Sage (Salvia spp.) has a longstanding reputation in British herbal tradition1 as a natural agent that enhances memory—even though there had not previously been much evidence of its efficacy from modern research. In recent years, however, that changed. This article will discuss the evidence of memory enhancement and cognitive function for extracts of garden sage and Spanish sage. Let’s begin with a brief discussion of the brain health supplement category and a review of the research on the individual herbs before we talk about research on the combination of the two.

The Brain Health Supplement Category

Today, declining cognitive function are plaguing not just older adults, but young adults, too. As a result, consumer demand for well-formulated brain health supplements is rapidly increasing. In fact, the global brain health supplements market size was valued at $7.21 billion in 2020 and is expected to expand at a compound annual growth rate (CAGR) of 8.0 percent by 2028.2 In particular, the nootropics category is gaining in popularity. Nootropics, or natural supplements that support cognitive function in healthy individuals, are known to have excellent effects on cognitive health and memory function. Garden sage and Spanish sage are two such promising nootropics.

Garden Sage Leaf Background

Garden sage leaf (Salvia officinalis) is an herbal medicine that is native to the Middle East and Mediterranean, but has been naturalized throughout the world. In traditional medicine, garden sage has been used for treating a wide variety of disorders including seizure, ulcers, gout, rheumatism, inflammation, dizziness, tremor, paralysis, diarrhea and hyperglycemia. More recently, this herb has been a subject of studies documenting its traditional use and finding new biological effects. These studies have demonstrated a plethora of pharmacological activities, including anticancer, anti-inflammatory, antinociceptive, antioxidant, antimicrobial, antimutagenic, antidementia, hypoglycemic and hypolipidemic effects.3

Garden Sage Leaf Research

More specific to the topic of this article, garden sage has been shown to have cognitive benefits. One mechanism of action seems to be related to acetylcholine, a neurotransmitter involved in cognitive functions, such as learning and memory.4 The enzyme acetylcholinesterase (AChE) inactivates acetylcholine, thereby interfering with these cognitive functions. Research has demonstrated that garden sage significantly decreased acetylcholinesterase (AChE) activity in vitro5-7 and in vivo.8

Another mechanism of action concerns calcium/calmodulin-dependent enzyme kinase II (CaMKII), a key protein kinase in neural plasticity and memory. This role was shown in several studies since the first evidence in long-term potentiation (LTP) more than 30 years ago. This enzyme is involved in various processes such as mobilization of synaptic vesicles, modulation of ion channels, regulation of gene expression, regulation of muscle contraction and LTP. Over the last two decades CaMKII has become one of the most studied proteins in the nervous system, and it has proven to be a key protein involved in learning, memory and synaptic plasticity.9 CaMKII expression has been shown to be significantly increased in animals supplemented with garden sage leaf extract.10

There have been a few human studies on the effects of standardized garden sage leaf extract. One randomized, placebo-controlled, double-blind, crossover study11 investigated the effects on cognitive performance of in 20 older adults. Results showed that, compared with the placebo condition, the garden sage had a significant effect on performance of the ‘secondary memory’ factor—long-term memory, and dealing with information to be retained for a long amount of time. Another randomized, double-blind, placebo controlled, crossover study12 showed that garden sage leaf helped reduced stress and anxiety, improved calmness and improved alertness. Still another study13 on patients with mild to moderate Alzheimer’s disease found that garden sage leaf extract produced a significantly better outcome on cognitive functions than placebo.

Spanish Sage Leaf Background

Spanish sage leaf (Salvia lavandulaefolia) has a range of southwest Europe through Spain. The properties of the leaves include alterative, antiseptic, astringent, depurative, digestive, expectorant, febrifuge and tonic. They are used in the treatment of digestive and respiratory complaints, menstrual problems, infertility, nervous tension and depression.14

Spanish Sage Leaf Research

Two double-blind, placebo-controlled crossover studies15 were conducted to examine the effectiveness of Spanish sage for enhancing memory in young adult volunteers. In Trial 1, 20 participants received a standardized essential oil extract of Spanish sage and a placebo. In Trial 2, 24 participants also received a standardized essential oil extract of Spanish sage and a placebo. Doses were separated by a seven-day washout period. The primary outcome measures were immediate and delayed word recall. Results were that the Spanish sage oil significantly improved immediate word recall in both studies. These results represent the first systematic evidence that Spanish sage is capable of acute modulation of cognition in healthy young adults.

A Combination of Garden Sage Leaf and Spanish Sage Leaf Extracts

A combination of garden sage leaf and Spanish sage leaf extracts known as Cognivia (by Nexira) has been investigated for its effects on cognitive health.

A two-week study16 on mice explored the potential of the garden sage leaf and Spanish sage leaf extract combination (Cognivia) on memory during prolonged administration. Cognitive functions have been assessed throughout Y-maze and Morris water maze models. Results were at all sage groups had a significant effect on Y-maze markers on day 1 of administration. Only the mix of two sage species demonstrated significant improvements in Morris water maze markers at the end of administration. The combination of the two sages were shown to improve memory and present specific synergistic effects after chronic administration in healthy mice.

Subsequently, a randomized, double-blind, placebo-controlled, parallel groups trial17 investigated the impact of this sage combination on cognitive functions in humans with acute and chronic outcomes. Participants (n = 94, 25 M, 69 F, 30-60 years old) were assessed for comprehensive array of cognitive functions 120- and 240-minutes post-dose acutely and following 29-day supplementation with either 600 mg of the sage combination (Cognivia) or placebo. Results were that a consistent, significant benefit of the sage combination was observed throughout working memory and accuracy task outcome measures with sage (e.g., short-term working memory, numeric working memory, and name to face recall tasks) both acutely (i.e., changes within day 1 and day 29) and chronically (i.e., changes between day 1 to day 29).

Another randomized, cross-over, double-blind, placebo-controlled study18 was conducted to explore the acute effects of the sage combination (Cognivia) or placebo on cognitive function in 26 athletes performing a fatiguing cycling task. Results were that rating of perceived exertion was significantly lower during the sage session as compared to placebo (P = 0.002). Reaction time was significantly shorter with sage as compared to placebo (P = 0.023). The digit span memory test (a way of measuring the storage capacity of a person’s working memory) revealed a significant greater span score with sage as compared to placebo (P = 0.044). In conclusion, the combination of sage improved the cognitive functions (perceived exertion, working memory and reaction time).

Conclusion

Consumer interest in brain health supplements is growing. Two nootropics that have shown much promise—particularly in combination—are garden sage and Spanish sage extracts. Human clinical studies have demonstrated that combination known as Cognivia (by Nexira) improved working memory and accuracy task outcome measures both acutely and chronically, as well as improving cognitive performance, focus, attention (reaction time) and decrease your overall perceived fatigue during intense physical activity. VR

References:

1 Tildesley NTJ, Kennedy DO, Perry EK, et al. Salvia lavandulaefolia (Spanish sage) enhances memory in healthy young volunteers. Pharmacol Biochem Behav. 2003 Jun;75(3):669-74.

2 Brain Health Supplements Market Size, Share & Trends Analysis Report By Product (Natural Molecules, Herbal Extract), By Application (Memory Enhancement, Depression & Mood), By Region, And Segment Forecasts, 2021 – 2028. Jan, 2021. Retrieved May 1, 2022 from www.grandviewresearch.com/industry-analysis/brain-health-supplements-market.

3 Ghorbania A, Esmaeilizadeh M. Pharmacological properties of Salvia officinalis and its components. J Tradit Complement Med. 2017 Oct; 7(4): 433–440.

4 Hasselmo ME. The role of acetylcholine in learning and memory. Curr Opin Neurobiol. 2006 Dec; 16(6): 710–715.

5 Vladimir-Knežević S, Blažeković B, Kindl M, Vladić J, Lower-Nedza AD, Brantner AH. Acetylcholinesterase inhibitory, antioxidant and phytochemical properties of selected medicinal plants of the Lamiaceae family. Molecules. 2014 Jan 9;19(1):767-82.

6 Scholey AB, Tildesley NT, Ballard CG, Wesnes KA, Tasker A, Perry EK, Kennedy DO. An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers. Psychopharmacology (Berl). 2008 May;198(1):127-39.

7 Kennedy DO, Pace S, Haskell C, Okello EJ, Milne A, Scholey AB. Effects of cholinesterase inhibiting sage (Salvia officinalis) on mood, anxiety and performance on a psychological stressor battery. Neuropsychopharmacology. 2006 Apr;31(4):845-52.

8 Smach MA, Hafsa J, Charfeddine B, Dridi H, Limem K. Effects of sage extract on memory performance in mice and acetylcholinesterase activity. Ann Pharm Fr. 2015 Jul;73(4):281-8.

9 Zalcman G, Federman N, Romano A. CaMKII Isoforms in Learning and Memory: Localization and Function. Front Mol Neurosci. 04 December 2018; https://doi.org/10.3389/fnmol.2018.00445.

10 Dinel A-L, Lucas C, Guillemet D, et al. Chronic Supplementation with a Mix of Salvia officinalis and Salvia lavandulaefolia Improves Morris Water Maze Learning in Normal Adult C57Bl/6J Mice. Nutrients. 2020 Jun 15;12(6):1777.

11 Scholey AB, Tildesley NT, Ballard CG, Wesnes KA, Tasker A, Perry EK, Kennedy DO. An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers. Psychopharmacology (Berl). 2008 May;198(1):127-39.

12 Kennedy DO, Pace S, Haskell C, Okello EJ, Milne A, Scholey AB. Effects of cholinesterase inhibiting sage (Salvia officinalis) on mood, anxiety and performance on a psychological stressor battery. Neuropsychopharmacology. 2006 Apr;31(4):845-52.

13 Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, Khani M. Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: a double blind, randomized and placebo-controlled trial. J Clin Pharm Ther. 2003 Feb;28(1):53-9.

14 Bown D. Encyclopaedia of Herbs and their Uses. London: Dorling Kindersley;1995. ISBN 0-7513-020-31.

15 Tildesley NTJ, Kennedy DO, Perry EK, et al. Salvia lavandulaefolia (Spanish sage) enhances memory in healthy young volunteers. Pharmacol Biochem Behav. 2003 Jun;75(3):669-74.

16 Dinel A-L, Lucas C, Guillemet D, et al. Chronic Supplementation with a Mix of Salvia officinalis and Salvia lavandulaefolia Improves Morris Water Maze Learning in Normal Adult C57Bl/6J Mice. Nutrients. 2020 Jun 15;12(6):1777.

17 Wightman EL, Jackson PA, Spittlehouse B, et al. The Acute and Chronic Cognitive Effects of a Sage Extract: A Randomized, Placebo Controlled Study in Healthy Humans. Nutrients. 2021 Jan 14;13(1):218.

18 Babault N, Noureddine A, Amiez N, et al. Acute Effects of Salvia Supplementation on Cognitive Function in Athletes During a Fatiguing Cycling Exercise: A Randomized Cross-Over, Placebo-Controlled, and Double-Blind Study. Front Nutr. 2021 Nov 30;8:771518.

Gene Bruno, MS, MHS, the provost for Huntington University of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 40 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at [email protected].