ACUITOL® turned around my life

I'm 71. The last 10 years have been all down hill for me. Things went south when I started to forget names and faces. It wasn't that bad at first, but it got worse. Then my friends would tell me that I was repeating myself. That made me really self conscious which made it harder for me to hold a conversation because I was so worried that I'd stumble or repeat myself. One thing led to another. Eventually I felt like I was annoying people so I avoided being around them. Luckily my neighbor gave me a copy of From Darkness Into Light. I ordered ACUITOL® immediately. It turned around my life! The most important thing ACUITOL® did was give me back my confidence. Yes my memory got much better, so did my focus and understanding. But take it from me, once your start to see any improvement your confidence skyrockets. I realized that my worst enemy was myself. I just stoped listening to the negative voice in my head and started living again.

Stanley M.
Cedar Rapids, IA

I can run circles around the hot shots!

I have zero issues with mental acuity. I'm 42 and my recall, focus and concentration are great. I ordered ACUITOL® because I thought it might give me an edge. It did in spades. I am a coder and now no one in my office can keep up with me. No one and that includes the young hot shots. I can run circles around them! The coolest part is ACUITOL® doesn't feel like and energy shot or any other super caffeinated drink. It's different. The best word I can think of to describe its effects is clarity, massive clarity.

Reed S.
Los Angeles, CA

I got my mom back!

My mother is 84 years old and lives with me. She's definitely all there but for the last few years she's slowed down. Hardly talks at all. The one thing my mom liked to do the most was play canasta. That stopped 2 years ago. My mom and I have been loyal customers of IMMUNOCORP® for twenty years so when I received your new book I ordered ACUITOL®. I figured if it worked as well as your other products I should try it on mom. For the first week I didn't notice much, maybe she was a little more talkative but not much. The next week the miracle happened. One night she suddenly asked me to play canasta. I was shocked. Not only did we play, she beat the living day lights out of me. Now we play almost every night. ACUITOL® gave me my mom back. The only down side, she never stops talking. lol. BTW I take ACUITOL® now. I need all the help I can get to beat mom.

Sally B.
Salt Lake City, UT

Polygala tenuifolia (Yuan Zhi): is an herb used in traditional Chinese medicine (TCM) for its calming effects and cognitive benefits. The triterpenoid saponin in Polygala improves hippocampus-dependent learning and memory, possibly through improvement of synaptic transmission, activation of the MAP kinase cascade and enhancement of levels of brain derived nerve growth factor (BDNF) (Xue, 2009). Human subjects using Polygala had increases in immediate memory recall and recognition ability (Lee, 2009). Some users have found it mentally stimulating while being calming.

Acorus gramineus: is used in TCM for improving “intelligence”. It has neuroprotective and cognitive benefits according to scientific research. This is based on mostly on its content of alpha asarone content. Acorus gramineus has been shown in studies to improve central nervous system disorders. α-asarone dose-dependently inhibits acetylcholinesterase activity and improves acetylcholine levels (Qiu, 2016). These effects reduce hyperactivity, a problem which is often found in ADHD. Yet from the β-asarone, the herb has antidepressant effects which may help to stimulate brain activity in a beneficial manner (Sun, 2015). In the modern world one is constantly exposed to toxins in food and the environment that can increase brain inflammation resulting in brain fog, mental fatigue, and difficulty in concentrating. α-asarone reduces microglia- mediated neuroinflammation, an effect which improves brain function (Kim, 2015).

Notoginseng (Panax Notoginseng): Besides supporting blood vessel health and healthy blood flow, panax notoginseng root also shields the brain from damage made by oxidative stress in neurological illnesses. Overall, panax notoginseng is shown to have a function of anti-brain aging as the main ingredients help prevent cell senescence-associated diseases.6 As more studies are being completed, it is becoming increasingly apparent that ginsenosides yield neuroprotective effects by reducing free radical production and improving brain function.

Clubmoss (she zu shi shan): contains an alkaloid known as huperzine A that has brain health and memory benefits. Huperzine A has impressive bioactivity from several pathways related to brain cell function and health. It works by increasing the levels of the neurotransmitter acetylcholine in the brain by inhibiting the enzyme acetylcholinesterase that normally breaks it down. It also increases the levels of norepinephrine and dopamine to the same extent (Du, 2017; Zhu, 1995). A large number of human clinical studies have shown that huperzine A can significantly improve the memory, cognitive skills, and daily life abilities in people with Alzhiemer’s disease without severe side effects.

Huperzine A: is also used in treating memory impairment in vascular dementia patients, schizophrenia, and insomnia. It has beneficial effects in brain mitochondrial dysfunction caused by decreased oxygen and blood levels and antagonizes NMDA receptors for neuroprotection. In addition, huperzine A enhances the expression and secretion of nerve growth factor, has an anti-inflammatory effect, and reduces production of reactive oxygen species (ROS) while increasing enzymes in the cell respiratory chain and the Krebs cycle (Zhang, 2012). Huperzine A has the ability to protect cells against hydrogen peroxide cell damage, beta-amyloid protein (or peptide), glutamate, ischemia, cytotoxicity and apoptosis.

Ginkgo biloba: has long been considered a memory herb. In mild cognitive impairment, a stage between normal aging and dementia, Ginkgo extract given for 6-months and 12-months of treatment to 58 patients with this diagnosis had improvement of their mental quotient by 50% compared to the control group who improved by only 27.27%. This included recognition, regeneration, understanding, and recitation tests (Yu, 2014). Ginkgo biloba extract has anti- inflammation and antioxidant effects and appears to have a neuroprotective effect against neurodegenerative diseases. Another study of Ginkgo biloba, related to improving episodic memory of mild cognitive impairment in patients 60 to 85 years old, found that 55.17% of the subjects had improved picture recognition, compared to only 32.73% in the control group. Logical memory improved in 58.62% of the Ginkgo group compared to 38.18% in the controls (Zhao, 2012).

Red Sage (Salvia miltiorrhiza): Red Sage root has multiple neuroprotective effects such as anti-beta amyloid, antioxidant, anti- apoptosis, acetylcholinesterase inhibition, and anti-inflammation. It promotes neurogenesis of neural progenitor cells/stem cells in vitro and in vivo (Zhang, 2016). A study compared it to huperzine A as a positive control and found it to improve long-term memory of rats through a potent inhibition of acetylcholinesterase in the frontal cortex (Ozarowski, 2017). Total tanshinones, tanshinone I and dihydrotanshinone I have a remarkable inhibitory effect on acetylcholinesterase thereby increasing acetylcholine activity (Zhou, 2011). Salvia also improves microcirculation to enhance delivery of oxygen and nutrients throughout the brain.

Pueraria: promotes a significant increase in the numbers and maturation of dendritic connections in brain cells, potentiates synaptic transmission, enhances NMDA receptor-mediated postsynaptic currents involved in new memory formation, and induces synaptic plasticity in learning (Bhuiyan, 2017). Puerarin plays a morphological and functional role in the maturation of brain neurons and helps with memory-related issues (Wang, 2018).

Lovage (Ligusticum chuanxiong): helps improve microcirculation throughout the body, including the brain to optimize its function. Tetramethylpyrazine (TMP) originally isolated from lovage promotes the migration of neural progenitor/precursor cells (NPCs) in the brain (Kong, 2016). In addition, TMP actually promotes stem cell proliferation and differentiation into new neurons (Tian, 2010). Stem cells and neurogenesis help to rejuvenate the brain to help it functions better.

Rhodiola rosea: Rhodiola species acts as a psychostimulant that increases mental work capacity during stress, and facilitates learning based on emotionally positive reinforcement. Overall, in small and medium doses, R. rosea stimulates norepinephrine (NE), dopamine (DA), serotonin (5-HT), and has nicotinergic-cholinergic effects in the central nervous system (CNS). It enhances the effects of these neurotransmitters on the brain by increasing the permeability of the blood brain barrier to precursors of dopamine and serotonin. Rhodiola may prevent or ameliorate some types of age-related dysfunction in neurons. Rhodiola crenulata extract, a related species of rhodiola, was shown to promote neurogenesis in the hippocampus of depressive rats by its main ingredient salidroside, which scavenged intracellular reactive oxygen species (Qu, 2012).

Rosemary: has long been reputed in Europe to be good for memory since medieval times when it was used for this purpose. An extract given to 68 students was found to significantly improve prospective and retrospective memory performance, depression, anxiety and sleep quality (Nematolahi, 2017). Rosemary extract containing carnosic acid and rosmarinic acid improved memory acquisition and retention in mice undergoing the T-maze foot shock, object recognition and lever press tests. A marker of free radicals from lipid peroxides, 4-hydroxynonenal (HNE), was reduced in the brain cortex and protein carbonyls were reduced in the hippocampus as well (Farr, 2016). The extract inhibited the acetylcholinesterase activity in parts of the rat brain to improve long-term memory in rats (Ozarowksi, 2013). Twenty-eight older adults (mean age, 75 years) were tested for speed of memory at 500 mg and 750 mg doses and had a statistically significant beneficial effect compared with the placebo (Pengelly, 2012).

Lion's Mane Mushroom (Hericium erinaceus): has recent studies demonstrating its role in supporting memory associated with mild cognitive decline in elderly subjects, and has been used for promoting healthy mood and relaxation in menopausal subjects. Prior research has shown that diterpene compounds in Lion’s Mane known as hericenones and erinacines have the ability to stimulate the synthesis of Nerve Growth Factor (NGF), which as its name suggests promote nerve or brain cell outgrowth which may facilitate improved cognitive function and memory.

Fo Ti (Polygonum multiflorum): In TCM, He Shou Wu, is a long-revered antiaging tonic herb in China that contains abundant levels of a stilbene compound TSG (tetrahydroxystilbene glycoside), chemically similar in composition and bioactivity to resveratrol, yet has profoundly different regenerative and antiaging effects. TSG has several brain health properties including powerful neuroprotective effects by stimulating the formation of new brain cells through hippocampal brain-derived neurotrophic factor (BDNF), improving nerve cell signaling pathways, and reducing depressive-like symptoms (Wang, 2017). TSG has strong bioactive effects for the brain including anti-inflammatory, anti-oxidant, and promoting cell survival. Chronic administration of TSG promotes improved hippocampal memory in normal mice, suggesting that supplementation of TSG might enhance memory also in humans (Chen, 2016). TSG induces astroglia-derived neurotrophic growth factors release (Lin, 2016). TSG also facilitates the high-frequency stimulation of hippocampus long-term potentiation (LTP) and enhances learning and memory in animal models (Wang, 2011).

Schisandra (Schisandra chinensis): Schisandra has antioxidant effects and is an adaptogen, nervine tonic, and mild antidepressant useful for improving mental and physical performance, endurance, and adaptation to stress. (Bone, 2003:405; Braun & Cohen, 2005:327). Gomisin A is a component of the fruits of Schisandra chinensis that significantly reverses scopolamine-induced cognitive impairments and inhibits acetylcholinesterase activity in a dose-dependent manner (Kim, 2012). The compound Schizandrin found in Schisandra reverses scopolamine-induced memory impairment, in part, by enhancing cholinergic function, an effect theoretically useful for treating memory deficits (Egashira, 2007)

Rehmannia glutinosa (Shu Di Huang): Prepared (or cooked) Rehmannia glutinosa, also known as Shu Di Huang, is an important liver-kidney tonic that not only nourishes blood and yin, but also reinforces essence and marrow. In TCM, the essence and blood are the most fundamental material basis of the body. Rehmannia, as a traditional herb, has a long history in age-related disease therapy. Catalpol, an iridoid glycoside isolated from the fresh rehmannia roots has positive effects on the behavior and brain energy metabolism of senescent mice by improving cognitive deficits and reversing the biochemical markers in energy metabolism failure in aging model mice (Wang, 2008). Catalpol ameliorates beta amyloid-induced degeneration of cholinergic neurons by elevating brain-derived neurotrophic factors (Wang, 2009). Catalpol as the main active ingredient increases presynaptic proteins and up-regulates signaling molecules in the hippocampus of aged rats (Liu, 2006).

Green Tea: Green Tea was tested in a study and found to produce increases in theta brain waves between 30 minutes and 1 hour post-consumption which is an indication of its influence on cognitive function, specifically alertness and attention. (Okello, 2016). Another study used functional magnetic resonance imaging while 12 healthy volunteers performed a working memory task following administration of 250 or 500 ml of a milk whey based green tea containing soft drink or milk whey based soft drink without green tea as control. Green tea extract increased activation in the dorsolateral prefrontal cortex, a key area that mediates working memory processing in the human brain. This neural effect was related to the green tea dosage (Borgwardt, 2012).

Sichuan Pepper (Zanthoxylum spp): Sichuan Pepper Oil is derived from the plant species Zanthoxylum spp. of the Citrus family and its bark, seeds and fruits have a long history as sources of medicinal treatments. This is particularly prevalent in Chinese, Nepalese and Ayurvedic medical systems with indications including treatment for depression, gastro-intestinal and digestive disorders and as a topical treatments for toothache and skin irritation/wounds. Zanthoxylum genus generically known as Sichuan (or Szechuan pepper) is a traditional Chinese and Nepalese culinary spice comprising the fruit pericarp which is typically added to wok and dumpling dishes to provide a characteristic grapefruit-like taste and flavor and a tingling numbness in the mouth. Zanthoxylum spp is rich in monoterpenes such as hydroxy-sanshool. Mechanistic interactions with the monoamine, cholinergic and cannabinoid neurotransmission systems, as well as transient receptor potential (TRP) and potassium ion channels, may predispose ZA to modulate human brain function. A single dose and 56-days supplementation with a lipid extract of ZA was tested on cognitive function, mood and cerebral blood-flow (CBF) parameters in the pre-frontal cortex during cognitive task performance. In a double-blind, randomized, parallel groups study with N = 82 healthy males and females between the ages of 30 and 55 years, 80 mg of the oil was given for 56 days. A single dose of ZA on day 1 resulted in acute improvements on a ‘Speed of Attention’ factor and the Rapid Visual Information Processing (RVIP) task, in comparison to placebo. After 56 days of ZA consumption (Day 56), speed was enhanced on a global ‘Speed of Performance’ measure, comprising data from all of the timed tasks in the computerized battery. Participants also completed more correct Serial 3s Subtractions at the 3 h assessment and were less mentally fatigued throughout (Kennedy, 2019).

Celastrus seed (Celastrus paniculata): Celastrus paniculata oil has a longstanding historic background for human medicinal use in India. It grows throughout India, and has therapeutic value for the treatment of cognitive dysfunction, epilepsy, insomnia, rheumatism, gout, dyspepsia.[14] Oil from the seeds (called as Jyothismati oil), which contains the alkaloids celastrine and paniculatin in varying amounts. Externally, the seed oil is used for massage with great benefit, especially in vata diseases like sciatica, lumbago, paralysis, arthritis and facial palsy. This has been in use in indigenous medicinal systems for centuries with known brain stimulating and antioxidant effects. An aqueous extract of Celastrus paniculatus seed has dose-dependent cholinergic activity, thereby improving memory performance. The mechanism by which Celastrus paniculatus enhances cognition may be due to increased acetylcholine level in rat brain (Lehka, 2010).

Celastrus paniculatus seed oil produced significant antidepressant-like effect in mice possibly through interaction with dopamine D2, serotonergic, and GABAB receptors; as well as inhibition of MAO-A activity and decrease in plasma corticosterone levels. Stressed rats showed enhanced anxiety-like behavior in EPM (P < 0.001) and impaired performance in RAM (P < 0.001) and T-maze tasks (P < 0.001) compared to normal animals. In contrast, CP oil treatment to these rats improved their performance in both RAM (P < 0.001) and T-maze (P < 0.001). In addition, CP oil significantly reduced stress-induced anxiety behavior (P < 0.001).

Chronic treatment with CP oil is to improve cognitive abilities in chronically stressed rats. A study provides a novel perspective on beneficial effect of herbal therapy on stress-induced cognitive dysfunctions. C. paniculatus is a rich source of several secondary metabolites, such as β-Dihydroagarofuranoids sesquiterpenes, alkaloids (Celastrine, Celapanin, Celapagin, and paniculatin), flavonoids, terpenoid (β-amyrin, Lupeol, Pristimerin), sterols (β-sitosterol, campesterol, stigmasterol, α-tocopherol, γ-Tocopherol), fatty acid (palmitic, stearic, oleic, linoleic, linolenic acids) and non-fatty acids (Benzoic acid, Cinnamic acid). Various studies show that the extracts and active constituent of this plant possess potent nootropic activity. Besides nootropic activity, it has also been reported for anti-Alzheimer, anticonvulsant, antidepressant, antioxidant, analgesic, anti-inflammatory (Aleem, 2021).

Celastrus seed oil extract's efficacy was tested against immobilization stress in albino mice. The animals were kept in a restrainer for short and long durations, grouped separately and fed with the drug. Animals were sacrificed and the samples were analyzed. The antioxidant enzyme levels of the animals regained and markedly increased in the acute and chronic immobilized groups, respectively. The results suggested that the extract of C. paniculatus seed was highly efficacious in reducing the stress induced by least mobility for hours (Lekha, 2010). The Celastrus oil, extracted from seeds of Celastrus paniculatus tested at 2 dose levels (1 and 1.5 g/kg), exhibited significant anxiolytic activity and did not produce tolerance. The non-sedative nature and reversal of buspirone induced behaviour (in open field exploration) point to the serotonergic mechanism underlying the anxiolysis, inspiring further research (Rajkumar, 2007). CP, when administered chronically, selectively reversed the impairment in spatial memory produced by acute central muscarinic receptor blockade, supporting the possibility that one or more constituents of the oil may offer cognitive enhancing properties.

Pyrroloquinoline quinone (PQQ) : is a highly unique naturally occurring quinone compound first identified in 1979 and having a unique almost vitamin-like essential role in plants, animals, human milk, and bacteria. Free PQQ is detected in food samples in the range of concentrations of 3.7-61 ng/g (Kumazawa, 1995). It has been reported that PQQ functions as an essential nutrient in cell culture experiments and in animal models of human diseases. In human trials as a dietary supplement PQQ has been shown to improve cognitive function, cardiovascular markers of inflammation, and skin health, and has been found to have a vital action in growth and development by activating cell signaling pathways directly involved in cellular energy metabolism, development, and function. For immune function and other health parameters, oral supplementation of PQQ in nanomolar amounts increases the responsiveness of B- and T-cells to mitogens and improves neurologic function and reproductive outcome in rodents (Stites, 2000). In animals, PQQ is involved in a wide range of biological functions including improved growth of newborns and reproductive performance. PQQ supplementation may provide protection from cardiac and neurological problems such as stroke or insufficient blood flow to the brain.

Mitochondria health and energy production

Quinone compounds have redox or electron transfer effects in chemical reactions which play an important role in the body’s production of energy and quenching of free radicals. PQQ protects mitochondria from oxidative stress in liver cells and promotes the spontaneous generation of new mitochondria within aging cells. It has an influence on cell signaling pathways, related to the formation of mitochondria in experimental animal models. (Rucker, 2009). PQQ is an effective antioxidant protecting mitochondria against oxidative stress-induced lipid peroxidation, protein carbonyl formation and inactivation of the mitochondrial respiratory chain (He, 2003). It has neuroprotective effects in rotenone-induced Parkinson's disease (PD) models by decreasing neuronal loss, increasing the ROS-scavenging ability, regulating intracellular expressions of mitochondrial complex and improving mitochondrial integrity and dopamine functions (Qin, 2015).

Cognitive function and neuro-protection

PQQ given as supplements in animals improved learning ability and a similar effect has been found in humans. PQQ disodium salt was tested on cognitive functions in 41 elderly healthy subjects. Subjects given 20 mg of PQQ per day or placebo, for 12 weeks had improvements in visual-spatial cognitive function tests and increased cerebral blood flow in the prefrontal cortex. Results of the study revealed that PQQ can prevent reduction of attention and working memory in aged persons (Itoh, 2016).

PQQ protects neurons against glutamate-induced damage both in vitro and in vivo and prevents neurotoxic effects of rotenone. The mechanism of action was determined to be through preventing cell death, restoring the mitochondrial membrane potential, inhibiting intracellular reactive oxygen species (ROS) production, suppressing tyrosine residues nitration, and dopamine redistribution. PQQ also exerted protective effects in an in vivo PD model, which was created by rotenone injection in the medial forebrain bundle of rats. Results show that PQQ provides neuroprotection through complex mechanisms involving oxidative stress, mitochondrial integrity, and dopamine function (Qin, 2015).

Vitamin B6 (pyridoxal-5 phosphate), B12 (methylcobalamin)/Citicholine/Folic acid (methylfolate): are important B vitamins for the synthesis of brain neurotransmitters. They are required for methylation reactions to form SAMe or S-adenosyl methionine which is involved in the synthesis of dopamine and norepinephrine, increasing the levels by as much as 15-fold and 50% in some experiment, and supports serotonin and acetycholine levels (Schalinske, 2015; Wu, 2014) . A lack of proper methylation factors can result in a buildup of homocysteine, the toxic byproduct of amino acid metabolism. Excessive homocysteine leads to depression, memory problems and increases the risk of stroke and heart attack. In addition to citicholine being a methyl donor compound, it is also the precursor to the memory neurotransmitter, acetylcholine. Improved SAMe synthesis and availability by its cofactors and precursors improves spatial capacity through the upregulation of acetylcholine and brain-derived neurotrophic factor (BDNF) rather than alteration of DNA methylation levels (Wu, 2014).

Pyridoxal-5-phosphate (P5P): is the physiologically active form in the body of vitamin B-6 that many people have difficulty synthesizing from its inactive precursor vitamin B-6 (pyridoxine) found in most multivitamins. Aging, the use of OTC pain relievers, and alcohol intake can reduce the conversion of pyridoxine to its active form which is why the coenzyme form, pyridoxal-5-phosphate, is used instead in this formula. Multifactorial neurological pathologies, such as autism, schizophrenia, Alzheimer's disease, Parkinson's disease and epilepsy have also been correlated to inadequate intracellular levels of P5P (Di Salvo, 2012). Pyridoxal-5-phosphate dependent enzymes were inhibited by pyridoxine. Neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine. The inactive form pyridoxine in most B-6 vitamin supplements competitively inhibits the active pyridoxal-5'- phosphate. Consequently, symptoms of vitamin B6 supplementation are similar to those of vitamin B6 deficiency (Vrolijk, 2017). Patients who were taking COX2 inhibitors had lower circulating pyridoxal-5'-phosphate, especially those taking NSAIDs >6 mo. Long-term celecoxib and naproxen use reduced hepatic pyridoxal-5'-phosphate in mice. Nonselective cyclooxygenase inhibitor naproxen significantly decreased vitamin B-6 vitamin isomers in the kidney (Chang, 2013). Vitamin B1 (benfotiamine) and B2 (Riboflavin phosphate) in the active, coenzyme forms help in the production of energy in brain cells.