Human kind is facing increasing global health challenges through aging populations in many westerncountries, and through expanding westernization of life-styles and loss of traditional ways of living andeating. In many western societies like the US, Great Britain, Australia and New Zealand, but also easternsocieties particularly China and India, chronic disease burden is on the rise. Chronic diseases andconditions—such as heart disease, stroke, cancer, type 2 diabetes, obesity, arthritis, Alzheimer’s diseaseand other dementias—are among the most common, costly, and preventable of all health problems.Modern mainstream medical practice that concentrates on using pharmaceutical and surgicalinterventions to treat or suppress symptoms of diseases or conditions often struggles to achieve healingoutcomes in patients with chronic conditions. Traditional “whole-body” healing systems, for exampleIndian Ayurvedic medicine and traditional Chinese medicine, as well as dietary and nutritionalinterventions can beused in combination with modern medicine to improve outcomes in many chronicconditions. Practicing this combined approach of integrative medicine is becoming more common, andin part is driven by demand from patients seeking more holistic treatments and better outcomes. From amodern scientific perspective there is a great need for more research into nutritional and traditionaltreatments to increase the evidence base for the effectiveness of these treatments so they willpenetrate mainstream medicine.

History of conifer bark as an ancient remedy

The bark of a tree is an outer skin that functions to protect the inner tissues from disease, invasion bypathogens and UV radiation. Part of the tree’s defense system is an abundance of phytochemicals in thebark, including many polyphenol-type compounds that upon consumption can work as antioxidants andprotect our health.

The first historic account of using conifer bark to cure human disease stems from the French explorerJacques Cartier who in May 1535 set outon his second voyage of discovery to the new “Western lands”.His ship made landfall in what is now Quebec, Canada, and he stayed there for one year. During thewinter of 1535 many of the crew of Cartier’s ships fell ill with scurvy. The local Iroquois had a traditional remedy that could cure the illness–a tea prepared from the bark and leaves of a local conifer. Despitesome reluctance of the crew to consume the beverage, a few tried it and it turned out to help. Theremedy allowed many of the crew to survive the winter and the expedition sailed home to France inMay 1536.

Discovery, development and composition of ENZOGENOL®

In the 1990s a multidisciplinary research team at The University of Canterbury in Christchurch, NewZealand, identified the barkof Pinus radiata, also known as Monterey pine or radiata pine, to be anexcellent raw material for the extraction of polyphenols, and in particular proanthocyanidins (PAC) andother flavonoids.They developed awater-based extraction methodthatdid not rely on solvents orchemicals, and delivered a high antioxidant pine bark extract in dry powder form that was namedENZOGENOL®. The production method was later patented in several countries with patent text beingavailable online from respective patent offices, for example New Zealand patent no. NZ329658, or USApatent no. US5968517.

The extraction process is a closed continuous flow system involving grinding, washing, extraction withde-ionized hot water, removal of extracted solids, cooling of the raw liquor by heat exchanger, andconcentrating raw liquor by reverse osmosis with removal of undissolved solids. Subsequent freezedrying, milling, blending, and quality control steps deliver the final extract. Only pine bark and de-ionized water are used in theprocess. Quality controls include physical, chemical, microbiological, heavymetal, herbicide and pesticide testing to ensure the final product conforms to specifications.

Compositional analyses of ENZOGENOL have shown that the extract has a very high batch to batchconsistency with approximately 84% PAC content (specifications > 80%) and 1.5% taxifolin content(specification > 1%)1 . Other polyphenols found in the extract include catechin, astringenin (=piceatannol), quercetin, and several phenolic acids. Co-extracted carbohydrates are present atapproximately 8.6%.

Safety and toxicology of ENZOGENOL®

Research of antioxidant properties

Research into the potential health benefits of ENZOGENOL started with testing the free radicalscavenging abilities using in-vitro antioxidant assays. ENZOGENOL was comparedto other well knownpolyphenol extracts and antioxidants including Pinus pinaster (maritima) bark extract, grape seed andgrape skin extracts, catechin and ascorbic acid7. Antioxidant activities were measured at different pHvalues to represent the different pH environments that these extracts would encounter within thehuman body while moving through the digestive tract and into the blood stream. Results showed thatENZOGENOL had the strongest antioxidant activity across the range of pHs. Antioxidant activities weremeasured as superoxide radical scavenging ability using NBT and WST-1 assays, and reported as IC50-values.

Antioxidant activity in ENZOGENOL was also tested using the popular and widely used Oxygen RadicalAbsorbance Capacity (ORAC) assay8. The ORAC value of ENZOGENOL was determined to be 8974 μmolTrolox Equivalents per 1 gram of extract (independently tested by Brunswick Laboratories, USA. April2004). By comparison, blueberries, which are commonly regarded to be a high antioxidant “superfood”have an ORAC value of 4669 μmol Trolox Equivalents per 100 gram of fresh fruit according to the USDAdatabase for ORAC of selected foods (Release 2). These tests confirm that ENZOGENOL pine bark extractis a concentrated source of highly active antioxidants.

In-vitro studies

Atherosclerosis is the process of hardening of arterial blood vessel walls and narrowing of the arterieswhich may eventually result in cardiovascular diseases (CVD) such as coronary thrombosis, myocardialinfarction, and stroke. Many complex steps have to occur for this progressive disease to initiate anddevelop to the stage were atherosclerotic changes of the blood vessels can be diagnosed. These stepsinvolve inflammatory mediators and the immune system, and begin with the interaction of vascularendothelial cells and circulating leukocytes. Leukocytes adhere to the inside of the inflamed vessel walland transmigrate through the endothelial cell layer into the extracellular matrix. These processes involveseveral key molecules including the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α), adhesion factors vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1(ICAM-1), and e-selectin, and the matrix-degrading metalloproteinase 9 (MMP-9) required for monocytepenetration into the vessel wall.

Polyphenol-rich plant extracts containing different types of flavonoids and proanthocyanidins have beenreported to possess various anti-inflammatory properties in different cellular and animal based tests.Kim et al9. investigated the anti-atherogenic properties of ENZOGENOL in a leukocyte endotheliuminteraction system with human umbilical vein endothelial cells (HUVEC) and human monocytic THP-1cells.

This study showed that ENZOGENOL can substantiallyreduce the expression of the adhesion moleculesICAM-1, VCAM-1, and E-selectin in TNF-α stimulated endothelial cells and greatly reduce adhesion of theTHP-1 monocytes to activated HUVEC cells. These results suggest that ENZOGENOL may reduceleukocyte adhesion in response to inflammatory signals from the endothelium. Increased expression ofPECAM-1, another adhesion molecule concentrated in the tight junctions of endothelial cells, andinduced on the surfaces of monocytes and neutrophils, was also inhibited by ENZOGENOL, as wasintegrinβ2. The study also showed that ENZOGENOL inhibited MMP-9 activity in monocytes, andmarkedly reduced their transmigration abilities. In the process of inflammation, MMP-9 plays a crucialrole for migration, extravasation, andinfiltration into surrounding tissue. Hence, ENZOGENOL may inaddition to the initial adhesion also attenuate trans-endothelial migration of leukocytes. The findings ofthis study are consistent with results from a human clinical trial discussed below inwhich ENZOGENOLwas part of a formulation that improved several cardiovascular risk factors including endothelialfunction2. Further research in this area is necessary, and it appears that ENZOGENOL would be anexcellent candidate for nutritional intervention trials in people with atherosclerosis.

Animal studies

Mouse longevity trials

The strong antioxidant properties of ENZOGENOL seen in the in-vitro assays led to further researchinvestigating possible effects on life-span in laboratory mice. The free radical theory of aging firstformulated by Harman in 195610suggests that free radicals produced internally by respiratory energyproduction and pathological disorders, and externally through environmental factors play a crucial rolein initiating and driving the aging processes in our body. Two small animal feeding trials were carried outat The University of Canterbury, Christchurch, New Zealand (previously unpublished data) to investigatewhether ENZOGENOL has an effect on lifespan. Results showed a significant increase in mean life spanof 18.4% from 84.7 weeks in the control group to 100.3 weeks in the ENZOGENOL group (p<0.05). Therewere 24 mice in each group with treatment starting at 52 weeks of age receiving either 21 mg/kgENZOGENOL in the drinkingwater or receiving water without ENZOGENOL. This increase in meanlifespan was remarkable considering that the feeding started at 52 weeks when the mice were alreadymiddle age. An earlier trial with younger mice also trended toward an increase in mean life span, butthis did not reach significance perhaps due to the low numbers of mice used in this trial (10 mice in eachof five feeding groups received 0, 1, 5, 21 and 100 mg/kg body weight of Enzogenol). Neither trial showed an increase in maximum life span. These findings suggest that ENZOGENOL may not slow therate of aging which would have resulted in increasing the maximum lifespan, but rather reduced thesusceptibility to disease leading to a greater number of mice living longer and apparently healthier lives.

Rat telomere trial

To further investigate the anti-aging properties of ENZOGENOL another animal feeding trial was carried out that analyzed telomere length in leukocytes. Telomeres are the end sequences of chromosomes in all vertebrates composed of the six nucleotides TTAGGG repeated a few hundred to several thousand times. During DNA replication in mitotic cell division the very ends of the telomeres are not replicated leading to a progressive shortening of the telomere sequence through cell divisions. This shortening is thought to contribute to cellular senescence. Hence, the length of telomeres can be used as a proxy of how well somatic cells age. In this trial three groups of Sprague Dawley rats (20 males and 18 females per group) received either 21 mg/kg bodyweight of ENZOGENOL, 9 mg/kg of vitamin C, or nothing with the drinking water. Telomere length was measured in leukocytes using a fluorescent telomere specific peptide nucleic acid hybridisation probe. Signals detected in flow cytometry analyses gave a measure of the total amount of telomeric sequence in the cellular DNA, corresponding to the length of the telomeres.

As a positive control telomeres from untreated young (3 months) and old (22 months) rats wereanalyzed and compared, results from this showed an approximately 50 % reduction in telomere lengthover this period of the animals life.

Comparing the three trial groups after nine months of treatment, the ENZOGENOL group hadsignificantly longer telomeres than both the control and the vitamin C groups. These results suggest thatENZOGENOL may help preserve telomeres, possibly indicating a slowing of the age-related telomereshorteningprocess.

Mouse diabetes trial

In 2014 a research group in Korea published initial investigations of ENZOGENOL’s antidiabetic effects ina mouse model of type-2-diabetes mellitus11. The researchers found that ENZOGENOL improveddiabetes related metabolic changes including improved glucose tolerance, reduced glycosylatedhemoglobin levels, as well as lower insulin and glucagon levels inthe blood, and improved liver lipidprofiles. In this study the diabetic mice received ENZOGENOL at 12.5, 25 and 50 mg/kg body weight,equivalent to 1, 2.1 and 4.2 mg/kg body weight in humans. Both, medium and high dose treatmentswere effective at improving glucose and lipid metabolism. In detail, ENZOGENOL medium-dosetreatment (equivalent to ≈210 mg for a 100 kg human) decreased fasting blood glucose levels by 27% at4 weeks and 20% at 6 weeks. The high dose treatment (≈420 mg for a 100 kg human) decreased fastingblood glucose levels by 37% and 41% at 4 and 6 weeks, respectively. A two hour oral glucose tolerancetest showed that ENZOGENOL significantly improved glucose clearance from the blood indicating asignificant decrease in insulin resistance. Inuntreated diabetic controls HbA1C, serum insulin andglucagon levels are elevated. ENZOGENOL at 25 and 50 mg/kg significantly reduced HbA1c by 35.2% and57.8%, serum insulin by 60.1% and 70% and glucagon levels by 46.1% and 66.8%, respectively.

Investigating parameters of lipid metabolism showed that ENZOGENOL increased activation of AMPK(AMP activated protein kinase). This liver enzyme stimulates hepatic lipid oxidation, and inhibitscholesterol and triglyceride synthesis. Reduced AMPK activity in diabetes leads to a negative liver fattyacid profile. Yet ENZOGENOL treatment was able to normalize triglycerides, total cholesterol and HDLcholesterol to non-diabetic levels in the mice. Further effects on liver enzymes included increasedamounts of glucokinase and glycogen synthase thereby improving glucose clearance from the blood, andreduced Glucose-6-Phosphatase and Phosphoenol-pyruvate-carboxykinase levels which reducedunnecessary glucose synthesis.

In conclusion, using a mouse-model of type-2-diabetesthis study showed that ENZOGENOL has potentialhypoglycaemic effects by modulating the expression of hepatic glucose-regulating enzymes, andenzymatic activity of AMPK in the liver. These potential benefits require further confirmation in clinicalstudies.

Clinical trials

An open-label pilot trial on cardiovascular and antioxidant benefits of ENZOGENOL

The first clinical study using ENZOGENOL was an open-label trial investigating cardiovascular2andantioxidant12health benefits of an established capsule product containing ENZOGENOL 120 mg andvitamin C 60 mg per capsule. Twenty-four generally healthy subjects (14 males, 10 females) agedbetween 55 to 75 years took 2 capsules twice daily for 12 weeks. Assessmentsat baseline, 6 and 12weeks included routine biochemical and hematological indices, and anthropometric, blood pressure,forearm blood flow and hemorheological measurements. Supplementation at a dosage of 480 mg/dayof ENZOGENOL and 240 mg/day vitamin C didnot result in any significant changes in biochemical orhematological indices and no adverse effects were reported supporting the safety of the treatment2.During the study there were significant decreases in mean body weight and mean percentage body fat.A significant reduction in mean systolic blood pressure was observed after 6 and 12 weeks of treatment[mean decrease = 7 mm Hg]. Diastolic blood pressure remained unchanged throughout the study. After12 weeks basal and hyperemic blood flow in forearm resistance vessels as measured byplethysmography had increased significantly by 17-20% indicating improvements in endothelialfunction. Plasma viscosity showed a small but physiologically significant decrease of 4%.

  • BP
  • Endothelial Function
  • Plasma Viscosity

To assess the antioxidant effects of the treatment oxidative damage to proteins and DNA wereanalyzed12. Protein oxidation in the blood plasma was measured using a protein carbonyl assay. DNAdamage was measured in isolated peripheral blood mononuclearcells using the comet assay. This studyshowed significant reductions in both oxidative stress markers. Protein carbonyl concentration fellsignificantly after 6 weeks by about 50%, and DNA damage was reduced significantly by about 40% after12 weeks of supplementation.

The findings of this pilot study indicated that dietary supplementation with ENZOGENOL and vitamin C issafe and well tolerated and may be associated with a number of beneficial effects on a range ofestablished cardiovascular risk factors2and oxidative stress markers12. Randomized controlled trials arerequired to verify these findings.

A RCT on cardiovascular and antioxidant benefits of ENZOGENOL in Smokers

Young et al.3investigated the effects of ENZOGENOL on cardiovascular, inflammatory and oxidativestress markers in a RCT in chronic smokers, as smoking has been shown to increase systemicinflammation and oxidative stress in the body. Forty-four chronic smokers without cardiovascularsymptoms received either 480 mg ENZOGENOL and 60 mgvitamin C, or 60 mg vitamin C alone daily for12 weeks. Endothelial function in the brachial artery was assessed as flow-mediated vasodilation (FMD)using ultrasound measurements. FMD improved in both treatment groups with the ENZOGENOL groupshowing greater improvement after 12 weeks compared to the vitamin C only controls. However, thedifference between the two groups did not reach statistical significance. Hence, a trial in individuals withestablished atherosclerosis or CVD comparing ENZOGENOL alone to placebo is recommended. However,there was a significant improvement in oxidative stress. Protein carbonyl content in the blood plasmawas reduced by 35 % after 12 weeks in the ENZOGENOL group, whereas vitamin C alone had no effecton protein oxidation.This finding confirmed the results obtained by Senthilmohan12 in the previousopen-label pilot trial. Another interesting finding was the significant reduction of fibrinogen levels in thesub-group of heavy smokers. Smokers with a long history of smoking or particularly heavy cigaretteconsumption had higher fibrinogen levels compared to lighter smoking subjects. In the heavy smokersthe ENZOGENOL formulation reduced fibrinogen levels down to the level found in the lighter smokingindividuals, whereas vitamin C alone did not show this effect. Elevated fibrinogen levels in the plasmacan signal inflammation, hence this reduction may indicate an anti-inflammatory action of theENZOGENOL formula.

A RCT on brain function benefits of ENZOGENOL in older men

Age-related cognitive decline, including mild cognitive impairment and dementias, are of great concernto many people and may become a major socioeconomic challenge for many countries with agingpopulations. Life-style choices including quality of diet and nutrition are important determinants of ourindividual capacity to maintain optimal brain health and function as we age. Dietary intake of flavonoidantioxidants has been shown in a prospective cohort study to be inversely correlated with cognitivedecline13. In this study 1640 subjects aged 65 and older without dementia were followed for 10 yearswith regular psychometric and reliable dietary assessments. Individuals with higher flavonoid intake,comparing the two highest quartiles to the lowest quartile, showed lesser cognitive decline over 10years. After 10 years, participants with the lowest flavonoid intake showed twice the decline in cognitivefunction assessed by the MiniMental State Examination compared to those with the highest quartileflavonoid intake, losing 2.1 versus 1.2 points on the MMSE scale.

Our brain has the propensity to suffer oxidative damage given its particular biochemical characteristics.One, the brain uses the greatest amount of oxygen in the body being solely dependent on glycolytic energy production; two, it is especially rich in peroxidizable fatty acids; and three, brain tissue has a highcontent of both Fe and ascorbate, key ingredients in causing membrane lipid peroxidation.

Given the brain’s susceptibility to oxidative damage andthe fact that increased dietary flavonoid intakeis associated with better cognitive function as we age, an intervention with a flavonoidbased antioxidantproduct may have potential to reduce cognitive decline or improve cognitive functioning. With thispremise researchers Pipingas and Silberstein at the Brain Sciences Institute of Swinburne University inMelbourne, Australia set out to test ENZOGENOL’s effects on brain function in individuals that are at riskof cognitive decline with age due to their negative cardiovascular risk profile4 . Hence, this RCT recruited42 overweight males (BMI>25) that were 50-65 years old, had a sedentary occupation and did notexercise regularly. Eleven participants were taking anti-hypertensive medications. The treatment group(n=22) received a daily dose of 960 mg ENZOGENOL and 120 mg vitamin C, whereas the control group(n=20) received 120 mg vitamin C only. Cognitive performance on verified computer-based cognitivetests, coherence analyses of brain electrical measurements, blood pressure and standard hematologicalsafety parameters were assessed before and after 5 weeks of treatment. The study hypotheses was thatperformance on cognitive tasks that are most sensitive to age-related cognitive impairment mayimprove with the treatment containing ENZOGENOL. Primary outcome measures were performance onspatial working memory (SWM) and immediate recognition memory (IRM) tasks as these have beenshown to be the most sensitive measures of age-related cognitive decline.

Study results showed that there were significant improvements in response times (RT) on SWM and IRMtasks in the ENZOGENOL group, butno improvements in the controls.SWM RT improved by 64 ms(6.4%) and IRM RT by 60ms (5.4%). These improvements can be put into clinical perspective on the basisof normal age-related decline. RT on the SWM task slows down with age from an average of about700ms for a 20 year old to approximately 1300 ms for a 90 year old. Roughly, this amounts to a declinein reaction time of 8.6 ms per year. The improvement seen with ENZOGENOL on the SWM task of 64 msafter only 5 weeks was therefore equivalent to 7.4 yearsrecovery in brain performance. Theimprovement in RT of 60ms on the IRM task was equivalent to 12 years of brain age recovery. Inotherwords, there is a possibility that a 60 year old person may improve their speed of memory to that of a48-52 year old person. This could obviously have considerable benefits for things like ability to safelyoperate a car or for performance in the work place and so on.

Blood pressure analyses showed a significant reduction in systolic blood pressure of 5mm Hg in theENZOGENOL group and no change in the controls. There were no changes in diastolic blood pressure.The positive safety results from thisstudy were discussed above in the safety and toxicology section.

To investigate whether ENZOGENOL may influence brain activities directly the study also examinedeffects on brain functional connectivity during the performance of a recognition memory task14.Functional connectivity is a term that describes how different brain regions interact or interfere witheach other. The hypothesis was that the ENZOGENOL formula would improve functional connectivity byreducing cortical coupling between certain neural regions. In this test, a constant 50Hz light flicker isprojected onto the retina which results in a constant EEG signal that was detected over 64 electrodesacross the scalp referred to as Steady-state visually evoked potential (SSVEP). This signal is influenced and modified by the brains own electrical activities during the task performance. Measuring this signalover the course of the task allows for calculation of event-related partial coherence (ERPC) which is ameasure of functional connections betweenbrain regions. These functional connections are referred toas cortical coupling. One could think of this as more coupling equates to more noise across the brain andless coupling indicates less noise.
Studies by Silberstein have shown that reduced long-range cortical coupling between frontal andposterior sites are a prominent feature of increased individual proficiency on this task. Other brainactive drugs like an acute dose methylphenidate, used as a medication for ADHD and as a brain functionenhancer, cause a robust reduction in long range cortical coupling associated with improved taskperformance15.
SSVEP-ERPC measures were calculated and compared before and after supplementation for eachgroup. Supplementation with the ENZOGENOL formula, but notvitamin C, was associated with a frontalto posterior decrease in SSVEP-ERPC that is characteristic for correct responses in this task. This findingwas similar to the effects seen with methylphenidate in ADHD and indicate that ENZOGENOL mayenhance brainmechanisms mediating memory processes.

Effects of an ENZOGENOL vitamin antioxidant formula on patients with severe migraine

Two open-label trials have investigated the use of ENZOGENOL antioxidant formulas in migraineprevention16,17. These studies were carried out in an outpatient clinic setting by Dr.Chayasirisobhon,Department of Neurology, Kaiser Permanente Medical Center, Anaheim, CA. In the first trial, twelvepatients with a long-term history of migraines with and without aura were enrolled16. All patients hadfailed to respond to multiple treatments with β-blockers, antidepressants, anticonvulsants, and 5-hydroxytryptamine receptor agonists. They received a once daily oral dose of 1200 mg ENZOGENOL, 600mg vitamin C, and 300 IU vitamin E for the duration of 3 months in addition to any pharmacologicalmedication. At baseline, before beginning the antioxidant treatment, patients completed a migrainedisability assessment (MIDAS) questionnaire which gives a measure of migraine impact on work, school,domestic, and social activities over the previous 3 months. After the 3 month treatment patientscompleted the MIDAS questionnaire again.

The study results showed a highly significant mean improvement in MIDAS score of 50.6% for the 3month treatment periodcompared with the 3 months prior to baseline. Patients also experienced asignificant reduction in the number of days they suffered a migraine attack, and the severity of themigraine headaches that did occur was significantly reduced. The mean number of headache days fellfrom 44.4 days during the previous 3 months to 26.0 days during the 3 month therapy. The meanheadache severity score was reduced from 7.5 out of 10 to 5.5 out of 10. These results suggested thatthe antioxidant therapy combining high dose ENZOGENOL with vitamins C and E as used in this studymay be beneficial as a migraine preventative treatment, and possibly reduce headache frequency andseverity.

In the second study, Dr Chayasirisobhon used the commercially available antioxidant formulacalledENZO Professional giving five capsules once daily for three months with some patients continuing treatment for 12 months17. With this formula patients received the same amount of ENZOGENOL with1200 mg, but much less vitamin C reduced from 600 mg to only 150 mg, and no vitamin E. This againwas an open-label uncontrolled study. Fifty five outpatients with chronic migraine that had failed torespond to at least two prophylactic pharmaceutical medications were enrolled. Five patients droppedout earlyin the study and were not analyzed. Among the 50 patients completing the 3 month treatmentthere were 44 women and 6 men aged 14 to 68 years, average age 41.6. Patients exhibited variousdifferent headache presentations including right or left sides or bilateral, and frontal, parietal, ortemporal, or diffuse, with and without aura. The age of onset varied widely from 6 to 57 (mean 23.3)years; headache frequency varied from 2 to 30 (mean 15.7) per month and duration varied from 0.25 to4 days (mean 1.4 days). As in the previous study, patients completed the MIDAS questionnaire at thebeginning and end of the study to compare migraine impact over the three months prior to enrollmentwith the three month treatment period. Patients continued on existing pharmacologic medicationsduring the study.

Twenty-nine patients (58.0%) demonstrated a reduction in MIDAS score, and reduced number ofheadache days and headache severity. It took on average 25 days for the headache relief to be noticed,ranging from 3 days to80 days.

Patients were graded according to their MIDAS scores indicating the overall level of disability: grade I,little or no disability (score of 0–5); grade II, mild disability (score of 6–10); grade III, moderate disability(score of 11–20); and grade IV, severe disability (score of ≥ 21). After 3 month of treatment 19 patientshad no change in their disability grade, whereas 31 patients were downgraded.The mean MIDAS scorefor all patients was significantly reduced from 30.3 to 14.4; a mean improvement of 52.3%. The averagenumber of headache days for the 3 months before treatment for all patients was 47.9 days, and thisreduced significantly during the 3 month treatment period to 25.9 days. Headache severity over thesame periods was reduced from anaverage score of 8.1 to 5.6 out of 10. When looking at the patientsthat had responded to the treatment, the results were even more impressive with average reductions inMIDAS score by 25.8 points (91%), number of days with headaches down by 39.7 (82%), and headacheseverity down by 4.1 points (51%).

In conclusion, both of these open-label trials have shown great promise for the use of ENZOGENOL withvitamin C in the treatment of migraine. A well designed controlled clinical study is now needed toconfirmthese findings and allow ENZOGENOL to be accepted as a general medical treatment formigraine.

Effects of ENZOGENOL on brain function in patients with mild traumatic brain injury

Analyses of CFQ scores showed a significant reduction in cognitive failures with ENZOGENOL versusplacebo after 6 weeks [mean CFQ score-6.9 (95% confidence interval-10.8 to-4.1)].The reduction incognitive failures continued over the 12 weeks of treatment, and stayed at their reduced level at theend of the 4 week wash-out period. Other outcome measures also showed positive trends but did notreach statistical significance, among these were anxiety and depression often associated with TBI. Morepatients in the ENZOGENOL group showed improvements on the Hospital Anxiety and Depression Scale(HADS) compared to the placebo group.

Effects of ENZOGENOL on brain function in student-athletes with concussion history

Doctor Slobounov at Penn State Center for Sport Concussion, Pennsylvania State University, tested thefeasibility of dietary supplementation with 1000 mg ENZOGENOL daily as a treatment modality incollege-age athletes with a history of sports-related concussions6 . The participants were in a chronicphase of concussion, with 6 to 36 months post-injury and still experiencing residual symptoms thatimpacted their ability to study and perform in training. Twenty male and 22 female student-athletes, 18-24 years old, were enrolled. Equal numbers of participants were randomly assigned to receiveENZOGENOL as 2 x 500 mg capsules taken approximately 15 minutes before breakfast or identicallooking placebo capsules. The students underwent two testing sessions at baseline and after 6 weeks oftreatment. Brain activities were measured by electroencephalography (EEG) during neuropsychologicaltasks used to induce cognitive challenges.

The EEG analyses revealed that after six weeks of treatment,the ENZOGENOL group showed enhancedfrontal-midline theta, and decreased parietal theta power during the brain loading with thepsychological tests. These findings indicated reduced mental fatigue when performing the brain  challenging tasks. In contrast to the controls, the student-athletes receiving ENZOGENOL also reportedexperiencing lesser mental fatigue and reduced sleep problems. This suggested that ENZOGENOL canreduce brain fatigue during cognitive loading and has the potential to improve brain functioning in thechronic phase of concussion.

Effects of ENZOGENOL on cerebral circulation in a patient with history of concussions

In an attempt to elucidate mechanism of action a feasibility study was undertaken to see if ENZOGENOLcould impact blood circulation in the brain in an individual that had suffered several sports-relatedconcussions over previous years. The participant was a 47 year old, right handed male, practicing martialarts for 25 years. During this time he had experienced several hits tothe head, sometimes severe. In2012, three years before this experimental study, he was hit in the middle of his face leading to severenose bleed and some headaches. In a second incident 10 days later he experienced another blow to theback of his head and neck. In the following months he experienced severe headaches, fatigue whilelooking at screens, mental fatigue, and greatly reduced mental stamina. Those symptoms slowlyimproved over several months before becoming asymptomatic.

To investigate the impact the concussive injuries had, and the potential effect ENZOGENOL may have onbrain perfusion, the individual underwent two high-resolution brain SPECT (Single Photon EmissionComputed Tomography) imaging scans at CereScan in Denver, Colorado. The two scans were performedunder equal conditions 48 hours apart at 9 am on day 1 and day 3 of the experiment. The individual hadrefrained from taking any medications or supplements for two weeks prior to the first scan. This firstscan on day 1 established the baseline brain perfusion pattern. Immediately following the scan on day 1the individual took the first dose of 1000 mg ENZOGENOL, a second dose on the morning of day 2 and athird dose on day 3 exactly one hour before the second scan. This second scan established the impact of3 doses of ENZOGENOL on brain perfusion.

Analyses showed the high-resolution brain SPECT images at baseline and after treatment were of goodquality. No abnormal motion or artifact was detected. The overall cortical activity was withinnormallimits to slightly reduced. At baseline, focal areas of abnormal cortical hypoperfusion were noted infrontal, temporal, occipital and cerebellar lobes. Focal areas of abnormal subcortical hypoperfusionwere noted in the bilateral lentiform and right caudate areas. Talairach comparisons of the baseline datato an age-match normal sample, as well as the 3D/isocontour and surface-rendered images, revealedhypoperfusion abnormalities consistent with those seen on the tomographic images. The nature,location, and pattern of these abnormalities was primarily consistent with the scientific literaturepertaining to traumatic brain injury and the individuals’ history of repeated concussive injury.

In the second scan a generalized cortical activation was noted after the ENZOGENOL treatment, andTalairaich comparison of baseline and post-treatment scans showed increases in cortical activity withthe intervention. Table 1 shows the increases in blood circulation to those regions that were foundhypoperfused in the baseline scan.

Another interesting finding was a small reduction in perfusion of the left and right amygdala ofapproximately-4% post treatment. This reduction in activity appears unusual given that the treatment led to a generalized activation acrossthe brain averaging +11%. This is particularly interesting in view ofthe function of the amygdala in behavior traits and neuropsychological disorders including anxiety anddepression. Reduced activity of the amygdala following ENZOGENOL treatment would beconsistentwith the trend of reduced anxiety and depression seen previously in the study of mTBI patients.

In summary, clinical research has shown that ENZOGENOL improves brain functions that ordinarilydecline with age, assists in recovery of brain functions after concussion/TBI, may be used as a migrainepreventative, supports cardiovascular health and reduces oxidative stress.


Research has demonstrated that ENZOGENOL is very safe and well tolerated. No serious adverse eventshave surfaced inany clinical study or during the 18 years it has been in the market as a dietarysupplement. The excellent safety profile qualifies ENZOGENOL for use as a natural support agent in anyof the applications it has been studied in. The body of research to dateshows ENZOGENOL has greatpotential as a natural neurotherapeutic with applications in brain injury rehabilitation, migraineprevention, and as a nootropic that may be used in prevention or treatment of cognitive decline withage. Other applications include the use as a support agent for maintenance of cardiovascular, oxidativeand metabolic health. Further research is necessary to promote ENZOGENOL for use in all of these areasand to fully penetrate mainstream medical practice.


1. Frevel, M.2012. Production, composition and toxicology studies of Enzogenol Pinus radiata bark extract. Food and ChemicalToxicology 50:4316–24

2. Shand, B. 2003. Pilot Study on the Clinical Effects of Dietary Supplementation With Enzogenol®, A Flavonoid Extract ofPineBark and Vitamin C. Phytotherapy Research 17:490-94

3. Young, J. 2006. Comparative effects of enzogenol and vitamin C supplementation versus vitamin C alone on endothelialfunction and biochemical markers of oxidative stress and inflammation in chronic smokers. Free Radical Research 40:85-94

4. Pipingas, A. 2008. Improved Cognitive Performance after Dietary Supplementation with a Pinus radiata Bark ExtractFormulation. Phytotherapy Research 22:1168-74

5. Theadom, A. 2013, Enzogenol for cognitive functioning in traumatic brain injury: a pilot placebo-controlled RCT. EuropeanJournal of Neurology 20:1135-44

6. Walter, A. 2017. Effect of Enzogenol® Supplementation on Cognitive, Executive, and Vestibular/Balance Functioning inChronic Phase of Concussion. Developmental Neuropsychology 42:93-103

7. Wood, J. 2002. Antioxidant activity of procyanidin-containing plant extracts at different pHs. Food Chemistry 77:155-161

8. Ou, B. 2001. Development and validation of an improved oxygen radical absorbance capacity assay using fluorescein as thefluorescent probe. Journal of Agricultural and Food Chemistry 49:4619-26

9. Kim, D. 2010. Pine Bark Extract Enzogenol Attenuated Tumor Necrosis Factor-r-Induced Endothelial Cell Adhesion andMonocyte Transmigration. Journal of Agricultural and Food Chemistry 58: 7088-95

10. Harman, D. 1956. Aging: a theory based on free radical and radiation chemistry. Journal of Gerontology 11:298–300

11. Bang, C-Y. 2014. Enzogenol improves diabetes-related metabolic change in C57BL/KsJdb/db mice, a model of type 2diabetes mellitus. The Journal of Pharmacy and Pharmacology 66: 875-85

12. Senthilmohan, S. 2003. Effects of flavonoid extract Enzogenol® with vitamin C on protein oxidation and DNA damage inolder human subjects. Nutrition Research 23: 1199–1210 13

13.Letenneur, L. 2007. Flavonoid Intake and Cognitive Decline over a 10-Year Period. American Journal of Epidemiology165:1364-71

14. Pipingas and Silberstein. 2007. Effects of flavonoids on brain functional connectivity during a recognition memory task.Journal of Clinical EEG & Neuroscience. 16th Annual Conference of the Australasian Society for Psychophysiology.

15. Silberstein, R. 2005. Effects of methylphenidate on cortical connectivity during an attention task in children diagnosed withattention deficit hyperactivity disorder (ADHD). Australian Journal of Psychology 57: p36

16. Chayasirisobhon, S. 2006. Use of a Pine Bark Extract and Antioxidant Vitamin Combination Product as Therapy for Migrainein Patients Refractory to Pharmacologic Medication. Headache 46:788-93

17. Chayasirisobhon, S. 2013. Efficacy of Pinus radiata bark extract and vitamin C combination product as a prophylactictherapyfor recalcitrant migraine and long-term results. Acta Neurologica Taiwanica 22:13-21.