Beta-Caryophyllene, an Anti-Inflammatory Natural Compound, Improves Cognition in an Elderly Group who has Concerns about Memory

Specific actions of beta-caryophyllene (BCP)

It is likely that BCP protects the brain and body based on its anti-inflammatory/anti-oxidant properties. Transgenic mice mimicking Alzheimer’s disease experienced reduced inflammation that prevented cognitive decline after oral ingestion of BCP [3]. BCP has been shown to improve conditions related to its anti-inflammation property: inflammatory bowel disease, pain and inflammation in a neuropathic pain model, and oxidative stress reduction in the glial cells [6, 7, 9]. BCP has also shown promise for treating anxiety and depression, being a plausible therapeutic in diabetes and associated complications, preventing and ameliorating non-alcoholic fatty liver disease, lessening acute and chronic pain, and having an anti-convulsive effect against seizures [10, 11, 12, 13, 14]. In addition, BCP may offer benefit to promote weight loss and reduce cardiovascular disease. In an animal model, BCP was able to decrease the visceral fat index, total and LDL cholesterol, very low-density lipoprotein (VLDL), and pro-inflammatory cytokines [15]. These effects were reversed by treatment with CB2 cannabinoid receptors and PPAR-antagonists, suggesting that BCP activity is mediated by direct binding to CB2 receptors and by the activation of PPAR-agonists.

One clinical study showed that BCP from black pepper mitigates pain [16]. Of the 31 participants, half complained of either acute or chronic pain at the onset of the study. Each received 60 mg of BCP daily for eight weeks. By day 4, 60% reported mitigation of pain and the benefits lasted for one week. About one-third of the participants stated that the level of reduced pain was comparable to non-steroidal anti- inflammatory drugs (NSAIDs) that were used previously. Another group explored the effect of BCP on testosterone levels in women who complained of low libido [17]. The women had an olfactory exposure treatment of a control (glycerol) followed by 3% BCP, each over 20 minutes. Salivary testosterone increased without changing estrogen for the BCP treatment compared to the control period. These findings suggest that BCP may be a remedy with few side effects for women with decreased libido.

It is possible that activation of CB2R from orally consumed BCP may lead to beneficial cognitive effects by reducing the neuroinflammatory response. Admittedly, more involved dietary plans like the Mediterranean and MIND diets have been shown to reduce the risk of cognitive impairment [18, 19]. Both diet plans include mostly fresh foods like fruits, vegetables, whole grains, healthy oils like olive oil, legumes, and seeds and nuts, which are not foods typically consumed by most Americans. The purpose of this 8-week, randomized, prospective study is to evaluate the effect of two different doses of BPC on cognition in an elderly population, who have not been diagnosed with mild cognitive impairment or dementia, yet have noticed poorer cognition themselves.

Entry criteria and recruitment

The entry criteria were to be aged 60-80 years, worried about their own brain function (e.g., losing memory, concentration, focus), and being overweight or obese according to body mass index (BMI; 25-40 kg/m2) [20]. Each candidate needed to own a computer and be versatile on its use in order to complete weekly data collection forms and perform online brain games. Participants could not have been diagnosed with Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment, or any other neurodegenerative condition, but could have other chronic conditions, as long as they were well controlled. No one with COVID-19 was admitted to the study, and throughout the 8 weeks, if anyone contracted the coronavirus, they were excluded from the study. Candidates had to be naïve to using supplements of beta-caryophyllene (BCP).

The participants were screened and recruited by L&E Research, who then remained in regular contact with them to assure weekly compliance with requested data. If more than one questionnaire was submitted, the last one was used. Participants were compensated $100 upon submission of all data at week 8.

Cognitive testing using the Cognitive Failures Questionnaire (CFQ)

(https://www.ocf.berkeley.edu/~jfkihlstrom/ ConsciousnessWeb/Meditation/CFQ.htm)

The CFQ probes minor mistakes that most people make occasionally but sometimes they happen more frequently. The 25-question survey was developed to assess the frequency that individuals experience these mistakes in cognitive function, such as absent-mindedness, in everyday life – slips and errors of perception, memory, and motor functioning. The CFQ scoring system used for each question was: 0=Never; 1=Very rarely; 2=Occasionally; 3=Quite often; 4=Very often. Four summed sub-scale scores with similar attributes were also determined for a Total CFQ score; Forgetfulness (a tendency to forget something that is known or planned, for example, names, intentions, appointments, and words); Distractibility (mainly in social situations such as being absentminded or easily disturbed with one person or in a group); and False triggering (interrupted ability to pay attention leading to making errors in thinking and acting logically).

The CFQ cognitive test was sent to the participants electronically at baseline, week 4, and week 8. A lower score indicated better cognitive function.

Nutrition Intervention and Baseline Dietary Survey

Clove oil, (Syzygium aromaticum, was provided by Biosfered, Torino, Italy and served as the source of BCP. Capsules for the study were prepared by Tishcon Corp. (http://www.tishcon.com/), Westbury, New York. Each capsule contained 100 mg of clove oil containing 90% BCP and 350 mg of rice bran oil. The group taking one capsule daily received 90 mg of BCP and the group taking two capsules received 180 mg. Each capsule had a screw-off top. Participants were told to empty the contents of the capsule into the mouth and leave it under the tongue for a couple of minutes before swallowing. Everyone was told to take the one or two capsules in the morning. Capsules were provided at no charge to the participants.

At baseline, subjects provided information about their current dietary habits. Questions probed the frequency of consumption of sugar, fish, red meats and cold cuts, fruits and vegetables, seeds and nuts, and alcohol. Also, the frequency of eating at a fast food restaurant was asked.

Cognitive Failures Questionnaire (CFQ)

Four summed sub-scale CFQ scores: For each of the four sub-scale scores, all measurements at week 4 and week 8 were lower than at baseline for both dietary intervention groups (i.e., one or two BCP capsules), indicating improvement in cognition (Tables 2a-2d). Taking two BCP capsules resulted in significant improvement for all four sub-scale scores at week 4 and week 8 compared to baseline (P ≤ 0.05). Unlike taking two BCP capsules, those taking one BCP capsule only had a significant improvement for Forgetfulness at week 8 compared to baseline (P ≤ 0.05) (Table 2b) and for False Triggering at weeks 4 and 8 compared to baseline (P ≤ 0.05) (Table 2d). The percentage improvement in the sub-scale scores for those taking two BCP capsules were about twice greater than experienced by those taking one BCP capsule (Tables 2a-2d).

*P ≤ 0.01 and **P ≤ 0.005 compared to baseline of two BCP capsules, using t-test, respectively. Table 2a: Changes in Total Summed Sub-score of the Cognitive Failures Questionnaire (CFQ) (lower scores are better).

*P ≤ 0.05 compared to baseline of one BCP capsule, by t-test ^P ≤ 0.01 compared to baseline of two BCP capsules, by t-test, respectively Table 2b: Changes in Forgetfulness Summed Sub-score of the Cognitive Failures Questionnaire (CFQ) (lower scores are better).

*P ≤ 0.001 compared to baseline for two BCP capsules, using t-test, respectively Table 2c: Changes in Distractibility Summed Sub-score of the Cognitive Failures Questionnaire (CFQ) (lower scores are better).

*P ≤ 0.05 compared to baseline for one BCP capsule, using t-test, respectively ^P ≤ 0.01 compared to baseline for two BCP capsules, using t-test, respectively Table 2d: Changes in False Triggering Summed Sub-score of the Cognitive Failures Questionnaire (CFQ) (lower scores are better).

The participants taking two BCP capsules experienced significant improvement in the Total CFQ sub-scale scores of 25% and 30% at weeks 4 (P ≤ 0.01) and 8 (P ≤ 0.005), respectively (Table 2a). Those taking one BCP capsule improved 14% at week 4 and 16% at week 8. For the Forgetfulness sub-score, those taking two capsules improved more than those taking one BCP capsules at week 4 (27% vs. 14%) and at week 8 (27% vs. 17%) (Table 2b). Those taking one BCP experienced a significant improvement at week 8 (P ≤ 0.05), and those taking two BCP capsules achieved a significant benefit at both weeks 4 and 8 (P ≤ 0.01) (Table 2b).

For the Distractibility sub-score, the participants taking two BCP capsules improved 20% at week 4 and 29% at week 8 (P ≤ 0.001, respectively), in contrast to non-significant improvements for those taking one BCP capsule of 8% at week 4 and 9% at week 8 (Table 2c). The False Triggering sub-scores improved the most in the group taking two BCP capsules compared to any other sub-score for either one and two BCP capsule groups (Table 2d). For those taking one BCP capsule, significant improvement was observed at week 4 (18%, P ≤ 0.05) and week 8 (19%, P ≤ 0.05). With the group taking two BCP capsules, a greater improvement was observed at week 4 (33%, P ≤ 0.01) and week 8 (36%, P ≤ 0.01).

Changes in individual CFQ questions: Of the 25 questions on the CFQ questionnaire, improvement was observed for nearly all questions over 8 weeks, but only eight achieved significance. In most cases, greater improvement was found in those taking two BCP capsules compared to one; often it was two or three times more.

Changes in CFQ that achieved statistical significance (Table 3a-3h): Eight of the twenty-five CFQ questions improved significantly for both dietary options (one or two BCP capsules) (Tables 3a-3h). Baseline questions were 2.0 or greater for 10 of the 16 options (8 for one BCP capsule and 8 for two BCP capsules), indicating difficulty at baseline in these aspects of cognitive function. Mostly two capsules showed greater improvement than taking one BCP capsule, and no worsening of cognition was observed for either dietary intervention.

*P ≤ 0.005 compared to baseline for two capsules, using t-test, respectively Table 3a: Do you read something and find you haven’t been thinking about it and must read it again?

*P ≤ 0.005 compared to baseline for one capsule, using t-test, respectively ^ P ≤ 0.0005 compared to baseline for two capsules, using t-test, respectively Table 3b: Do you find you forget why you went from one place of the house to the other?

*P ≤ 0.005 compared to baseline for two BCP capsules, using t-test, respectively Table 3c: Do you find you forget whether you’ve turned off a light or locked the door?

*P ≤ 0.05 compared to baseline for one BCP capsule, using t-test, respectively ^P ≤ 0.01 compared to baseline for two BCP capsules, using t-test, respectively Table 3d: Do you forget where you put something like a newspaper or a book?

*P ≤ 0.05 compared to baseline for two BCP capsules, using t-test, respectively Table 3e: Do you find you accidentally misplace things like placing the fruit in the cupboard and the bowl in the refrigerator?

*P ≤ 0.05 compared to baseline for two BCP capsules, using t-test, respectively Table 3f: Do you daydream when you ought to be listening to something?

*P ≤ 0.005 compared to baseline for two BCP capsules, using t-test, respectively Table 3g: Do you start doing one thing at home and get distracted and do something else (unintentionally)?

*P ≤ 0.01 compared to baseline for one BCP capsule, using t-test ^ P ≤ 0.01 compared to baseline for two BCP capsules, using t-test Table 3h: Do you find you can’t quite remember something although it’s “on the tip of your tongue”?

vs. Baseline 27% better 44% better

Do you lose track of paying bills?

$$ \text{Baseline} \quad 1. 3 \pm 0. 9 \quad 1. 0 \pm 0. 9 $$

Week 4 vs.

1.0 ± 0.8 0.9 ± 1.0 Baseline 23% better 10% better

Week 8 vs.

1.1 ± 0.8 0.7 ± 0.9 Baseline 15% better 30% better

Do you fail to notice signposts on the road?

$$ \text{Baseline} \quad 1. 2 \pm 0. 8 \quad 1. 0 \pm 0. 8 $$

Week 4 vs.

1.0 ± 0.7 0.7 ± 0.7 Baseline 17% better 30% better

Week 8 vs.

1.0 ± 0.8 0.8 ± 0.7 Baseline 17% better 20% better

Do you confuse left and right when giving people

directions?

$$ \text{Baseline} \quad 0. 6 \pm 1. 0 \quad 0. 9 \pm 1. 2 $$

Week 4 vs.

0.7 ± 1.0 0.7 ± 0.8 Baseline 17% worse 22% better

Week 8 vs.

0.7 ± 0.9 0.7 ± 0.8 Baseline 17% worse 22% better

Do you bump into people?

$$ \text{Baseline} \quad 0. 7 \pm 0. 6 \quad 0. 7 \pm 1. 0 $$

Week 4 vs.

0.5 ± 0.6 0.6 ± 0.8 Baseline 29% better 14% better

Week 8 vs.

0.7 ± 0.6 0.5 ± 0.6 Baseline No change 29% better

Do you fail to listen to people’s names when you

are meeting them for the first time?

$$ \text{Baseline} \quad 2. 2 \pm 1. 0 \quad 2. 3 \pm 1. 1 $$

Week 4 vs.

2.2 ± 1.1 1.8 ± 1.2 Baseline No change 22% better

Week 8 vs.

1.9 ± 1.2 1.9 ± 1.1 Baseline 14% better 17% better

Do you say something and realize afterwards that

it might be taken as an insult?

$$ \text{Baseline} \quad 1. 5 \pm 0. 9 \quad 1. 4 \pm 0. 8 $$

Week 4 vs.

1.1 ± 1.0 1.4 ± 0.9 Baseline 28% better No change

Week 8 vs.

1.2 ± 0.7 1.2 ± 0.7 Baseline 20% better 14% better

Do you fail to hear people speaking to you when

you are doing something?

$$ \text{Baseline} \quad 2. 0 \pm 0. 8 \quad 1. 7 \pm 0. 8 $$

Week 4 vs.

1.7 ± 0.9 1.5 ± 1.1 Baseline 15% better 12% better

Week 8 vs.

1.6 ± 0.9 1.3 ± 1.1 Baseline 20% better 23% better

Do you lose your temper and regret it?

Table 3i: Non-significant changes in responses to CFQ.

The question related to “having to re-read something because you were thinking of something else” significantly improved with two BCP capsules at week 4 (39%) and week 8 (39%) (P ≤ 0.005 for both time points; Table 3a). For both BCP capsule groups, significant benefit was observed in “remembering why you went from one room to another” (Table 3b). For those taking one BCP capsule, significant improvement was observed at week 4 (29%; P ≤ 0.005) and week 8 (29%; P ≤ 0.005) compared to baseline. For those taking two BCP capsules, compared to baseline, improvement was observed at week 4 (39%; P ≤ 0.0005) and week 8 (39%; P ≤ 0.0005).

The score for “remembering whether you turned a light off or locked a door” was significantly improved only for those taking two BCP capsules (Table 3c). Compared to baseline, at week 4 (45% better; P ≤ 0.005) and week 8 (40% better P ≤ 0.005). The “ability to remember where you put a newspaper or book” improved in both BCP groups (Table 3d). For those taking one BCP capsule, the percentage improvement at both weeks 4 and 8 was 22% (P ≤ 0.05) compared to baseline. Those taking two BCP capsules, compared to baseline, improved 19% at week 4 (P ≤ 0.01) and at week 8 improved 29% (P ≤ 0.01).

Accidently “misplacing something like putting fruit in the cupboard and the bowl in the refrigerator” was only significant for those taking two BCP capsules (Table 3e). Compared to baseline, at week 8 there was 63% improvement (P ≤ 0.05). The participants taking two BCP capsules daydreamed significantly less when they were supposed to be listening to something (Table 3f). At both week 4 (28% better; P ≤ 0.05) and week 8 (33%; P ≤ 0.05) improvement occurred compared to baseline.

Becoming less distracted and doing something else unintentionally after starting a task improved significantly for those taking two BCP capsules at weeks 4 and 8 (30%; P ≤ 0.005 for both time points) (Table 3g). The ability to remember things that are on the “tip of the tongue” improved significantly for those taking one BCP capsule at week 8 compared to baseline (19%; P ≤ 0.01) and for those taking two BCP capsules at week 4 compared to baseline (20%; P ≤ 0.01 (Table 3h).

Changes in CFQ that did not achieve statistical significance (Table 3i): Seventeen of the twenty-five CFQ questions did not achieve significance over the 8-week study for either dietary intervention (Table 3i). Most mean baseline responses (15/17) in both BCP groups have values of 2.0 or less, which indicated that they were near-normal, and, thus, significant improvements would be unlikely. Despite seemingly high percentage improvements (many of 20% to 30%), the large standard deviations made achieving significance less likely.

Individual questions that did not result in significance improvement included: forgetting someone’s name, forgetting why entered a store, failing to remember anything to say, forgetting which way to turn on a road, not paying bills, forgetting to look at signposts, confusing left and right when giving directions, bumping into people, not listening when told someone’s name, worrying that something said was insulting, failing to hear people when doing something else, loosing your temper, forgetting why went into the supermarket, using a word incorrectly, having trouble making up your mind, forgetting an appointment, and dropping things (Table 3i).

The only times that a response was worse at week 4 and 8 than baseline was in those taking one BCP capsule at week 4 and week 8 for confusing left and right when giving others directions; and at week 4 and week 8 for forgetting an appointment (Table 3i). However, none of these were significant.

Dietary History

Pre-study dietary habits that related to cognition showed little differences between the two groups (Table 4). Most participants (> 70%) consumed sugar-rich foods one to three times daily; more than half consumed fish once weekly; and more than half claimed to avoid fast food restaurants. The most common frequent response for consuming red meat and cold cuts was two to three times weekly. About half of the subjects consumed seven servings of fruits and vegetables daily. One-third consumed seeds and nuts about once weekly; a bit more (~40%) consumed them two to three times weekly. About half of the participants stated that they did not consume alcoholic beverages.