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L-Theanine and Caffeine in Combination Affect

Human Cognition as Evidenced by Oscillatory alpha-

Band Activity and Attention Task Performance1–3

1. Simon P. Kelly,

2. Manuel Gomez-Ramirez,

3. Jennifer L. Montesi, and

4. John J. Foxe*

+Author Affiliations

1. Cognitive Neurophysiology Laboratory, Nathan S. Kline Institute for Psychiatric Research,

Program in Cognitive Neuroscience and Schizophrenia, Orangeburg, NY 10962 and Program

in Cognitive Neuroscience, Department of Psychology, City College of the City University of

New York, New York, NY 10031

1. ↵*To whom correspondence should be addressed. E-mail: [email protected].

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Abstract

Recent neuropharmacological research has suggested that certain constituents of tea may have modulatory

effects on brain state. The bulk of this research has focused on either L-theanine or caffeine ingested alone

(mostly the latter) and has been limited to behavioral testing, subjective rating, or neurophysiological

assessments during resting. Here, we investigated the effects of both L-theanine and caffeine, ingested

separately or together, on behavioral and electrophysiological indices of tonic (background) and phasic (event-

related) visuospatial attentional deployment. Subjects underwent 4 d of testing, ingesting either placebo, 100

mg of L-theanine, 50 mg of caffeine, or these treatments combined. The task involved cued shifts of attention to

the left or right visual hemifield in anticipation of an imperative stimulus requiring discrimination. In addition to

behavioral measures, we examined overall, tonic attentional focus as well as phasic, cue-dependent

anticipatory attentional biasing, as indexed by scalp-recorded alpha-band (8–14 Hz) activity. We found an

increase in hit rate and target discriminability (d′) for the combined treatment relative to placebo, and an

increase in d′ but not hit rate for caffeine alone, whereas no effects were detected for L-theanine alone.

Electrophysiological results did not show increased differential biasing in phasic alpha across hemifields but

showed lower overall tonic alpha power in the combined treatment, similar to previous findings at a larger

dosage of L-theanine alone. This may signify a more generalized tonic deployment of attentional resources to

the visual modality and may underlie the facilitated behavioral performance on the combined ingestion of these

2 major constituents of tea.

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Introduction

In recent years, several potential health benefits of drinking tea (Camellia sinensis) have come to light through

systematic study of the effects of its constituent compounds (1,2). Although anecdotal evidence abounds, the

psychological and neurophysiological effects of tea have received relatively little experimental investigation and

thus remain unclear. Popular claims have centered on generalized state changes such as the reduction of

stress and induction of relaxed wakefulness. Psychopharmacological studies have indeed demonstrated mood

effects that support these claims and have further shown that tea affects elements of cognition (3,4). Although

caffeine (1,3,7-trimethylxanthine) is by far the constituent most studied, with findings of increased alertness and

speeded reaction time (RT)4 predominant (5,6), there exists evidence that caffeine alone cannot fully account

for the positive effects of tea drinking. Tea has been shown to raise skin temperature to a higher level (7), to

increase critical flicker fusion threshold (4), and to reduce physiological stress responses and increase

relaxation ratings (8) when compared with coffee or other control beverages matched for caffeine level.

L-Theanine (γ-glutamylethylamide), a unique amino acid present almost exclusively in the tea plant, has

recently received research interest in the neuroscience community with findings of neuroprotective effects [see

Kakuda (9)] and mood effects indexed both by subjective self-reports (10) and via psychological and

physiological responses to stress (11). Using electroencephalographic (EEG) recordings in humans, Kobayashi

et al. (12) and Juneja et al. (13) reported that activity within the alpha frequency band (8–14 Hz) increased in

reaction to L-theanine ingestion when measured during a state of rest. This was of interest to the attention

community, as the alpha rhythm has long been known to be sensitive to overall attentional states (i.e., intensity

aspects such as arousal) (14) and, further, is involved in the biasing of selective attention (15,16). In

intersensory attention tasks, where the relevant modality is cued ∼1 s before a compound audiovisual target

stimulus, parieto-occipital alpha power in the intervening period is increased for attend-visual trials relative to

attend-auditory trials (15,17). In Gomez-Ramirez et al. (18), this differential effect of cue information on

anticipatory alpha amplitude was found to be larger on ingestion of 250 mg of L-theanine relative to placebo. In

addition, tonic (background) alpha amplitude was relatively decreased for L-theanine, in apparent contradiction

to the findings of Juneja et al. (13). In a follow-up study, we tested whether an analogous alpha-mediated

attention effect seen in visuospatial attention tasks (16,19–22) is also affected by L-theanine ingestion (M.

Gomez-Ramirez, S. P. Kelly, J. L. Montesi, and J. J. Foxe, unpublished results). L-Theanine, at a dosage of

250 mg, was not found to increase the differential effect of attention. However, in a replication of the previous

intersensory attention study (18), overall tonic alpha was greatly reduced on L-theanine.

An immediate question, given this replication, is whether this tonic alpha reduction occurs at lower dosages

of L-theanine, closer to the amount ingested through a typical serving of tea. In the present study, we

administered a lower dosage of 100 mg to address this. Also of critical interest is whether the ingestion of

caffeine, another major component of tea, exerts behavioral and/or neurophysiological effects during such a

demanding visuospatial attention task, when ingested alone or when ingested together with L-theanine. Here

we present data from a 4-d experiment using a balanced repeated-measures design, with subjects receiving

either placebo (P), L-theanine alone (T), caffeine alone (C), or the combination of L-theanine plus caffeine

(T+C) on each day. We assessed effects of treatment with regard to basic behavioral measures of RT and

accuracy [including the so-called discriminability index (d′), which is independent of individual detection criteria],

and in relation to both tonic and phasic attentional processes as indexed by alpha power.

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Methods

Participants.

Sixteen (5 female) neurologically normal paid volunteers, aged between 21 and 40 y (mean 27.5 y),

participated in the study. All subjects provided written informed consent, and the Institutional Review Board of

the Nathan S. Kline Institute for Psychiatric Research approved the experimental procedures. All subjects

reported normal or corrected-to-normal vision. Four subjects were left-handed. The mean habitual tea

consumption across the subjects was 3.7 cups/wk, and for coffee, 3.8 cups/wk (∼250 mL/cup). Subjects arrived

at the laboratory in the morning between 0900 and 1200 h, having abstained from all caffeinated beverages for

the previous 24 h.

Treatment.

The timing of treatment administration relative to testing was based on published reports of amino acid

concentration and plasma concentration changes over time.L-Theanine concentration has been found to

increase significantly within 1 h after administration in rats, to continue to increase gradually up to 5 h, and to

decrease thereafter, with complete disappearance evident after 24 h (23). Peak plasma caffeine concentration

is reached between 15 and 120 min postingestion in humans, with a variable half-life typically between 2.5 and

4.5 h (5). Accordingly, participants abstained from consuming caffeine for at least 24 h before testing and

began experimental task runs 30 min after ingestion of any given treatment. Subjects underwent 4 d of testing,

ingesting either placebo, 100 mg of L-theanine, 50 mg of caffeine, or these treatments combined. Subjects

were uninformed of the treatment, which was served in 100 mL of water, with the placebo treatment consisting

only of water. Both theanine and caffeine are tasteless in water solution.

Stimuli and task.

Subjects were seated 150 cm from a CRT monitor and were instructed to maintain fixation on a central cross

(white on midgray background) at all times. Each trial began with a centrally presented arrow cue (“S1”) of 100-

ms duration, with equal probability pointing leftward or rightward toward 1 of 2 bilateral locations centered at a

horizontal distance of 4.2° from the fixation cross and 1.2° above the horizontal meridian. Each location was

marked by 4 dots outlining a 2.4° × 2.4° square. The cue consisted of a circle of 1° diameter with an embedded

arrow, designed to minimize any sensory effects related to physical differences between the left and right cues.

The colors of the arrow and circle were red on green for half of the blocks of recording and green on red for the

other half, with the order counterbalanced across subjects and days of testing. Red and green values were

precalibrated for each subject to be approximately isoluminant by flicker photometry. Then, 933 ms after cue

onset, a second imperative stimulus (“S2”) was presented at the left or right marked location (valid or invalid

with respect to cue direction) with equal probability. The S2s (100 ms duration) consisted of either a white × or

+ (0.75° × 0.75°) embedded in a circular array of 8 small circles such that the overall stimulus diameter was

1.95°. The target stimulus was chosen randomly at the beginning of each experimental run of ∼4.5 min, and

thereafter standard and target stimuli were equally likely on each trial. Subjects were instructed to shift their

attention covertly to the location indicated by the cue, to respond by pressing a mouse button with the index

finger of the right hand when a target S2 appeared on that side, and to ignore stimuli appearing on the invalid

side entirely. Trials were separated by a 1633-ms interval. A total of 100 trials were presented per run. Subjects

completed 20 runs on each day of testing.

Data acquisition.

Continuous EEG data, digitized at 512 Hz, were acquired from 164 scalp electrodes and 4 electro-oculographic

(EOG) electrodes with a pass-band of 0.05–100 Hz. Off-line, the data were low-pass filtered up to 45 Hz and

rereferenced to the nasion. Noisy channels, identified by taking the SD of amplitude over the entire run (from

first to last stimulus presented) and checking whether it is >50% greater than that of at least 3 of the 6 closest

surrounding channels, were interpolated. Horizontal EOG data were recorded using 2 electrodes placed at the

outer canthi of the eyes, allowing measurement of eye movements during testing. Based on a calibrated

mapping of EOG amplitude to visual angle, trials were rejected off-line if eye gaze deviated by >0.5° during the

cue-target interval.

Behavioral data analysis.

We employed a d′ as our principal performance metric, taking into account the accuracy of responding on

nontargets as well as targets and controlling for individual differences in detection criteria. The value of d′ was

derived from the hit rate (proportion of all valid targets detected) and false alarm rate (proportion of all valid

nontargets incorrectly responded to), calculated only from trials containing no eye movements or artifacts.

Ceiling effects on hit rate were corrected in the standard way by assuming 0.5 misses, and similarly, a floor

effect of zero false alarms was corrected to 0.5. RT was measured as the time (in milliseconds) from the point

of S2 onset at which the mouse button was correctly pressed in response to valid target trials.

To control for the potential confound of practice effects on the behavioral data, the order of treatments across

the 4 d of testing was fully counterbalanced across subjects. This is a standard procedure and ensures

unbiased comparison across conditions. However, in the case of the present data, the variance in behavioral

measures arising from the day of testing (order effect) far superseded that arising from treatment. Thus, a

normalization of these measures was necessary to remove the variance caused by practice, and this was

carried out by transforming each data point to a z-score with respect to the mean and SD of all scores

measured on that day (d 1, d 2, d 3, d 4). Because the distribution of scores for each day contains an equal

number of data points from each treatment, it cannot result in any bias for treatment but, rather, optimizes

statistical power to test for treatment effects.

Electrophysiological data analysis.

EEG data were epoched from −300 ms before to 1100 ms after cue onset and baseline-corrected relative to

the interval −100 to 0 ms, with an artifact rejection threshold of ±100 μV applied. Mean alpha amplitude was

calculated using the temporal spectral evolution (TSE) technique (15). TSE is carried out simply by filtering

each epoch with a passband of 8–14 Hz, rectifying, then averaging across trials. The averaged TSE waveforms

were then smoothed by averaging data points within a sliding 100-ms window.

The first analysis concerned tonic (background) alpha amplitude, which was found to decrease on L-theanine in

our previous 2 studies (18, M. Gomez-Ramirez, S. P. Kelly, J. L. Montesi, and J. J. Foxe, unpublished results).

Tonic alpha was measured as the integrated TSE amplitude within the baseline period −200 to 0 before the cue

stimulus, regardless of the direction of attentional deployment (i.e., to the left or right hemifield). The dependent

measure was computed as the baseline alpha amplitude averaged across 6 electrodes, chosen on the basis of

the grand-average scalp distribution of alpha amplitude, collapsed across the 4 d.

In a second analysis, we tested lateralized, anticipatory alpha amplitude for effects of attention and possible

interactions with treatment. We normalized alpha amplitude relative to baseline by dividing the TSE amplitude

by the mean amplitude within the baseline interval (−200 to 0) and log-transforming, making the measure

equivalent to a percentage change from baseline. This narrows down the analysis to attention-related

differential activity, independent of tonic effects. The anticipatory alpha dependent measure was computed as

the integrated TSE amplitude over the postcue interval 500 to 900 ms, ending just before the S2. Amplitude

was averaged across 6 electrodes over each hemisphere, determined based on grand-average difference

topographies (cue-left minus cue-right) collapsed across the 4 d.

Statistical methods.

A 4-d balanced repeated-measures design was employed, with subjects receiving 1 of the 4 treatments

(including placebo) on each day in counterbalanced order. SPSS for Windows (version 12.0) was used for all

statistical analyses. Tests were conducted with an α level of 0.05 unless otherwise stated. In the analysis of

behavioral data, we tested specifically for improvements in performance as a result of any of the 3 treatments.

Thus, 1-tailed, paired t-tests (df = 15) were conducted between the placebo condition and each of the 3

treatments for hit rate, RT, and d′ measures. Because 3 t-tests were performed including the same placebo

data, we applied a Bonferroni-corrected α-level of 0.016 here.

To test for effects of tonic alpha amplitude, a 1-way ANOVA was carried out with the factor of treatment having

the levels P, T, C, and T+C. Follow-up protected ttests were then conducted to unpack significant differences

existing between each of the T, C, and T+C conditions and the P condition. Further post hoc paired

comparisons among the 4 treatment conditions were conducted as appropriate through additional t-tests.

To test for effects on pretarget alpha amplitude a 4 × 2 × 2 ANOVA was carried out with factors of treatment (P,

T, C, T+C), attention (cue-left, cue-right), and hemisphere (left, right). To unpack a potential 3-way interaction,

we reduced the alpha cueing effect (typically seen as a hemisphere × attention interaction) to a single measure

by adding the differential over the 2 hemispheres, i.e., subtracting cue-right from cue-left on the left

hemisphere, subtracting cue-left from cue-right on the right hemisphere, and summing these 2 values. Thus

reduced, testing of treatment effects on the alpha cueing effect, as found in the analogous intersensory study of

Gomez-Ramirez et al. (18), could be done via paired t-tests comparing each of the 3 treatments T, C, and T+C

against P.

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Results

Behavioral performance.

Behavioral performance was significantly improved on the combined treatment (T+C) in terms of hit rate (P <

0.016) and d′ (P < 0.002). There was also a significant improvement in d′ on C compared with P (P < 0.016),

but not in hit rate. There were no significant effects of L-theanine, and no effects of any of the 3 treatments on

RT (Fig. 1).

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FIGURE 1

Mean hit rate (proportion of targets detected) (upper panel), mean d′ (middle panel), and mean RT (lower

panel) when subjects ingested placebo (P),L-theanine (T), caffeine (C), or these treatments combined (T+C).

Values are means (n = 16). Asterisks indicate difference from P: *P < 0.05, **P < 0.01).

Electrophysiology.

There was a significant effect of treatment on tonic alpha amplitude (P < 0.02). Follow-up t-tests revealed that

alpha was significantly lower for T+C than P (P < 0.02). P did not differ from either T or C (see Fig. 2). Tonic

alpha differed between T+C and T (P < 0.005) but not between T+C and C.

 Download as PowerPoint Slide

FIGURE 2

TSE waveforms at midline electrodes from which the baseline tonic alpha measure was derived (upper panel).

Cue-left and cue-right trials are collapsed. Integrated amplitude over the baseline period for each treatment,

with significant difference from placebo marked with an asterisk (lower panel). The electrodes from which tonic

alpha measures were derived are marked on the 168-channel montage.

The typical alpha cueing effect was readily apparent in both the nonnormalized alpha amplitude waveforms and

normalized pretarget measures (Fig. 3) for each treatment day. A strong attention × hemisphere interaction

(P < 0.0005) was found on the pretarget anticipatory alpha measures as expected, reflecting the typically

observed alpha-mediated cueing effect. In addition, there was a significant 3-way interaction among treatment,

attention, and hemisphere (P < 0.05). When we reduced the alpha cueing effect to a single metric as described

above, the effect was smaller on C than P (P < 0.02) but did not differ for the T or T+C conditions.

 Download as PowerPoint Slide

FIGURE 3

(Upper panel) TSE waveforms over left and right hemispheres, with cue-left (solid) and cue-right (dashed)

superimposed, collapsed across treatment. The overall alpha-mediated spatial cueing effect is highlighted.

Electrode sites for cueing effect measurement are marked on the montage. (Lower panel) Normalized alpha

measures forming the dependent variable in tests for effects of treatment on the alpha cueing effect (P,

placebo; T, L-theanine; C, caffeine; T+C, combined).

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Discussion

This study was aimed at extending our knowledge of the effects of compounds contained in tea on the

cognitive function of attention. Testing relatively low-dosage treatments of L-theanine alone (100 mg), caffeine

alone (50 mg), and their combination, we observed an interesting pattern of effects for both behavioral and

electrophysiological measures. Whereas no behavioral effects on hit rate were apparent for either treatment

alone at the low dosages tested here, when both L-theanine and caffeine were ingested together, hit rate

underwent an enhancement of ∼3%. In terms of d′, improvements were seen for both caffeine alone and L-

theanine plus caffeine, the latter having a larger effect size (0.55 vs. 0.42 calculated as Cohen’s d). Given the

absence of any difference in hit rate for caffeine, the d′ effect must result from subjects making fewer false

alarms on caffeine.

Tonic alpha amplitude was not found to decrease significantly on the lower dosage of L-theanine. This indicates

that the effect is dose dependent because a drop was seen in both of our previous studies using a 250-mg

dosage (18, M. Gomez-Ramirez, S. P. Kelly, J. L. Montesi, and J. J. Foxe, unpublished results). There was,

however, a significant decrease in tonic alpha for the combined treatment. That this decrease marks a synergy

between the 2 compounds is suggested by the numerical difference in the alpha decrease caused by L-

theanine with and without caffeine (Fig. 2). That is, it seems unlikely that the greater decrease on the combined

treatment is simply a linear sum of the decreases from each compound alone. Because only single dosages of

each compound were tested, however, a fair degree of caution is appropriate in the interpretation of synergy at

this juncture. This study marks the third finding of decreased alpha as a result of L-theanine ingestion (albeit a

partial cause here) to date, demonstrating the reliability of the effect. At this point, the question of whether it

translates to an improved functional brain state requires serious consideration. Should the finding of a decrease

be received with positive connotations for health and/or mental capabilities?

In the 80 y since the discovery of alpha waves (24), alpha has been measured in almost any experimental

situation and human population, with significant effects abounding, but with a complicated picture and quite

disparate theoretical frameworks arising (25–26). A consistent principle appears to be that stronger alpha infers

positive functioning across individuals (27,28), whereas phasic changes within individuals reflect immediate

stimulus processing and anticipatory enhancement and/or suppression, with a greater retinotopically specific

decrease in alpha being predictive of better detection performance (21). The tonic depression of alpha during

task performance over the day of testing, as observed here, is neither an individual trait nor a phasic event-

related response but a lasting, tonic treatment effect, making it difficult to draw comparisons with such previous

studies. The finding of increased alpha on ingestion of theanine has previously been taken to indicate

increased relaxation without increased drowsiness (13). But this qualification appears tenuous in light of other

observations of treatment-related increased alpha, e.g., during marihuana-induced euphoria (29). Can “good”

and “bad” really be ascribed to increases and decreases in alpha, in whatever direction? Certainly, that this

treatment-related decrease in tonic alpha does not have negative implications is suggested, if not already by

the fact that tea has been keenly, routinely consumed for centuries, by the concomitant facilitation in behavioral

performance found here in terms of both hit rate and d′.

Previous studies have reported a drop in absolute alpha power during resting with eyes open on ingestion of

caffeine at higher dosages, e.g., 200 mg (30) and 400 mg (31). Although alpha amplitude was numerically

lower on 50 mg of caffeine alone here, this did not reach significance (P = 0.18). From this, it is clear that alpha

effects of both L-theanine and caffeine are dose dependent, demonstrating that full characterization of dose-

response functions in future studies is called for.

Evidence of a synergistic relationship between L-theanine and caffeine has been presented in recent

behavioral studies. Parnell et al. (32) reported improved speed and accuracy on an attention-switching task at

60 min and reduced susceptibility to distracting information during a memory task at both 60 and 90 min

following ingestion of a combination of L-theanine and caffeine in the same dosages as used here. Haskell et

al. (33) administered a large battery of cognitive tests before and after consumption of a drink containing either

placebo, 250 mg of L-theanine, 150 mg of caffeine, or their combination. These authors found improvements in

simple and numeric working memory RT, sentence verification accuracy, and alertness ratings for the

combined treatment but not for either treatment alone. Using a similar crossover design but with a greater

dosage of caffeine (250 mg) than L-theanine (200 mg), Rogers et al. (34) found that L-theanine tended to

counteract the caffeine-induced rise in blood pressure but did not interact with caffeine-induced increases in

either alertness or “jitteriness” on state anxiety scales. Although the measures examined in these investigations

and our study are quite distinct in nature, an emerging possibility is that the presence of synergistic effects

closely hinges on dosages. That is, it may be that theanine was not effective in augmenting the caffeine-

induced effects in Rogers et al. (34) because these were present at a saturated level. In the present study,

lower dosages were used, and a significant drop in tonic alpha was observed for L-theanine and caffeine

ingested together but not for either L-theanine or caffeine when ingested alone. However, the absence of a

significant difference between the caffeine-alone and combined treatments calls for caution in making strong

claims of synergy at this point.

Similar to our previous visuospatial attention study (M. Gomez-Ramirez, S. P. Kelly, J. L. Montesi, and J. J.

Foxe, unpublished results), we did not find any change in the alpha differential cueing effect for the L-theanine-

alone treatment. However, it is interesting that the cueing effect was found to be smaller on caffeine alone but

not for the combined treatment. This result was unexpected and thus will bear replication and further

investigation. For now, it appears that within visual space, attentional biasing as indexed by alpha amplitude is

not affected by L-theanine. In contrast, the cued biasing of attention between sensory modalities does appear

to be affected (18). A tentative interpretation of the current pattern of results is thatL-theanine works to enhance

the tonic apportionment of attentional resources to the visual modality and does so to a significant degree when

a large dosage is ingested by itself or in combination with caffeine when a smaller dosage is ingested.

Other articles in this supplement include references (35–44).

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Footnotes

 ↵1 Published in a supplement to The Journal of Nutrition. Presented at the conference “Fourth International

Scientific Symposium on Tea and Human Health,” held in Washington, DC at the U.S. Department of

Agriculture on September 18, 2007. The conference was organized by the Tea Council of the U.S.A. and was

cosponsored by the American Cancer Society, the American College of Nutrition, the American Medical

Women’s Association, the American Society for Nutrition, and the Linus Pauling Institute. Its contents are solely

the responsibility of the authors and do not necessarily represent the official views of the Tea Council of the

U.S.A. or the cosponsoring organizations. Supplement coordinators for the supplement publication were

Lenore Arab, University of California, Los Angeles, CA and Jeffrey Blumberg, Tufts University, Boston, MA.

Supplement coordinator disclosure: L. Arab and J. Blumberg received honorarium and travel support from the

Tea Council of the U.S.A. for cochairing the Fourth International Scientific Symposium on Tea and Human

Health and for editorial services provided for this supplement publication; they also serve as members of the

Scientific Advisory Panel of the Tea Council of the U.S.A.

 ↵2 Author disclosures: S. P. Kelly, M. Gomez-Ramirez, and J. L. Montesi, no conflicts of interest; J. J. Foxe

received an honorarium and travel support from the Tea Council of the U.S.A. for speaking at the Fourth

International Scientific Symposium on Tea and Human Health and for preparing this manuscript for publication.

 ↵3 Supported by a grant from the Lipton Institute of Tea in association with Unilever Beverages Global

Technology Centre in Colworth House, Sharnbrook, UK.

 ↵4 Abbreviations used: C, caffeine-alone condition; d′, discriminability index; EEG, electroencephalographic;

EOG, electro-oculographic; P, placebo condition; RT, reaction time; T, theanine-alone condition; T+C,

combined condition; TSE, temporal spectral evolution.

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 CiteULike

 MICANS PharmB, PHIL

The National Institute on Aging (NIA) announced the final results of testing from three government labs regarding the

patented antioxidant nordihydroguaiaretic acid (NDGA). All three labs agreed that NDGA extended lifespan by a

resounding 12% in mice (1) (see Figure 1).

When some read this astounding news, they were skeptical. With a note of cynicism and doubt in their voices, they

said this report was probably hyperbole and the Federal government is not to be trusted. Yet these same three

government labs had also conducted lifespan studies with much-hyped anti-aging remedies, resveratrol, curcumin,

green tea, oxaloacetic acid and triglyceride oil (2) and found that these five supplements did not extend lifespan in

mice.

During the 1980s, researchers extensively tested NDGA in humans, mice and dogs. Results indicated that NDGA

extended lifespan in a variety of mammals. Even the US Patent and Trademark Office approved these results and

granted a patent. This office granted Dr. Richard Lippman a patent for NDGA, as part of a formula developed to slow

aging and extend human lifespan based on his extensive and convincing NDGA research (3).

Background Study of NDGA

Before Dr. Lippman was awarded a US patent on NDGA, several attorneys voiced skepticism. In firm language, they

stated that every law school student knows that two types of patents are never granted: a patent on a perpetual

motion machine and a patent on a fountain-of-youth remedy. Apparently, Dr. Lippman convinced patent examiners

that his clinical human, mice and dog studies of NDGA were sufficient to warrant a patent with claims to retard human

aging. These studies were also sufficient for the drug licensing authorities of Sweden and Italy to grant Dr. Lippman

marketing rights to sell NDGA under the name ‘Aging Control Formula 228’ (ACF228®).

Interestingly, a prominent American businessman, A. Glenn Braswell, had heard Dr. Lippman’s story, but Braswell

doubted that it was sold at the Vatican pharmacy in Rome, Italy. Consequently, he took his wife on a sudden trip to

Rome—and, to his surprise, found that ACF228 was indeed sold at the Vatican pharmacy with the pope’s blessings!

ACF228® Is Based on Extensive Free Radical Research

Today, we know free radicals are not antiwar activists out on bail. But when Dr. Richard Lippman was doing research

in Sweden many years ago, most people thought the term ‘free radicals’ referred to some kind of hippie politics.

No one then knew about these molecular sharks’ devastating effects on the human body and their role in aging.

Indeed, only twenty-five years ago, free radical chemistry and the toxic effects of free radicals on the human body

were unknown to most of the general public and even to many doctors and medical researchers.

Dr. Lippman first learned about the free radical theory of aging as an undergraduate student. When he began doing

graduate research work in cell biology, he and his colleagues held conferences at Pharmacia-Upjohn and the

University of Uppsala to discuss the exciting findings of Professor Denham Harman, whose experimental work at the

University of Nebraska in the 1950s showed that the life spans of mice could be extended 50%

with special antioxidant supplementation. The press and public responded; “So what?”

However, Sweden is well known in science and engineering for its industrial and technical advances. And Lippman

was the leader of a large medical staff that encouraged progressive research.

Raising Funds for Research

Dr. Lippman wanted to take Harman’s work one-step further and explore the relationship between free radicals and

aging. He turned to Professor Sven Brolin, chair of the University of Uppsala’s Department of Medical Cell Biology

and Professor Gunnar Wettermark, chair of the Royal Institute of Technology’s Department of Physical Chemistry, for

assistance in raising funds for research.

Dr. Lippman was successful, receiving significant medical and chemical grants from the Swedish Research Council to

develop antiaging strategies based on Harman’s groundbreaking discovery of the action of free radicals and the role

of radical scavengers (antioxidants) in destroying or inhibiting them. The Swedish Research Council financed years of

Dr. Lippman’s research at the Royal Institute of Technology in Stockholm and at the University of Uppsala,

Scandinavia’s oldest university, which has an anatomy lecture hall built in the 15th century.

Dr. Lippman’s research into the role that free radicals play in the breakdown of the aging body led him to develop one

of the most potent antioxidant combinations yet known, a unique antioxidant cocktail containing NDGA and called

ACF228®.

No Typical Scientist

Dr. Lippman’s normal lab attire—jeans, a khaki shirt, and ostrich leather boots—breaks from the conventional notion

of a white-coated scientist. Before his work in antiaging research that made him famous, he ate junk food. Now, a

typical lunch for him is salmon sashimi and salad or bi bim bop with a bowl of miso soup. He even developed his own

recipe for sugar-free, gluten-free, walnut cinnamon pumpkin muffins.

In speaking, Dr. Lippman presents an easy smile and laugh. He may not look like a typical scientist, but his passion

for longevity research is real. His innovative research into free radical pathology helped put antioxidants on the map,

in the dictionary and in the supermarket.

Once funding was in place, Dr. Lippman gathered a team of five prominent Swedish scientists to help him develop

methods for measuring free radicals and biochemical changes related to aging: Professor Agneta Nilsson, a

nutritionist and alternative medical professional with advanced degrees in nursing and teaching; Dr. Ambjörn Ågren,

MD, PhD, who had received numerous awards in the field of emergency medicine; Professor Mathius Uhlén, PhD, a

civil engineer, molecular biologist, and, later, professor and chair of the Royal Institute of Technology’s Department

Molecular Biology; Evald Koitsalu, an engineer and expert in computer hardware and software; and Dr. Kaj

Alverstrand, a psychologist and consultant to Volvo.

With these tremendous financial and personnel resources, Dr. Lippman was able to achieve great leaps in the field of

antiaging. Indeed, Paul Glenn of the Paul Glenn Foundation for Antiaging Research said that Dr. Lippman’s work

was; “light years ahead of everyone else!”

Dr. Lippman’s research resulted in a patent for NDGA and a product that promotes better health and longevity:

ACF228®.

Cellular Model—A Better Choice

The research team’s first task was to find a cellular model rather than an animal model to test for life extension, since

the Harman model of waiting for mice to grow old and die was costly and took years of patience before the results

came in.

The Lippman team had access to many different types of living cells in culture, such as human cells of the heart,

brain, liver and central nervous system. In 1980, Lippman invented special probes that would penetrate cell interiors

without harming them. For the first time in the history of cell biology, scientists were able to measure free radicals in

living cells (4). The first probe, carnitinylmaleate luminol (CML), measured superoxide radicals in live human liver

cells. Dr. Lippman and his team went on to test many different combinations of antiaging nutrients.

Developing the formula combinations was a tedious process. Live cells were harvested from biopsies, then separated

and kept metabolically alive in special culture dishes heated to a constant 98°F. The live cells were removed as

needed by the research team and tested for their health by means such as measurements of adenosine triphosphate

(ATP), the power source or ‘gasoline’ of most cell activities.

Then the cell cultures were impregnated with special CML probes and incubated with different mixtures of vitamins

and known antiaging nutrients. Lippman’s team eventually tested 227 different mixtures to find an optimal mixture

with pronounced longevity-promoting characteristics. Mixture number 228 was found to work best, and this and

several other promising mixtures such as 223 were tested further in mice and human volunteers. Now named

ACF228®, the mixture proved successful in extending mice health and life spans, (see Figure 2)

Scientific Community Astounded

The team published its results in more than twenty prominent medical journals. The work astounded the Swedish

scientific community and Lippman was nominated for a Nobel Prize in Medicine in 1996.

Further tests were conducted on hundreds of human volunteers recruited from several Swedish hospitals (3). The

volunteers were tested to establish their normal levels of fatty-acid peroxides, which are free-radical downstream

products, and then were fed varying amounts of ACF228® and other nutrients. Once again, the mixture known as

ACF228® caused normal peroxide levels to decline the fastest. Lippman and his researchers performed other human

tests that indicated ACF228® also had beneficial effects on the skin and sexual function (3).

“We found that the ACF228® formula truly is beneficial,” Dr. Lippman says. “It was especially helpful for middle-aged

and older people; their liver function became like that of teenagers. Often people experience reduced liver function as

they age, especially if they have abused their bodies with heavy

consumption of alcohol and a high sugar diet, causing metabolic syndrome (5). This nutrient mix offers protection

from a multitude of free radicals in the body.”

Ultimately, the ACF228® formula was approved for use by regulatory agencies in both Sweden and Italy and then

patented in the United States.

Indeed, based on these criteria, Dr. Lippman could rest easy. But he isn’t resting. The energetic, youthful-looking

father of three sons and four grandchildren still goes to his lab daily. And what is this Nobel Prize nominee working on

today for the betterment of humankind tomorrow? Dr. Lippman continues his medical research at the behest of

International Antiaging Systems, focusing on improved methods of delivering important vitamins and hormones via

transdermal patches and creams. “Failure to absorb nutrients is a tremendous problem, and 80% of Americans have

problems swallowing pills and capsules,” he says (5).

“The response to ACF228® worldwide has been enormous,” says Dr. Lippman; “that it is indeed gratifying. You know,

we should all be able to live to 120 years and perhaps even beyond. We don’t because of the free radical damage

and declining repair hormones our cellular systems sustain. Our brains shrink, our arteries become hardened and our

liver function declines, mostly because of free radical pathology and damaged endocrine glands. Aging is the ultimate

disease; if ACF228, with its unique blend of natural ingredients can help people to prevent their premature onset,

then I will have lived my life knowing that it has been a success.”

References

1.       Strong, R et. al., Oct. 2008, Aging Cell, 7(5), pp. 641-650.

2.       Strong, R et. al, Jan 2013, J Gerontology, 68(1), pp. 6-16.

3.       Harman, D., Jul. 1956, J Gerontology, 11(3), pp. 298-300.

4.       Lippman, R, 1987, US Patent No. 4,695,590.

5.       Lippman, R, 1980, Experimental Gerontology, vol. 20, pp. 46-52.

5.    Lippman, R. 2009, Stay 40, Outskirts Press Inc., Boulder, Colorado.

Men are exclusively simple, when it comes to a man’s critical hormones, which build a man up,

and causes regeneration of muscles bones and some extremely crucial brain function. These all

lie in a man’s ability to make youthful blood levels of Testosterone. Always remember it is

testosterone that keeps all muscles in the body at their normal size and ability to function in a

youthful manner.

A man produces testosterone when the posterior pituitary’s release of LH which then triggers

the release of HCG which further instructs a man’s testicles to make testosterone. The other

super powerful regenerator of all cells tissues and organs is HGH human growth hormone.

These two hormones kept at youthful blood levels will stop a man from early stage Andropause.

In fact with the correct program of Antioxidants added to the protocol along with the right

energy metabolites and a man never will enter into the debilitating state of advanced

Andropause…. All medical research scientists agree low testosterone is a main cause of male

Andropause….The inability for a man to make youthful blood levels of testosterone. Interesting

that the virtually all male board of American Medical Association (the AMA) does not recognize

the validity of male Andropause….. Ego and false pride changes nothing, when you can no

longer make the 2 critical male hormones at youthful blood levels, the reality is just like female

menopause, men change….and that change leads to old age, decrepitude which is horrific, and

early death.

Testosterone is made in great abundance in young men age 13 to 30. Testosterone is the

combination on the molecular level of Cholesterol, the B vitamins and Oxygen.

However as we age past age 35 there is a large drop off in about 70% of male production of

testosterone according to the national Institute for Health (NHI) If this drop off in production of

testosterone is to severe and too quick, the heart being a muscle can quickly get too small and

not be able to be strong enough to meet cardiac blood stroke volume….the amount of blood

needed by the entire body per beat of your heart. This can lead to a very sudden electrical

storm within the heart muscle causing severe arrhythmias’ followed by death according to the

Harvard ten year medical study on the human heart…. And we are not talking about a few men

dying this way per year, the CDC estimates nearly 150,000 men die each year caused by the

above mentioned severe loss of testosterone…

All men can avoid the above described horror by taking swift action and getting a blood test

done to see what your testosterone levels are….forget about the reference range we look at

what is the OPTIMAL range for testosterone at youthful levels I keep mine at 800 to 950. Most

men over 45 will come in with blood levels of roughly 250 to 475, AAI’s team of

scientist/doctors consider that range to be dangerously low.

So if you have symptoms of:

1. Low Energy, sudden fat built up around your waistline over the last 2 years,

2. Poor sleep

3. Inability to concentrate

4. Lower sex drive

5. And irritability….you are looking at Low Testosterone

6. If you have severe loss of testosterone you could lose hair, have muscle tears, and even

bone fractures…even if you are in your late 40’s and 50’s

Once we here at AAI restore you to youthful levels of testosterone you will have these great

benefits:

1. Decrease in body fat

2. Increased Muscle tone

3. Stronger muscles and bones

4. Improved mood

5. Higher sex drive

6. Improved sleep

7. Enhanced sense of well being

8. A stronger healthier heart

9. Increased stamina for work, play, and exercise

There is another factor in young men today showing up with low testosterone. The new

generation of pesticides sprayed on crops to give a bigger yields by killing bugs, is only one

molecule different then Estrogen the prime female hormone. Here at AAI we have a protocol

for removing the entire pesticide residues in your body.

Men need certain other aspects to be exceedingly healthy:

1. Exercise

2. Supplements with Nutraceutical(pharmaceutical-grade nutritional supplements that are

prescription strength, free from all contaminants…and fully absorbed by the body

3. Stop Smoking

4. Eat more fiber from ground organic Flax, prevents intestinal cancers.

5. Minimize stress, with yoga, meditation or structured relaxation exercises 20 min. each

day

6. Limit Xenoestrogens, substances in your diet that may mimic estrogen.

7. You must get 7 to 8 hours of deep restful, uninterrupted sleep each night

8. Allow us at AAI to place you on the most accomplished hormone optimization protocol

with the correct package of energy supplements and antioxidants.

Another incredible aspect of testosterone is that it can prevent type 2 diabetes and it can help

prevent cancer of the prostate according to the current Harvard Chief of Urology. In 1938 the

then, Chief of Urology at Harvard wrote a research paper with over 22 mistakes in it…one of

which was the statement that testosterone can cause cancer. That mistake in his research is still

quoted unto this very day even though 4 years ago the most accomplished urologist in modern

times at Harvard went into the basement of the medical research building…..found the 1938

research paper, and completely demolished it as mistake riddled especially with regard to

testosterone, saying and publishing that testosterone actually prevents prostate cancer

according to all of his research.

You know… that makes so much common sense….the #1 male hormone being testosterone for

a man, would of course be designed by nature to help all aspects of the male body….which

thankfully it does !

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