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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: These researchers showed that a tincture of sage, rosemary, and lemon balm improved one aspect of cognition after two weeks in healthy people.
SOURCE: Perry NSL, Menzies R, Hodgson F, et al. A randomised double-blind placebo-controlled pilot trial of a combined extract of sage, rosemary and melissa, traditional herbal medicines, on the enhancement of memory in normal healthy subjects, including influence of age. Phytomedicine 2018;39:42-48.
There is a growing body of evidence that spices may play an important physiologic role. Some past reviews in Integrative Medicine Alert have addressed some of the recent findings. In addition, there is the interest in the ethnobotanical research community to investigate the biochemical basis for and the clinical effects of “traditional remedies,” or those treatments that, throughout history, have been used in cultures around the world. This clinical trial by Perry et al brings together these two lines of inquiry: exploring the effect of an herbal spice combination on memory in healthy research participants.
The authors began their article with a compelling review of the physiological effects of some plants on processes relevant to neurological function. They mentioned sage (Salvia officinalis, the common culinary sage species), bacopa (Bacopa monnieri, a plant with roots in Ayurvedic medicine), turmeric (Curcuma longa), peppermint (Mentha x piperita), ginkgo (Ginkgo biloba), saffron (Crocus sativus), lemon balm (Melissa officinalis), and rosemary (Rosmarinus officinalis). They also cited studies showing positive effects on oxidation and inflammation, as well as effects that might classify the plants as “neuroprotectants.” From this information, the researchers honed their list to sage, rosemary, and lemon balm (which they called melissa) because there are studies supporting their “traditional use for cognitive function.” After assuring themselves of the three plant identities, they placed 0.5 grams of the plants per milliliter of 45% ethanol for three weeks in a dark room (a typical process for making a tincture). At the end of the extraction period, the liquid was placed in 50 mL bottles. The placebo extract was made with sweet cicely (Myrrhis odorata) by using 1 g/mL with 45% ethanol. Sweet cicely is a plant not known to affect cognitive function. Of note, sweet cicely was added to the treatment extract to account for 10% of the volume. With respect to study protocol dosing, the treatment extract was administered to those participants in the treatment group at a dose of 5 mL in warm water twice daily for two weeks. The placebo group received 5 mL of the placebo liquid twice daily for two weeks.
The study took place in the United Kingdom. To be included in the study, participants needed to be at least 40 years of age and “healthy,” with no reports of mental impairment or related diagnosis. People could not participate if they were taking warfarin, were pregnant or breastfeeding, or presumably had any condition or diagnosis that might label them as “unhealthy.”
At baseline (day 0) and at the end of the study period (day 14), study participants underwent a memory test. For this, the participants were tested on their abilities to recall 15 words both immediately and delayed. These words were displayed on cards individually to the participants and then they were asked to write down as many as they could remember in one minute. Ten minutes later, once again they were asked to write down as many of the 15 words that they could remember. The results of these tests were recorded simply as the number of words recalled.
Forty-four of 45 recruited subjects completed the study protocol. Baseline word recall was statistically similar between the treatment and placebo groups. (See Table 1.) The researchers split these analyses into older vs. younger age groups, which in fact may have occurred after they noticed that the placebo group had a mean age 4.5 years younger than the treatment group. All told, there were minimal differences in word recall counts for any time points and age/treatment status. They only called out one result: the 7.2 words of delayed recall for the younger treatment group at day 14. (See bold value, Table 1.) This was mentioned as statistically different from the corresponding placebo value of 5.4 (P = 0.0347) and much improved over the baseline value of 4.6 (P = 0.0123).
No adverse effects were documented in any of the study subjects. In addition, there were no conflicts of interest nor concerns about funding that would taint the results presented here.
As introduced in the first part of this review, this research study weaved an exploration of traditional remedies with the idea that spices and other herbal medicines might have tangible medicinal benefits. In addition, by studying a healthy population, the results nudge the reader to imagine how plants might promote wellness and serve as effective preventive treatments. Yes, these are high expectations, but the findings do seem to meet some of these parameters.
In some respects, the study might best be considered as a pilot study. On the positive side, the authors provided a lot of details about the plant preparation, including information about plant identification and the creation of the tinctures; it is useful and important to understand plant dosing and specifics relevant to clinical use. The authors described the placebo development and that it is a randomized, controlled trial. To be complete, they should have expanded on the one participant dropout and explained the randomization and blinding processes. On that note, technically, to be the most statistically accurate, the researchers would have used an intention-to-treat analysis, accounting for the one study dropout and detailed why the person dropped out, as well as from which group he or she dropped out, which was not done. However, given the low dropout number, this may not have made much of a statistical difference. Furthermore, it is unclear how standard word recall testing is for assessing subtle cognitive changes in a healthy population.
The researchers could have provided more justification for their methodology here. Perhaps a fatal statistical flaw was the adjustment of the analysis after noticing that there was potentially an age effect. A more ideal recruitment and randomization process would have included age in the process at the beginning of the trial. The authors had lofty goals, namely to find and promote “effective treatments and preventive strategies” addressing concerning trends for the incidence and prevalence of Alzheimer’s disease worldwide. Since this was a study in a healthy population, we are unable to apply the findings to those with a dementia diagnosis and feel confident that we will find the same effects. In addition, the benefits seen here were in a younger cohort, not the age at which Alzheimer’s disease is more commonly diagnosed. Just as it is difficult to conclude that clinicians should adjust their clinical practice for dementia treatment based on these results, it is also difficult to comment on herbal form and dosing other than exactly what was used in this trial. Rosemary and sage, common culinary spices, are used most often in doses lower than what was used in this study, so a food use of these two plants may not necessarily bring about “brain-enhancing” benefits. In addition, an alcohol extraction could yield different chemical and physiological properties than a water extraction (infusion or tea) or in a food recipe. These results are an intriguing first step in the search for tools to prevent, and maybe treat, cognitive decline or dementia.
Financial Disclosure: Integrative Medicine Alert’s Executive Editor David Kiefer, MD; Peer Reviewer Suhani Bora, MD; Relias Media Executive Editor Leslie Coplin; Editor Jonathan Springston; and Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.