objective

To investigate the efficacy and safety of open-label placebos (OLP) in premenstrual syndrome (PMS).

Design

Randomised controlled trial.

Setting

Switzerland, 2018-2020.

Participants

150 women (18-45 years of age) with PMS or premenstrual dysphoric disorder.

Intervention

Random assignment (1:1:1) to treatment as usual (TAU), OLP without treatment rationale (OLP-), or OLP with treatment rationale (OLP+). OLP consisted of two placebo pills per day for 6 weeks.

Main Outcome Measures

Primary outcomes were PMS symptom intensity and interference between groups across three menstrual cycles (MC1-MC3); adverse events (ie, safety) were measured at weeks 3 and 6 after the start of the intervention. Secondary outcomes were psychological and somatic subscales of PMS symptom intensity, and adherence.

Results

From 2 August 2018 to 3 December 2020, 150 women were randomly allocated to TAU (n=50), OLP- (n=50), and OLP+ (n=50), of whom 145 (96.7%) completed trial participation. Groups differed in symptom intensity (F(4)=4.419, p=0.002, r2=0.16) and interference (F(4)=3.159, p=0.014, r2=0.13) across three MCs. Mean symptom intensity at MC3 was lower for OLP+ compared to TAU (b=-9.97, SE=2.85, t(412)=3.50, p<0.001, d=0.90) and to OLP- (b=-6.10, SE=2.89, t(411)=2.11, p=0.036, d=0.55), but OLP- and TAU did not differ (b=-3.87, SE=2.87, t(411)=1.35, p=0.177, d=0.35). Mean interference at MC3 was lower for OLP+ compared to TAU (b=-1.23, SE=0.54, t(443)=2.30, p=0.022, d=0.55) and to OLP- (b=-1.10, SE=0.54, t(442)=2.02, p=0.044, d=0.48), but OLP- and TAU did not differ (b=-0.14, SE=0.54, t(442)=0.26, p=0.799, d=0.06). Four non-serious adverse events were reported in OLP- (n=1) and OLP+ (n=3). Improvement in psychological and somatic symptom intensity was comparable to primary outcomes. Adherence to the OLP intervention was high (93.18±18.95%), with no difference between groups.

Conclusions

The results of our clinical trial indicate that OLP provided with a treatment rationale is an effective, safe, and acceptable treatment for PMS.

Trial Registration

ClinicalTrials.gov NCT03547661 (submitted 2 May 2018).

Topics

Menstrual Cycle Premenstrual Disorders Premenstrual Syndrome Treatment

Menstrual Cycle › Premenstrual Disorders › Premenstrual Syndrome Treatment

Antje Frey Nascimento, Jens Gaab, Bojana Degen, Mareike Rytz, Anja Holder, Dilan Sezer, Sarah Buergler, Andrea H Meyer, Irving Kirsch, Joe Kossowsky, Cosima Locher

A Nascimento, J Gaab, B Degen, M Rytz, A Holder, D Sezer, S Buergler, A Meyer, I Kirsch, Joseph Kossowsky, J Kossowsky, C Locher

PMID 40132912 40132912 DOI 10.1136/bmjebm-2024-112875 10.1136/bmjebm-2024-112875 Frey Nascimento et al. 2025, Frey Nascimento 2025

Efficacy of open-label placebos for premenstrual syndrome: a randomised controlled trial

Open-label placebos with an explanation lowered PMS symptoms

Key Findings

Interpretation

RRM Context

Abstract

Topics

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