Research into the historical literature has identified several quotes in 16th- and 17th-century English herbals, describing sage (species of Salvia (Lamiaceae)) to improve memory. In his late-16th-century English herbal, Gerard writes about sage: ‘It is singularly good for the head and brain and quickenethe the nerves and memory’, and Culpeper, writing about 50 years later, says that ‘It also heals the memory, warming and quickening the senses’, whilst Hill in 1756 poignantly describes the tragic effects associated with ageing by stating, ‘Sage will retard that rapid progress of decay that treads upon our heels so fast in latter years of life, will preserve faculty and memory more valuable to the rational mind than life itself. Effects on the CNS have been reported for a number of species of Salvia, including sedative and hypnotic, hallucinogenic, memory-enhancing, anticonvulsant, neuroprotective and anti-Parkinsonian activities.
In recent years a variety of studies have been conducted to investigate if there is any scientific evidence to explain the traditional uses of sage for improving memory, with many studies focusing on extracts and essential oils from Salvia officinalis L. and Salvia lavandulifolia Vahl. An ethanolic extract and the steam-distilled oil of Salvia officinalis, and the oil of Salvia lavandulifolia gave inhibition of acetylcholinesterase at relatively low concentrations in vitro. The cyclic monoterpenoids 1,8-cineole and α-pinene were shown to inhibit acetylcholinesterase in vitro and were considered to explain the anti-cholinesterase activity of the Salvia lavandulifolia oil, although other constituents of the oil may also have contributed, perhaps synergistically.
Although the observed anti-cholinesterase activity of the monoterpenoids is particularly interesting, since many of the previously reported acetylcholinesterase inhibitors of natural origin were amines, the monoterpenoids were considerably less potent by a factor of at least 103 than the alkaloid inhibitors such as physostigmine. The relevance of in vitro test results with sage extracts and oils has been explored by further tests in vivo. One study showed that oral administration of Salvia lavandulifolia oil to rats decreased acetylcholinesterase activity in both the striatum and the hippocampus, compared to the control rats, suggesting that one or more oil constituents or their metabolites reach the brain and inhibit acetylcholinesterase in select brain areas, which is consistent with evidence of inhibition of acetylcholinesterase in vitro. Another study assessed the effect of an ethanolic extract of Salvia officinalis on memory retention of passive avoidance learning in rodents; the potentiation of memory retention observed with this treatment may have been associated with an interaction with the muscarinic and nicotinic cholinergic systems.
Extracts from some species of Salvia, including from both Salvia officinalis and Salvia lavandulifolia, have also shown antioxidant effects. An aqueous methanolic extract of Salvia officinalis dose-dependently inhibited lipid peroxida-tion, and antioxidant effects were also shown with an ethanolic extract of Salvia lavandulifolia; both the water-soluble and chloroform-soluble fractions of the latter extract gave similar activity. Compounds isolated from species of Salvia that have shown antioxidant effects include salvianolic acids I, K and L and various other phenolic compounds.
Species of Salvia have also been investigated for activities relevant to producing an anti-inflammatory action. Inhibition of eicosanoid synthesis was observed with an ethanol extract of Salvia lavandulifolia, although this effect was relatively weak. Some essential oil constituents from S. lavandulifolia have also been assessed for their effects on eicosanoid synthesis, but only the monoterpenoid α-pinene (comprising 5% of the essential oil) produced significant activity, although it did show some weak selectivity for inhibition of leukotriene B4 (leukotriene B4) generation. Ursolic acid, from Salvia officinalis, has anti-inflammatory activity in vivo.
Some other, perhaps relevant, activities have also been reported for sage. A standardised extract of Salvia officinalis and one of its components rosmarinic acid were neuroprotective against beta-amyloid-induced toxicity in vitro. In addition, dose-dependent estrogenic activity was observed in vitro with an ethanolic extract from Salvia lavandulifolia, and although the possible benefits of estrogenic compounds on cognition are still unclear, an estrogenic effect of sage might also provide some explanation for the reputed effects in traditional medicine.
Some clinical studies with human volunteers, including Alzheimer’s disease patients, have also been reported. In a placebo-controlled, double-blind, balanced, crossover study, subjects (healthy young adults) received a standardised oil extract of Salvia lavandulifolia and vehicle (sunflower oil) alone, with a 7-d washout period between each treatment. The sage treatment was associated with significant effects on cognitive ability, including improvements in immediate word-recall scores. A similar study also showed a positive modulation of mood and cognition in healthy young adults when given doses of a standardised essential oil of Salvia lavandulifolia in a placebo-controlled, double-blind, balanced, crossover study. In a small pilot trial, 11 patients showing mild to moderate symptoms of Alzheimer’s disease were orally administered Salvia lavandulifolia oil, which significantly improved cognitive function; a reduction in neuropsychiatric symptoms and an improvement in attention were observed. Further evidence for the cognitive enhancing effects of sage was shown in a multicentre, double-blind, randomised, placebo-controlled trial. In this study, patients showing some typical Alzheimer’s disease symptoms were treated with an extract of Salvia officinalis and significantly better outcomes in measurements of cognitive function were observed; there was no significant difference in side-effects between the treated and placebo groups, but a greater incidence of agitation in the placebo group was observed, suggesting the sage treatment may have also alleviated agitation.