How Sage can be used as a Cognitive Enhancer (Past Academic Essay)

The following essay was written whilst I was attending Northumbria University in 2021-23. The essay title was as follows, "A nutraceutical company is considering incorporating a dietary compound into one of their products so that they might market it as ‘cognitively enhancing’. They have approached you as a biological psychologist, working within this area of nutritional research, to evaluate the efficacy of this ingredient. You are required to critically discuss, utilising existing literature, the suitability of ONE of the following bioactive compounds/extracts: caffeine, sage or cocoa flavanols as an ingredient in a product to be labelled as a cognitive enhancer." This is an example of academic work I have conducted during my studies.

Salvia officinalis is a common type of sage, otherwise known as ‘an evergreen Shrub growing to 0.6m (2ft) by 0.6 m (2ft in) at a medium rate’.. The plant is toxic when taken in excess or when taken for extended periods and predominantly grows in Southern Europe. (Lopresti A.L., 2017) In ancient and modern cultures, sage was used as a medicinal treatment. The earliest texts indicate sage as a treatment for age-associated memory loss, and studies have shown that Salvia lavandulaefolia (Spanish Sage) and Salvia officinalis (Garden Sage) possess properties ‘potentially relevant to the attenuation of the cognitive decline associated with the downregulation of the cholinergic system seen in natural ageing and dementia’. This can primarily be due to inhibiting the cholinesterase group of enzymes known as butyryl-cholinesterase and acetylcholinesterase, demonstrated on human postmortem brain tissue or bovine erythrocytes. (ibid., Lopresti A.L., 2017) This essay will evaluate whether Sage can be used as an anxiolytic for a state of mental or emotional strain or tension resulting from adverse or demanding circumstances based on neurological cognition. Cognition can be defined as ‘the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses’, using attention, memory, judgment and evaluation, reasoning, problem solving and decision making. Researchers have found interest in 3 herbal remedies that may act as cognitive-enhancing agents such as Curcumin, Ginkgo biloba, Bacopa monnieri, and perhaps the most promising Salvia (sage) from the Lamiaceae family. (What is Cognition?, 2015) Salvia has been used in the past to treat a range of problems, including ‘digestive and circulation disturbances, bronchitis, coughs, asthma, memory problems, angina, mouth and throat inflammation, depression and excessive sweating'. (ibid., Lopresti A.L., 2017)

Salvia contains a variety of nutrients and vitamins, one teaspoonful of ground sage contains 3 milligrams of magnesium which is essential for lowering blood pressure and improving cognitive functions such as mood. 1 mg of phosphorus which is crucial for muscle recovery, as well as other physical aids. 7 mg of potassium is vital to regulate fluid balance, muscle contractions and nerve signals. 2 micrograms of folate, which is needed to make red and white blood cells in the bone marrow, convert carbohydrates into energy produce DNA and RNA’. (Ware, M., 2018) 24 mcg of beta-carotene, a 5 vital nutrient for vision, 41 international units (IU) of vitamin A which supports your immune system, and 12 mcg of vitamin K, essential for blood clotting, bone metabolism, and regulating blood calcium levels.

Neurological and biochemical factors can significantly influence cognitive activity and

performance; for example, damage to neurological structures can be associated with cognitive deficits, which influence different hormones and neurotransmitters on cognitive activity. (ibid., Lopresti A.L., 2017) Salvia can influence multiple physiological pathways due to its chemical constituents of phenolic acids, flavonoids, terpenoids, and polysaccharides, in addition to many essential oils.

One example of how Salvia may increase cognitive function is via the use in patients with Alzheimer's disease through the targeting of the amyloid-b peptide. Alzheimer's disease is a ‘type of dementia that affects memory, thinking and behaviour’, often displaying the symptoms of ‘disorientation, mood and behaviour changes; deepening confusion about events, time and place; unfounded suspicions about family, friends and professional caregivers; more severe memory loss and behaviour changes; and difficulty speaking, swallowing and walking’. (What is Alzheimers Disease?, 2021) In patients with Alzheimer's disease, there is an accumulation of the amyloid-b peptide (Ab), and its deposition is theorised to be partially responsible for the cognitive dysfunction displayed. This is because the unregulated increase of aggregates is neurotoxic, causing the deterioration of cholinergic neurons and calcium homeostasis, in addition to stimulating the production of reactive oxygen species and pro-inflammatory responses.

The amyloid-b peptide has also been acknowledged as the causation of specific learning and memory impairment, and its ‘administration has been renowned for inducing memory loss in animal models’. (More, S.V., & Others, 2016) Salvia has been used through animal studies to protect mice from Ab-induced neurotoxicity by inhibiting increases in tumour necrosis factor-a, interleukin-6 levels and acetylcholinesterase activity. (Teng, Y., & Others, 2014) These animal studies have demonstrated that supplementation of salvia weakened memory deficits whilst using rosmarinic acid to prevent Ab-induced nitration of proteins in the hippocampus.

Another way Salvia may be able to increase cognitive function is via the use in patients with Alzheimer's disease through the targeting of central cholinergic signalling, which has been associated with features of memory, motivation and mood. (ibid., Lopresti A.L., 2017) Acetylcholine is a neurotransmitter involved in cholinergic signalling and has been believed to contribute to attention, learning, memory, and motivation. Recent studies prove that it has been involved in the pathophysiology of many neurodegenerative disorders, including Alzheimer's disease, in addition to cortical acetylcholine in the attentional effort, orientation and the detection of behaviorally significant stimuli. (Klinkenberg, I., & Others, 2011) Drugs have been produced using acetylcholinesterase, an enzyme that catalyses the breakdown of acetylcholine to improve cognitive function by enhancing neuron-to-neuron transport

in the brain. (Colovic, M.B., & Others, 2013)

Through animal studies, it has been shown that Salvia contains effective acetylcholinesterase inhibitors. A liquefied extract of Salvia lowered acetylcholinesterase activity in mice, in addition to ethanolic extracts of Salvia reducing acetylcholinesterase with ‘greater effects on butyrylcholinesterase’. (Kennedy, D.O., & Others, 2006) The same mice subjected to amyloid-b peptide showed pre-treatment with Salvia to have significant reductions in acetylcholinesterase activity and memory performance. (Foolad, F., & Others, 2013) Many of the active constituents found in several Salvia species also inhibit 14 acetylcholinesterase activity, specifically rosmarinic acid, carnosic acid and quercetin.

Rosmarinic acid, found in salvia, protects against memory deficits induced by cerebral

artery occlusion in mice. In rats exposed to persisting erratic stress, rosmarinic acid restored hippocampal brain-derived neurotrophic factor, otherwise known as a neutrophin which plays a role in the survival of existing neurons and encourages the growth of new neurons. (Qin, X.Y., & Others, 2016) Brain-derived neurotrophic factor levels are typically lower in patients with mild cognitive impairment. In addition to using rosmarinic acid in rats, caffeic acid reduced stress-induced levels of a brain-derived neurotrophic factor in the frontal cortex. As well as the flavonoid luteolin being reasoned as an active agent influencing the secretion of neurotrophic factors, ‘including nerve growth factor, glial-derived neurotrophic factor and brain-derived neurotrophic factor in cultured astrocytes’. (Xu, S.L., & Others, 2013)

In the analysis of 10 Salvia species, it has been confirmed that they all displayed compelling antioxidant activity when measured by ‘oxygen radical absorbance capacity, radical scavenging capacity and total phenolic content’. (ibid., Lopresti A.L., 2017) The major phenolic compounds which cause this antioxidant activity are rosmarinic acid, salvianolic acid, sagecoumarin and sagerinic acid—these display radical scavenging activity with approximately 90% of 2,2-diphenylpicrylhydrazyl under experimental conditions. (ibid., Lopresti A.L., 2017) Oxidants are present in multiple neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and many mental health disorders such as major depressive disorder and Attention Deficit Hyperactivity Disorder. These cause a significant impact on working memory and cognitive performance. Salvia reduces the production of reactive oxygen species by discouraging oxidases and reducing the production of superoxide. This reduced the oxidative stress and, in an animal model, prevented the ‘diabetes-induced acquisition and memory deficits by inhibiting lipid peroxidation and enhancing antioxidant defence systems’. (Hasanein, P., & Others, 2016)

In major depressive disorders, there is a direct impairment in memory, attention and

learning. Treatment for depression, such as antidepressants, has been shown to have positive effects on cognitive performance. In a neuropharmacological analysis, it was found that sage possessed antidepressant and anxiolytic-like activity, along with other essential oils such as Anthemis nobilis (chamomile), Rosmarinus officinalis (rosemary), and Lavandula angustifolia (lavender). (ibid., Lopresti A.L., 2017) The essential oils were most helpful when pre-treated with dopamine receptor antagonists such as benzodiazepines. (Kavvadias, D. & Others, 2003)

A study conducted in 2013 found that compounds within salvia had an inflammatory

response in gingival fibroblasts, which is a common type of cell found in the connective tissue of the gums. It was found that sage reduced inflammation and supported the use of sage in dentistry. (Miriam, M., & Others, 2013) Inflammation plays a significant role in cognitive functioning as it has been confirmed that ‘an elevated level of C-reactive protein was associated with a 45% increased risk of all-cause dementia, and a higher level of IL-6 was associated with a 32% increased risk’. (ibid., Lopresti A.L., 2017) Increased inflammatory markers are also present in disorders such as ADHD, associated with decreased psychomotor speed. Salvia has been demonstrated in vitro and animal studies to have anti-inflammatory effects by inhibiting nitric oxide production stimulated by bacterial lipopolysaccharides in mouse macrophages. (Abu-Darwish, M.S., & Others, 2013) The administration of turpentine oil and salvia caused a significant reduction of acute inflammation, explicitly targeting the reduction of total leukocyte and monocyte percentages. Bioactive essence in salvias such as the tanshinones and salvianolic acids have also been shown to have anti-inflammatory mechanisms. (ibid., Lopresti A.L., 2017)

Sage has been investigated in multiple human trials to determine its cognitive-enhancing efficacy. One trial conducted by Perry NS, Bollen C, Perry EK, Ballard C. (2003) took 11 patients with Alzheimer’s disease and administered 50 lL of S. lavandulaefolia essential oil three times per day over three weeks. (Perry, N.S., & Others, 2003) It was found that there was a significant reduction in neuropsychiatric 26 symptoms related to Alzheimer’s disease and improvements in attention over the six weeks compared to a placebo study. In 5 other studies conducted, there was significant positive cognitive and mood-enhancing effects from a single administration of salvia. (Kennedy, D.O., & Others, 2011) There was also a colossal enhancement in memory and attention. The studies were conducted to support acute cognitive enhancement using salvia over short term investigations.

The Human Cognitive Neuroscience Unit, Division of Psychology, University of Northumbria, completed a study that aimed to confirm improved mood and cognitive performance following single doses of sage to healthy young participants. They claimed that 'CNS availability has been confirmed by observing that five days in vivo oral administration to rats of essential oil led to dose-dependent decreases in AChE activity in selected brain regions'. (Perry, N.S.L., & Others, 2002) The cognitive and mood 28 stabilising effects of single doses of extracts with confirmed AChE-inhibiting properties have been assessed in placebo-controlled, randomised, balanced crossover studies in both young and older human participants. (Tildesley, N.T.J., & Others, 2003) In a case of three studies that assessed cognitive function, treatment with both encapsulated S. lavandulaefolia essential oil and a dried ethanolic extract of S. Officinalis, all of which treatments had AChE-inhibiting properties, led to improved memory performance on a computerised cognitive assessment battery in addition to self-ratings of 'alertness', 'calmness' and 'contentedness'. (Tildesley, N.T.J., & Others, 2005)

The research concludes that the salvia plant has been shown to have benefits for mental and neurological conditions, and this is due to its biological processes, which impact neurological and cognitive function. Thus, the sage would be very suitable as a chosen compound as a cognitive enhancer as found in both young, healthy patients and those suffering from neurological disorders such as Alzheimer’s disease or ADHD.

There are also many disadvantages of using the sage plant in medications, in any case. Sage has been shown to have many interactions with other medicines for lowering blood sugar in diabetes, anticonvulsants, and sedatives. (SAGE, 2013) This means that the herb should be used with caution for those already medicated. In addition to this, when taken orally, sage is likely safe in food and when taken in medicinal amounts for up to four months. However, it is unsafe to digest sage if taken orally in high doses for long periods. This is because, in some species of sage, including the most common species Salvia Officinalis, there is a particular chemical called thujone, which is considered poisonous in excess. (ibid., SAGE, 2013)The side effects of ingesting large amounts of thujone include seizures alongside damage to the nervous system and liver. This indicates that sage would not be suitable for long term use in treating medical conditions. In addition to this, it is unsafe to digest sage at all during pregnancy because of the risk of digesting thujone. Thujone has been proven to begin a woman’s menstrual cycle, which may cause miscarriage. (ibid., SAGE, 2013) Breast-feeding whilst taking sage may also reduce the supply of milk. Though, it could be argued that the sage would not have to be digested by the participant orally. Sage is safe when applied to the skin using a cream for up to one week. Alternatively, it has been shown as safe when inhaled in aromatherapy using an essential oil without limiting its time frame.

My interpretation of the literature I have discussed in this essay would be that sage appears to be a safe and positive approach to cognitive enhancement. Not only has it been proven to contain multiple ingredients which benefit the body physically, but it has also been shown to influence cognitive activity in participants with depression, ADHD, and Alzheimer's, in addition to those who did not display signs of any disorders. The key enhancements that sage influences are working memory, attention, and mood behaviour. It would be beneficial to have this ingredient included in the pharmaceutical market. In the future, the use of sage could improve cognitive function, which is why it has been suggested that sage be used in or in therapeutic medications. One example is the medication suggested for ADHD.

The currently recommended medication for ADHD is amphetamine-based pharmaceuticals. These have been proven to enhance memory and attention by relieving the patient of their impulsivity, allowing them to 'concentrate better, be less impulsive, feel calmer, and learn and practise new skills'. (ADHD Treatments, NHS., 2018) The effects of this medication have been positive, but it also comes with many dangers and side effects. For one, it is a highly addictive drug that is often abused, especially when administered to patients with ADHD who tend to have a more challenging time controlling their impulsive behaviours. In addition to this, the side effects of dizziness, weight loss, mood swings, psychosis, and heart problems, can cause distress for the patient and even death. (Amphetamines Side Effects., 2018) Sage has been shown in research to improve the cognitive function in attention, motivation, and working memory of participants who are diagnosed with ADHD. In the future improvement of ADHD treatment, it should be noted that sage is implemented as an essential oil alternative before trialling amphetamines.

In conclusion, sage has recently been explored to find a medicinal substitute for the treatment and possible cure of illnesses such as 'Obesity, Diabetes, Depression, Dementia, Lupus, Autism, Heart Disease, and Cancer'. (ibid., Lopresti A.L., 2017) Sage provides a safe and effective treatment for such diseases naturally without the risks associated with other unnatural chemical-based medications, so long as it is used as aromatherapy rather than by ingesting the substance. Research has shown that sage has antibacterial, antioxidant, and anti-inflammatory activities, which have been proven to 'prevent, control, and treat many minor health problems as well as more serious and complicated diseases'. (ibid., Lopresti A.L., 2017) Thus, sage provides a compelling alternative or complementary drug for cognitive function.

Primary Resources

• Lopresti A. L. (2017). Salvia (Sage): A Review of its Potential Cognitive-Enhancing and

Protective Effects. Drugs in R&D, 17(1), 53–64. https://doi.org/10.1007/s40268-016-0157-5

Secondary Resources

• Abu-Darwish MS, Cabral C, Ferreira IV, Goncalves MJ, Cava- leiro C, Cruz MT, et al. Essential oil of common sage (Salvia officinalis L.) from Jordan: assessment of safety in mammalian cells and its antifungal and anti-inflammatory potential. Biomed Res Int. 2013;538940.

• Amphetamine | Side Effects, Dosage, Uses, and More. (2018). Retrieved 25 November 2021, from https://www.healthline.com/health/drugs/amphetamine-oral-tablet#side-effects

• Attention deficit hyperactivity disorder (ADHD) - Treatment. (2018). Retrieved 25 November 2021, from https://www.nhs.uk/conditions/attention-deficit-hyperactivity-disorder-adhd/treatment/

• Cherney, K. (2019). Potassium. Retrieved 9 November 2021, from https://www.healthline.com/health/potassium

• Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM. Acetylcholinesterase

inhibitors: pharmacology and toxicol- ogy. Curr Neuropharmacol. 2013;11(3):315–35.

• Foolad F, Khodagholi F. Dietary supplementation with Salvia sahendica attenuates

acetylcholinesterase activity and increases mitochondrial transcription factor A and antioxidant proteins in the hippocampus of amyloid beta-injected rats. J Pharm Phar- macol. 2013;65(10):1555–62.

• Hasanein P, Felehgari Z, Emamjomeh A. Preventive effects of Salvia officinalis L. against

learning and memory deficit induced by diabetes in rats: Possible hypoglycaemic and

antioxidant mechanisms. Neurosci Lett. 2016;27(622):72–7.

• Miriam M. Ehrnhöfer-Ressler, Kristina Fricke, Marc Pignitter, Joel M. Walker, Jessica Walker, Michael Rychlik, and Veronika Somoza. Journal of Agricultural and Food Chemistry 2013 61(14), 3451-3459 DOI: 10.1021/jf305472t

• More SV, Kumar H, Cho DY, Yun YS, Choi DK. Toxin-induced experimental models of

learning and memory impairment. Int J Mol Sci. 2016;17(9).doi:10.3390/ijms17091447.

• Perry NS, Bollen C, Perry EK, Ballard C. Salvia for dementia therapy: review of

pharmacological activity and pilot tolerability clinical trial. Pharmacol Biochem Behav.

2003;75(3):651–9.

• Perry NSL, Houghton PJ, Jenner P, Keith A, Perry EK (2002). Salvia lavandulaefolia essential oil inhibits cholinesterase in vivo. Phytomedicine 9: 48–51.

• Kavvadias D, Monschein V, Sand P, Riederer P, Schreier P. Con- stituents of sage (Salvia

officinalis) with in vitro affinity to human brain benzodiazepine receptor. Planta Med. 2003;69(2):113–7.

• 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;31(4):845–52.

• Kennedy DO, Dodd FL, Robertson BC, Okello EJ, Reay JL, Scholey AB, et al. Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults. J Psychopharmacol. 2011;25(8):1088–100.

• Klinkenberg I, Sambeth A, Blokland A. Acetylcholine and attention. Behav Brain Res.

2011;221(2):430–42.14

• Qin XY, Cao C, Cawley NX, Liu TT, Yuan J, Loh YP, et al. Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer’s disease: a meta-analysis study (N = 7277). Mol Psychiatry. 2016. doi:10.1038/mp.2016.62.

• SAGE: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews. (2018). Retrieved 25 November 2021, from https://www.webmd.com/vitamins/ai/ingredientmono-504/sage

• Teng Y, Zhang MQ, Wang W, Liu LT, Zhou LM, Miao SK, et al. Compound danshen tablet

ameliorated abeta25-35-induced spa- tial memory impairment in mice via rescuing imbalance between cytokines and neurotrophins. BMC Complement Altern Med. 2014;14:23.

• Tildesley NTJ, Kennedy DO, Perry EK, Ballard C, Savelev S, Wesnes KA et al (2003). Salvia

lavandulaefolia (Spanish Sage) enhances memory in healthy young volunteers. Pharmacol Biochem Behav 75: 669–674. https://www.nature.com/articles/1300907

• Tildesley NTJ, Kennedy DO, Perry EK, Ballard C, Wesnes KA, Scholey AB (2005). Cognitive

and mood effects of acute administration of Salvia lavandulaefolia (Spanish Sage) to healthy young volunteers. Physiol Behav 83: 699–709.

• Ware, M. (2018). Folate: Health benefits and recommended intake. Retrieved 9 November 2021, from https://www.medicalnewstoday.com/articles/287677

• What is Alzheimer’s Disease?. (2021). Retrieved 8 November 2021, from https://www.alz.org/alzheimers-dementia/what-is-alzheimers

• What is cognition?. (2015). Retrieved 8 November 2021, from https://

www.cambridgecognition.com/blog/entry/what-is-cognition

• Xu SL, Bi CW, Choi RC, Zhu KY, Miernisha A, Dong TT, et al. Flavonoids induce the synthesis and secretion of neurotrophic factors in cultured rat astrocytes: a signaling response mediated by estrogen receptor. Evid Based Complement Alternat Med. 2013;2013:127075.

Citing this essay:

Article Title:	How Sage can be used as a Cognitive Enhancer
Author:	Mx. R.J. Gittins
Publisher:	SheThinkDifferent (The Unseen Spectrum)
Date Written:	December 2021
Date Published:	August 2024