Clinical Assistant Professor, Department of Family Medicine, University of Wisconsin; Clinical Assistant Professor of Medicine, Arizona Center for Integrative Medicine, University of Arizona, Tucson

Dr. Kiefer reports no financial relationships relevant to this field of study.

SYNOPSIS: The authors of this single-blind randomized study found that 1,000 mg of culinary lettuce seed nightly for two weeks can improve sleep in pregnant women with insomnia.

SOURCE: Pour ZS, Hosseinkhani A, Asadi N, et al. Double-blind randomized placebo-controlled trial on efficacy and safety of Lactuca sativa L. seeds on pregnancy-related insomnia. J Ethnopharmacol 2018;227:176-180.

For obvious reasons (think teratogens or abortifacients), clinicians are wary about prescribing anything for the myriad of conditions that can accompany pregnancy. These Iranian researchers are filling a void in such options for pregnant women by exploring one specific herbal medicine for insomnia. The researchers provided significant background about traditional Iranian medicine, within which is a robust history of herbal medicine use. One such plant, called khas or lettuce (Lactuca sativa, Family Asteraceae), and the seeds and the seed oil have a history of use as a sedative in general and for pregnancy. This is indeed the same culinary lettuce of which the leaves are a common part of salads in many cultures.

One hundred pregnant women with insomnia were included in this prospective, randomized, controlled trial. The participants needed to have a score of > 5 on the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a self-administered questionnaire that assesses seven areas (subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction). Each area is rated from 0 to 3, and a lower score indicates better sleep. The researchers excluded women with a body mass index > 30 kg/m² or a history of sleep disorders before pregnancy, mood disorders, gestational diabetes mellitus, drug abuse, or hypertension (including pre-eclampsia), as well as vague conditions such as “fetal disorder” or “history of chronic somatic disease.”

The women were randomized to 1,000 mg of lettuce seed nightly for two weeks (n = 50) or matched placebo containing corn starch (n = 50). This appeared to be a single-blind study; only the women were unaware of the group to which they were assigned. To obtain the product for use in the study, the researchers purchased “plant samples” (presumably seeds) in a local market, confirming the identification by using the herbarium of the Faculty of Pharmacy at Shiraz University of Medical Sciences. The seeds also were cold pressed to determine the seed oil content.

Only 35 women in each group completed the study. Reasons for lack of completion included stopping the treatment or being lost to follow-up. It is unclear whether an intention-to-treat analysis was used for the final statistical analysis.

Table 1 shows the results of the lettuce seed and placebo on the sleep scores. Overall, the intervention led to a statistically significant improvement in overall sleep as demonstrated by a lower PSQI (P = 0.021).

The researchers did not find any adverse effects in the women attributable to the intervention. One fetal death occurred in a woman assigned to the lettuce seed group at an estimated gestational age of 29 weeks due to placenta previa, but this was not thought to be caused by the lettuce seed. They documented three adverse neonatal outcomes in the treatment group (two sepsis and one transient tachypnea of the newborn) and one in the placebo group (sepsis). Again, none were considered a treatment effect nor significantly different from typical community disease incidences.

COMMENTARY

There are scant scientific data upon which to draw and assess the results presented here. Yes, lettuce is a common culinary plant, but the use of this species as a medicine does not enter into the Western herbal conversation regularly, if at all. Wild lettuce (Lactuca virosa) occasionally is mentioned as a sedative, using the leaves and/or latex.^1,2 Furthermore, it is unclear whether the seeds or seed oil would have the same effects as the leaves or latex. That said, in their introduction, Pour et al weaved in traditional use data (often the start of the investigation of plant medicines) and mentioned an animal model that corroborated sedative properties. Also, as per another reference in the paper, the seed oil fatty acid profile has been elucidated; the relevance to insomnia and sedation remains to be explained.

The study itself was well-organized, and the results simple enough to understand and follow. It could have been made more rigorous by also blinding the pharmacist who prepared the treatments and placebos (making it “double-blinded”). Also, the significant dropout rate could have been addressed more convincingly by using intention-to-treat analyses. As is, it is entirely plausible that study dropouts did so because of untoward side effects, or, alternatively, because their insomnia was cured miraculously and they did not need any more treatment. We would not know given the approach to data analysis in this paper.

Is this research important to clinicians in the United States? A qualified yes. There are still compelling reasons to explore traditional herbal remedies for safe and effective treatments for a variety of medical conditions. Lettuce seeds in Asia have this traditional use, but information is necessary before they can be a part of a clinician’s toolbox. Mechanistic studies, perhaps animal models, and certainly clinical research are important in this regard. This study begins that process, but it needs to be improved and expanded to include more participants in rigorous clinical trials. Lettuce seed might improve insomnia and it might be safe; we just do not know enough yet. Furthermore, anyone can buy garden lettuce seeds and make their own medicine, provided it is determined that is the best form for this herbal medicine. However, a quick search found a dearth of actual sedative herbal medicines based on this species; the preponderance of products available were for wild lettuce. In conclusion, this is an interesting herbal treatment for a demographic without many current options, and there is a tradition of use outside of the United States. More basic science and clinical work, and then adequate sources and products, are necessary before this can be recommended confidently.

REFERENCES

1. Mitchell WA. Plant Medicine in Practice. Edinburgh: Churchill Livingstone; 2003.
2. Mills S, Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine. Edinburgh: Churchill Livingstone; 2000.