Nootropics, also known as brain supplements, smart drugs, or cognitive enhancers, are substances purported to increase energy and cognitive functions. Nootropics, first defined by Cornelius E. Girugea in 1972, enhance learning and memory, show neuroprotective effects, have low toxicity and few adverse events, and lack sedation and motor stimulation effects [1]. Although many nootropics are available on the market, they are commercialized with unproven marketing claims. In 2019, the FDA expressed great concern about nootropics. As these substances are not approved drugs, there is a lack of clinical evidence regarding their efficacy and safety, particularly for long-term use [2]. Here, we will review the current clinical evidence of seven plant-derived nootropics including Centella asiatica, Coffea arabica L., Ginkgo biloba, Panax ginseng, Rhodiola rosea, Salvia officinalis L., and Withania somnifera.
Centella asiatica (commonly known as gotu kola or tiger grass)
Centella asiatica is an herbaceous plant native to tropical regions of Africa, Asia, and Australia, among others, and consumed as a vegetable. This plant contains pentacyclic triterpenoids, trisaccharide derivatives, and more than 100 other chemical compounds [3].
A randomized, placebo-controlled, double-blind study involving 28 healthy elderly participants was conducted to assess Centella asiatica's effects on cognitive functions. The results showed that Centella asiatica extracts at 750 mg once daily for 2 months enhanced working memory, improved self-rated mood, and attenuated this population's age-related decline in cognitive function [4]. Another study involving 33 patients with generalized anxiety disorder assessed the efficacy of Centella asiatica extract in reducing anxiety and stress. In addition, this extract (500 mg twice daily) also significantly improved cognition [5]. Finally, a phase I clinical study involving healthy volunteers concluded that Centella asiatica extract of multiple doses of 500 mg was well-tolerated [6].
These findings suggest that Centella asiatica extract is safe and may enhance cognitive function and reduce anxiety and stress in both elderly and anxiety disorder patients.
Coffea arabica L. (source of caffeine)
Caffeine is a methylxanthine molecule found in the Coffea arabica L. plant, among others, and is present in coffee, tea, chocolate, and guarana [7]. A systematic review published in 2014 concluded from 11 randomized placebo-controlled studies that caffeine and L-theanine (a substance present in tea leaves) show synergistic effects on attentional switching accuracy [8]. Administered as herbal-caffeine chewing gum (containing caffeine, vinpocetine, and Ginkgo biloba), it improved short-term and long-term memory, but not concentration in 62 healthy participants [9]. When combined with L-theanine or glucose, caffeine exerts effects on attention in healthy volunteers, improving both sustained visual selective and target-specific attention, with increased performance in accuracy and reaction speed [10,11], In a double-blind placebo-controlled trial involving 50 healthy volunteers, caffeine, at moderately high doses of 600 mg, improved vigilance and alertness as effectively as Modafinil, a drug prescribed to improve attention [12]. Interestingly, caffeine consumption from guarana gave a better response to acute mood and cognition at a lower dose than caffeine alone, highlighting potential synergistic effects between caffeine and other guarana compounds [13]. These findings highlight caffeine's potential to enhance cognitive functions, particularly attention and memory, especially when combined with other compounds like L-theanine, glucose, or guarana. However, high intake of caffeine can result in anxiety, restlessness, insomnia, irregular heart rate, disorientation, hallucinations, psychosis, or seizures [14-16].
In summary, caffeine shows promise in enhancing cognitive functions such as attention and memory, especially when combined with compounds like L-theanine, glucose, or guarana, but excessive consumption can lead to serious adverse effects.
Ginkgo biloba
Ginkgo biloba is a widely used plant containing many bioactive compounds such as flavonoids, terpenoids, proanthocyanidins, phytosterols, and carotenoids [17].
As a nootropic, the efficacy of Ginkgo biloba extracts has been assessed in clinical trials for improving attention and memory as well as addressing cognitive decline and impairment. Clinical trials evaluating the efficacy of Ginkgo biloba to improve memory, information processing speed, and attention led to conflicting results in healthy participants.
A systematic review published in 2007, based on 15 randomized clinical trials, concluded that Ginkgo biloba shows no convincing evidence of improving any aspect of cognitive function in healthy young people, regardless of whether it was administered acutely or over the long term [18]. However, a double-blind, placebo-controlled 30-day clinical trial found significant improvement in working memory and information processing speed in 61 young and healthy participants, but only as positive subjective effects [19]. Another trial with 40 and 52 healthy young participants in two experiments showed that Ginkgo biloba improved attention and memory after acute administration, but these effects disappeared after 6 weeks, suggesting tolerance development [20].
In Alzheimer’s patients, clinical trials demonstrated that Ginkgo biloba treatment (240 mg per day for more than 24 weeks) improved clinical symptoms associated with cognitive decline, such as attention, memory loss, vigilance, and mental fluidity [21]. In 48 elderly healthy participants, treatment with Ginkgo biloba extract for 8 months improved cognitive performance, including attention processes related to task execution speed [22]. In 59 patients with age-related mild cognitive impairment excluding Alzheimer's, Ginkgo biloba fresh extract (90 mg twice a day for 6 weeks) was effective in improving memory and concentration [23].
No side effects have been reported at regular doses, however, mild stomach irritation and headaches can occur with excessive consumption. In addition, bleeding episodes have been reported due to Ginkgo biloba inhibition of platelet aggregation, therefore, patients with anticoagulants must be cautious [24,25] Finally, no adverse clinical effects or increase of liver injury markers were observed in an elderly institutionalized population receiving Ginkgo biloba 120 mg twice daily for 6 months [26].
These findings suggest that while Ginkgo biloba may offer some cognitive benefits, particularly in elderly individuals and those with cognitive impairments, its efficacy in healthy young people remains uncertain and warrants further research.
Rhodiola rosea (commonly known as golden root)
Rhodiola rosea is a plant that grows naturally in cold regions of the Arctic, Asia, and North America. Rhodiola rosea extract is made from dried roots. Few clinical trials report its effects on cognition and stress. A randomized clinical trial assessed Rhodiola rosea efficacy in managing self-reported anxiety, stress, and cognition among others in 80 mildly anxious participants. The results showed a significant reduction in self-reported anxiety, stress, and improvements in mood at 14 days of treatment (200 mg twice daily). However, no relevant differences in cognition were observed [27]. Another randomized, placebo-controlled study evaluated the efficacy of a combination of magnesium (150 mg), vitamins B6 (0.7 mg), B9 (0.1 mg), B12 (1.25 μg), Rhodiola rosea (222 mg), and L-theanine (50 mg) in reducing stress among 100 otherwise healthy, stressed participants. The results demonstrated that this treatment was effective in managing stress, as evidenced by a significant reduction in Depression Anxiety Stress Scale (DASS)-42 scores in the treated participants compared to the control group. [28]. A double-blind, randomized, placebo-controlled study evaluated the efficacy of magnesium (150 mg), vitamin B, green tea (125 mg containing 50 mg of L-theanine), and Rhodiola rosea (222 mg) supplementation once daily in moderating stress effects in 100 moderately stressed participants. The results showed that the combined treatment significantly increased the brain resting state observed in electroencephalograms, which indicates a relaxed, alert state with attenuated stress and anxiety [29]. Finally, another clinical trial concluded that Rhodiola rosea extract was safe, well-tolerated, and effective in improving life-stress symptoms at a dose of 200 mg twice daily for 4 weeks [30].
These findings support the potential of Rhodiola rosea as a beneficial supplement for stress management and mood improvement, while also being well-tolerated.
Panax ginseng
Panax ginseng is a plant whose root is the source of ginseng to produce white (peeled and dried root) or red ginseng (steamed without peeling). This root contains ginsenoside saponins, which are divided into panaxadiol, panaxatriol, and oleanolic acid groups.
A double-blind, placebo-controlled, crossover-designed trial evaluated the cognitive effects of Panax ginseng extract (500 and 1000 mg) in 24 young and healthy participants. Panax ginseng extract did not affect cognition as evaluated by a series of cognitive tests [31]. Another randomized, double-blind, placebo-controlled, crossover-designed trial assessed the effects of a combination of Panax ginseng, Ginkgo biloba, and Crocus sativus on cognitive and cardiovascular function in 48 healthy participants. After one week of treatment, the results demonstrated small improvements in working memory without changes in participants’ encephalograms, but further research is needed on a larger sample size [32]. Another study with 30 healthy participants found no evidence of Panax ginseng's effects on subjective mood and memory processes [33]. A double-blind, placebo-controlled, balanced-crossover designed trial involving 27 healthy participants showed that Panax ginseng (200 mg) combined with glucose (25 mg) enhanced performance of a mental arithmetic task and attenuated the feelings of mental fatigue during the later stages of cognitively demanding task performance [34]. Another randomized, double-blind, placebo-controlled, crossover-designed trial evaluated the effects of a combination of omega 3 (eicosapentaenoic acid, 960 mg; docosahexaenoic acid, 624 mg), green tea (26 mg), and ginsenosides (16 mg) on brain functioning and cognition in 10 healthy older participants. This study demonstrated that after one month of supplementation, brain activation during task performance increased significantly during supplementation than with a placebo [35].
Finally, a randomized, open-labeled, placebo-controlled trial involving Alzheimer's disease patients evaluated the effects of Panax ginseng (4.5 g per day) on cognitive performance. The results demonstrated that after Panax ginseng treatment, cognitive performance improved as assessed by the mini-mental state examination and the Alzheimer's disease assessment scale. Cognitive improvement continued up to 12 weeks after Panax ginseng discontinuation [36].
Panax ginseng is contraindicated in case of acute asthma or hypertension. At high doses, it can cause restlessness, insomnia, nervousness, headaches, increased blood pressure, difficulty concentrating, and nosebleeds [25,37].
These findings suggest that Panax ginseng may enhance cognitive performance, particularly in older adults and Alzheimer's patients, though its effects in healthy individuals are less clear. Due to potential side effects, it should be used with caution, especially in those with acute asthma or hypertension.
Salvia officinalis L. (commonly known as sage)
Salvia officinalis L., commonly known as sage, is a member of the mint plant Lamiaceae family with blue flowers. The leaves of the plant are primarily used for medicinal and culinary purposes.
A double-blind, placebo-controlled, crossover study evaluated the effects of sage on memory in 20 and 24 young and healthy participants. The results of two experiments demonstrated that a dose of 50 µmol of sage can modulate cognition, and significantly improve immediate word recall [38]. Another randomized, double-blind, placebo-controlled study involving 44 healthy participants failed to show any effects after 2-weeks of treatment combining Salvia officinalis L., Rosmarinus officinalis L., and Melissa officinalis L. on verbal recall except in participants below 63 years of age [39]. A systematic review published in 2014 integrated the results from 8 clinical trials and concluded that Salvia species (Salvia officinalis L. and Salvia lavandulaefolia) enhance cognitive performance in healthy participants as well as patients with cognitive impairment or dementia [40]. A randomized, placebo-controlled trial with 42 Alzheimer’s disease patients evaluated the effects of Salvia officinalis L. extract (60 drops per day) in improving cognitive function on mild and moderate symptoms. After 4 months, the group treated with Salvia officinalis L. extract showed better cognitive functions than the placebo group as assessed by the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Dementia Rating. There were no significant differences in adverse events between the two groups, indicating that Salvia officinalis L. was well-tolerated [41]. Finally, another randomized, double-blind, placebo-controlled trial with 20 older participants demonstrated the efficacy of a 333 mg dose of a standardized extract of Salvia officinalis L. in enhancing secondary memory performance, with significant improvements in attention accuracy [42].
In clinical trials, this plant extract did not cause any serious adverse reactions. It is generally considered safe and well-tolerated. However, a case report describes an allergic dermatitis after applying a cosmetic cream in an 83-year-old woman [43], Another case report describes generalized tonic‐clonic seizures after accidental ingestion of Salvia officinalis L. oil in a newborn and a toddler [44].
Research highlights the potential of Salvia officinalis L. to enhance cognitive function and memory, demonstrating its promise for both healthy individuals and patients with cognitive impairment. It is generally safe despite isolated reports of allergic dermatitis (skin application) and seizures (accidental ingestion).
Withania somnifera (commonly known as Ashwagandha)
Ashwagandha is a plant highly appreciated in India, its leaves, stems and roots are used to obtain extracts to improve sleep, mood, and anxiety. Multiple clinical trials assessed the efficacy of Ashwagandha extracts on memory, learning, anxiety, and depression. A randomized, double-blind, placebo-controlled study involving 50 elderly participants with mild cognitive impairment demonstrated that root extracts (300 mg twice daily for 8 weeks) improved memory and learning, including verbal recall and visual memory [45]. In 2024, another randomized, double-blind, placebo-controlled study with 59 young participants aged less than 30 reported an improvement in memory, attention, vigilance, and executive function after an acute (1 hour) and longer period (30 days) of Ashwagandha supplementation (225 mg per day) [46].
A systematic review published in 2014 included five clinical studies using extracts from different parts of the plant to evaluate its efficacy in treating anxiety and stress [47]. All of them were randomized placebo-controlled trials although their design, dosage, and treatment duration varied. Four studies reported significant differences in anxiety levels between the Ashwagandha and placebo groups [48-50]. Only one study failed to achieve significance. Interestingly, it also had the shortest trial duration (6 weeks) and the smallest sample size (39 participants) [51]. None of these trials reported significant adverse events. Other clinical trials reported Ashwagandha extract's efficacy in treating stress and anxiety in different populations from stressed healthy participants to bipolar disorder patients, or schizophrenic patients with depression and anxiety symptoms. All trials reported a significant reduction of stress and anxiety [52,53] along with a reduction of cortisol (stress hormone) levels for some [50,54-56]. More recent randomized, double-blind, placebo-controlled studies have demonstrated Ashwagandha's ability to reduce stress and anxiety in healthy adults with mild to moderate symptoms [57], as well as in those with self-reported high stress [58].
A randomized, double-blind, placebo-controlled trial assessed Ashwagandha safety in 80 healthy participants receiving Ashwagandha 300 mg twice daily for 8 weeks and concluded that it was safe at this posology [59]. These findings demonstrated that Ashwagandha extracts have the potential to improve memory, attention, and vigilance, and reduce stress and anxiety while being well-tolerated.
Difficulties in the clinical and safety evaluation of plant-derived nootropics
Plant-derived nootropics are challenging products for clinical and safety evaluation in clinical trials. Indeed, the combined effects of a plant extract arise from a complex mixture of molecules whose concentrations vary based on the plant's growing conditions and the preparation or extraction methods used (extracts, essential oils, or raw materials). In addition, in clinical trials, a large panel of dosages is tested by applying different intervention designs, making direct results comparison particularly challenging [60]. Detailed descriptions of the extracts used are often missing, and the assessment of combination products containing multiple nootropics to evaluate potential synergies further complicates this field of research [40].
Conclusion
In conclusion, nootropics and nootropic compounds, particularly those derived from plants, show potential for enhancing cognitive functions and managing stress and anxiety. However, the efficacy and safety of these substances remain uncertain due to the lack of rigorous clinical evidence and standardized testing methods. Further research is essential to understand their long-term effects and mechanisms of action. Plant-derived nootropics face unique challenges in clinical evaluation, including variability in extract composition and complex interaction effects.
Methylene blue, which is present in both
Blue Cannatine and
Just Blue, is also a HON that supports your system by optimizing energy products via several mechanisms and is also an antioxidant that protects your cells from oxidative stress. It also works as a PON that increases neurotransmitter release and revs up complex IV of your mitochondria.
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