Avoid toxins that inflame the brain causing Alzheimer

. 2012 Jan; 9(1): 35–66.
Published online 2012 Jan. doi: 10.2174/156720512799015037
PMCID: PMC3349985
PMID: 22329651

Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer’s Disease


Alzheimer’s disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.

Keywords: Alzheimer’s disease, dementia, neurofibrillary tangles, neurodegeneration cascade.


Alzheimer’s disease [AD] is the most common cause of dementia in North America, and over the past several decades, the prevalence rates of sporadic AD have become epidemic []. Although the clinical diagnosis of AD is based on criteria set by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS/ ADRDA) and DSM-IV criteria [], embracement of additional tools such as neuroimaging and standardized biomarker panels could facilitate early detection of disease []. Characteristic neuropathological hallmarks of AD include: neuronal loss, abundant accumulations of abnormal, hyperphosphorylated cytoskeletal proteins in neuronal perikarya and dystrophic fibers, and increased expression and abnormal processing of amyloid-beta precursor protein (AβPP), leading to AβPP-Aβ peptide deposition in neurons, plaques, and vessels. For nearly three decades, the dominant trends have been to interpret selected AD-associated abnormalities, namely the hyper-phosphorylation of tau and deposition of AβPP-Aβ as causal rather than consequential to the neurodegeneration cascade. This approach posed significant limitations on the scope of investigation and the goals with respect to designing new treatments; ergo, success has been either modest or disappointing. On the other hand, due to collected contributions of a number of researchers, the field has recently become more receptive to alternative concepts, opening the doors to exciting new avenues of investigation and therapeutic strategies.

Growing evidence supports the concept that AD fundamentally represents a metabolic disease in which brain glucose utilization and energy production are impaired []. Metabolic abnormalities have been linked to brain insulin and insulin-like growth factor (IGF) resistance with disruption of signaling pathways that regulate neuronal survival, energy production, gene expression, and plasticity []. On a cellular basis, inhibition of insulin/IGF signaling contributes to AD-type neurodegeneration by increasing: 1) the activity of kinases that aberrantly phosphorylate tau; 2) expression of AβPP and accumulation of AβPP-Aβ; 3) levels of oxidative and endoplasmic reticulum (ER) stress; 4) the generation of reactive oxygen and reactive nitrogen species that damage proteins, RNA, DNA, and lipids; 5) mitochondrial dysfunction; and 6) activation of pro-inflammatory and pro-death cascades. On a functional basis, insulin/IGF resistance causes down-regulation of target genes that are needed for cholinergic homeostasis, and it compromises systems that mediate neuronal plasticity, memory, and cognition.

The gold standard for definitively diagnosing AD is to perform a postmortem examination of the brain, with the objective of demonstrating beyond-normal aging associated densities of neurofibrillary tangles, neuritic plaques, and AβPP-Aβ deposits in corticolimbic structures, bearing in mind that neurodegeneration frequently involves multiple other cortical regions as well. The common thread among these characteristic lesions is that they harbor insoluble aggregates of abnormally phosphorylated and ubiquitinated tau, and neurotoxic AβPP-Aβ in the form of oligomers, fibrillar aggregates, or extracellular plaques. Secreted AβPP-Aβ oligomers have been demonstrated to be neurotoxic and to inhibit hippocampal long-term potentiation, i.e. synaptic plasticity [].

Ultimately, to improve our capacity for diagnosis and treatment, we should be able to connect the development and progression of neuropathological lesions with the molecular, biochemical, physiological, neuro-imaging, and clinical abnormalities that correlate with AD. Therefore, gaining a better understanding of the pathophysiology of these lesions could improve our current diagnostic and treatment approaches to AD. One way to begin the process in earnest is to acknowledge that the rigid employment of standardized criteria for diagnosing AD, in fact, restricts our ability to fully comprehend the underlying disease process. For example, in addition to the characteristic lesions noted above, AD is associated with loss of neurons, fibers, and synapses, disruption of the cortical-laminar architecture, gliosis, proliferation of dystrophic neurites, and neuro-inflammatory responses, including microglial cell activation. For unclear reasons, these abnormalities are not systematically quantified, and consequently, they are not routinely incorporated into the AD diagnostic equation. At the same time, many basic cellular, molecular, biochemical, and structural abnormalities in AD overlap with those in other neurodegenerative diseases such as dementia with Lewy bodies, fronto-temporal dementias, and multiple systems atrophy, indicating that one or two biomarkers might not be sufficient to consistently and accurately diagnose AD.

Hints that AD could represent a metabolic disease emerged from studies showing that the early stages of AD were marked by deficits cerebral glucose utilization [], and that as the disease progressed, metabolic and physiological abnormalities worsened [,]. Subsequently, AD was shown to be associated with brain insulin resistance and insulin deficiency, with significant abnormalities in the expression of genes and activation of kinases that are regulated by insulin and insulin-like growth factor (IGF) signaling []. Moreover, it was shown that in AD, progressive declines in cerebral glucose utilization, and deficits in insulin signaling and insulin-responsive gene expression worsen with severity of disease. In particular, insulin/IGF regulated genes, including choline acetyltransferase, tau, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which mediate cholinergic/cognitive, neuronal cytoskeletal, and metabolic functions, are suppressed in AD []. Insulin resistance mediated impairments in energy metabolism lead to oxidative stress, generation of reactive oxygen species (ROS), DNA damage, and mitochondrial dysfunction, all of which drive pro-apoptosis, pro-inflammatory, and pro-AβPP-Aβ cascades. Experimental animals in which brain insulin receptor expression and function were suppressed exhibited cognitive impairment and neurodegeneration with features that overlap with AD [].

In AD brains, deficits in insulin/IGF signaling are due to the combined effects of insulin/IGF resistance and deficiency. Insulin/IGF resistance is manifested by reduced levels of insulin/IGF receptor binding and decreased responsiveness to insulin/IGF stimulation, while the trophic factor deficiency is associated with reduced levels of insulin polypeptide and gene expression in brain and cerebrospinal fluid [,]. In essence, AD can be regarded as a form of brain diabetes that has elements of both insulin resistance and insulin deficiency. To consolidate this concept, we proposed that AD be referred to as, “Type 3 diabetes” [,].


In the central nervous system (CNS), insulin and IGF signaling play critical roles in regulating and maintaining cognitive function. Insulin, IGF-1 and IGF-2 polypeptide and receptor genes are expressed in neurons [] and glial cells [] throughout the brain, and their highest levels of expression are in structures typically targeted by neurodegenerative diseases [,]. Insulin and IGFs regulate a broad range of neuronal functions throughout life, from embryonic and fetal development to adulthood. The corresponding signaling pathways are activated by insulin and IGF binding to their own receptors, resulting in phosphorylation and activation of intrinsic receptor tyrosine kinases. Subsequent interactions between the phosphorylated receptors and insulin receptor substrate (IRS) molecules promote transmission of downstream signals that inhibit apoptosis, and stimulate growth, survival, metabolism, and plasticity. Anti-apoptotic mechanisms inhibited by insulin/IGF stimulation include BAD (inhibitor of Bcl-2), Forkhead Box O (FoxO), glycogen synthase kinase 3β (GSK-3β), and nuclear factor kappa B (NF-κB). GSK-3β regulates Wnt signaling by phosphorylating β-catenin and thereby targeting it for ubiquitin/proteosome-mediated degradation. Wnt signaling mediates synaptic plasticity in the CNS. Therefore, major functions supported by the insulin/IGF signaling axis include, neuronal growth, survival, differentiation, migration, energy metabolism, gene expression, protein synthesis, cytoskeletal assembly, synapse formation, neurotransmitter function, and plasticity [,]. Correspondingly, impaired signaling through insulin and IGF receptors has dire consequences with respect to the structural and functional integrity of the CNS.


The major neuronal cytoskeletal lesions that correlate with severity of dementia in AD, including neurofibrillary tangles and dystrophic neurites, contain aggregated and ubiquitinated insoluble fibrillar tau. In other words, tau accumulation and pathology are the most significant structural correlates of dementia in AD [,]. In AD, tau, a microtubule-associated protein, gets hyperphosphorylated due to inappropriate activation of several proline-directed kinases, including GSK-3β. As a result, tau protein misfolds and self-aggregates into insoluble fibrillar structures [paired helical filaments and straight filaments] that form neurofibrillary tangles, dystrophic neurites, and neuropil threads []. Intra-neuronal accumulations of fibrillar tau disrupt neuronal cytoskeletal networks and axonal transport, leading to synaptic disconnection and progressive neurodegeneration []. Besides fibrillar tau, pre-fibrillar tau can aggregate, forming soluble tau oligomers or insoluble granular tau, which contribute to neurodegeneration by causing synaptic disconnection and neuronal death []. The eventual ubiquitination of hyper-phosphorylated tau [], combined with dysfunction of the ubiquitin-proteasome system [], cause further accumulation of insoluble fibrillar tau, oxidative stress, and ROS generation, which together promote neuronal apoptosis, mitochondrial dysfunction, and necrosis in AD [].

Growing evidence suggests that many of the aforementioned cellular aspects of AD neurodegeneration may be caused by brain insulin/IGF resistance [,] which, as in other brain insulin-resistance states, results in inhibition of downstream pro-growth and pro-survival signaling pathways (Fig. 11) []. Tau gene expression and phosphorylation are regulated by insulin and IGF stimulation [,]. In AD, brain insulin and IGF resistance result in decreased signaling through phosphoinositol-3-kinase (PI3K), Akt [,], and Wnt/β-catenin [], and increased activation of glycogen synthase kinase 3β (GSK-3β) []. GSK-3β over-activation is partly responsible for the hyper-phosphorylation of tau, which leads to tau misfolding and fibril aggregation []. In addition, tau hyper-phosphorylation in AD is mediated by increased activation of cyclin-dependent kinase 5 (cdk-5) and c-Abl kinases [,], and inhibition of protein phosphatases 1 and 2A [,,]. Besides hyper-phosphorylation, tau pathology in AD is mediated by impaired tau gene expression due to reduced insulin and IGF signaling []. Consequences include, failure to generate sufficient quantities of normal soluble tau protein, vis-a-vis accumulation of hyper-phosphorylated insoluble fibillar tau, and attendant exacerbation of cytoskeletal collapse, neurite retraction, and synaptic disconnection.

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Roles of brain insulin deficiency and brain insulin resistance in Tau pathology. Tau protein is normally regulated by insulin and IGF signalling. Insulin deficiency [effective trophic factor withdrawal] and insulin resistance lead to the over-activation of kinases and inhibition of phosphatases, which result in hyper-phosphorylation of tau. Attendant increased oxidative stress leads to ROS generation and ubiquitination, followed by misfolding of Tau. Misfolded tau aggregates and forms insoluble twisted fibrils that are neurotoxic and mediate dementia-associated neuropathological processes, i.e. neurofibrillary tangle formation, proliferation of dystrophic neuritis and neuropil threads, and synaptic disconnection.


AD is associated with dysregulated expression and processing of amyloid precursor protein (AβPP), resulting in the accumulation of AβPP-Aβ (Aβ) oligomeric fibrils or insoluble larger aggregated fibrils (plaques) that are neurotoxic (Fig. 22). Pathophysiologically, increased AβPP gene expression, together with altered proteolysis, result in accumulation of 40 or 42 amino acid length Aβ peptides that can aggregate. In familial forms of AD, mutations in the AβPP, presenilin 1 (PS1), and PS2 genes, or inheritance of the Apoliprotein E ε4 (ApoE- ε4) allele, are responsible for increased synthesis and deposition of Aβ peptides in the brain. However, in sporadic AD, which accounts for 90% or more of the cases, the causes of Aβ accumulation and toxicity are still under intense investigation. Over the past few years, interest in the role of impaired insulin/IGF signaling as either the cause or consequence of dysregulated AβPP-Aβ expression and protein processing has grown.

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Brain insulin resistance and AβPP-Aβ deposition and toxicity. Brain insulin resistance caused by peripheral insulin resistance diseases or primary toxic and neurodegenerative processes in the brain promote neuroinflammation and increased expression of AβPP. Throught the action of Beta and Gamma secretases, AbPP is cleaved to generate excessive 40-42 kD AβPP-Aβ peptides that aggregate and form insoluble fibrils and plaques, or oligomers and AβPP-Aβ-derived diffusible ligands (ADDLs), which are neurotoxic. AβPP-Aβ oligomers and ADDLs promote oxidative stress and increased activation of kinases that lead to Tau hyperphosphorylation, and its eventual ubiquitination, misfolding, and aggregation. AβPP-Aβ oligomers and ADDLs may also block insulin receptor function and contribute to insulin resistance. Carriers of the ApoE e4 allele or Presenilin mutations are predisposed to excessive and abnormal AβPP cleavage, and AβPP-Aβ accumulation, aggregation, and fibril formation, correlating with increased rates and familial occurrences of AD.

The concept that Aβ toxicity causes insulin resistance, and the opposing argument that brain insulin resistance with attendant oxidative stress and neuro-inflammation promotes Aβ accumulation and toxicity are both supported by experimental data. For example, studies have established that insulin stimulation accelerates trafficking of Aβ from the trans-Golgi network, where it is generated, to the plasma membrane, and that insulin stimulates Aβ extracellular secretion [] and inhibits its intracellular accumulation and degradation by insulin-degrading enzyme [,]. Although it remains uncertain as to whether these physiological actions of insulin on AβPP processing contribute to Aβ burden, what is apparent is that impaired insulin signaling can disrupt both the processing of AβPP and clearance of Aβ []. The accumulation of Aβ exacerbates the problem because Aβ disrupts insulin signaling by competing with insulin, or reducing the affinity of insulin binding to its own receptor [,]. In addition, AβPP oligomers inhibit neuronal transmission of insulin-stimulated signals by desensitizing and reducing the surface expression of insulin receptors. Furthermore, intracellular AβPP-Aβ directly interferes with PI3 kinase activation of Akt, which leads to impaired survival signaling, increased activation of GSK-3β, and hyper-phosphorylation of tau. Hyper-phosphorylated tau is prone to misfold, aggregate, and become ubiquitinated, leading to the formation of dementia-associated paired-helical filament-containing neuronal cytoskeletal lesions. Since IGF-1 or IGF-2 suppression of GSK-3β activity [] reduces the neurotoxic effects of AβPP [], the neuro-protective properties of these and related trophic factors could be exploited for therapeutic purposes in AD.


Insulin and IGF signaling pathways regulate glucose utilization, metabolism, and ATP synthesis needed for cellular homeostasis and dynamic modulation of a broad range of functions (Tables 1,1,22). Deficits in cerebral glucose utilization and energy metabolism occur very early in the course of AD, such that they are detectable either prior to, or coincident with the initial stages of cognitive dysfunction [,,]. These findings lend strong support the concept that impairments in insulin signaling have important roles in the pathogenesis of AD []. Glucose uptake and utilization in brain are dependent upon glucose transport. Glucose transporter 4 (GLUT4) is abundantly expressed along with insulin receptors, in medial temporal lobe structures, which notably are major targets of AD neurodegeneration. Insulin stimulates GLUT4 gene expression and protein trafficking from the cytosol to the plasma membrane to modulate glucose uptake and utilization. Therefore, insulin stimulation of GLUT4 is critical to the regulation of neuronal metabolism and the generation of energy needed for memory and cognition. Although postmortem brain studies have not detected significant reductions in GLUT4 expression in AD [], the well-documented deficits in brain glucose utilization and energy metabolism vis-a-vis brain insulin/IGF resistance could instead be mediated by impairments in GLUT4 trafficking between the cytosol and plasma membrane.

Table 1.

Metabolic Hypothesis of Alzheimer’s Disease-Consequences of Brain Insulin Resistance

Impairment Adverse Effect Role in Alzheimer’s Disease
GLUT4 function Reduced glucose uptake and utilization Energy deficits; compromised homeostatic functions, disruption of neuronal cytoskeleton, synaptic disconnection
Insulin receptor function Decreased signaling through IRS, PI3K-Akt Reduced neuronal and oligodendroglial survival, neuronal plasticity, myelin maintenance
Increased activation of GSK-3β and phosphatases that negatively regulate insulin signaling Increased tau phosphorylation, oxidative stress, neuro-inflammation, pro-apoptosis signaling
Decreased Wnt signaling
Reduced insulin-responsive gene expression Reduced choline acetyltransferase expression –> deficits in acetylcholine
Decreased GAPDH expression, further impairment of glucose metabolism
Insulin receptor function or hyper-insulinemia Endothelial cell injury, intimal thickening, and vessel wall fibrosis Microvascular disease and cerebral hypoperfusion
Mitochondrial function Increased oxidative stress, ROS, RNS DNA damage, lipid peroxidation, energy deficits, cell death, increased AβPP expression, Aβ42 deposition and fibrillarization
Myelin maintenance Myelin breakdown, increased generation of ceramides and other toxic sphingolipids; lipid peroxidation; ROS Increased neuro-inflammation, oxidative stress, pro-apoptosis signaling, further insulin resistance
White matter atrophy due to fiber and myelin loss
Insulin/IGF availability Trophic factor withdrawal Death or impaired function of insulin/IGF dependent neurons and glial cells
Hyperglycemia Accumulation of advanced glycation end-products Disrupts removal of Aβ42

Abbreviations: GLUT4=glucose transporter 4; IRS= insulin receptor substrate; PI3K= phosphoinositol-3- kinase; GSK-3β = glycogen synthase kinase 3β; GAPDH=glyceraldehyde-3-phosphate dehydrogenase; ROS=reactive oxygen species; RNS=reactive nitrogen species; AβPP= amyloid-β – precursor protein; Aβ 42=amyloid beta peptide-42 amino acids 1-42 cleavage product; IGF=insulin-like growth factor.

Table 2.

Neuropathologic Processes Contributing to Brain Insulin Resistance in Alzheimer’s Disease

Neurodegenerative Disease Process Mechanism of impairing brain insulin signaling Consequences in relation to brain insulin signaling
Aβ42 toxicity Competes with insulin and reduces affinity of insulin binding to its receptor
AβPP oligomers desensitize and reduce surface expression of insulin receptors
Interferes with PI3K activation of Akt
Disrupts insulin signaling
Impairs insulin stimulated neuronal survival and plasticity
Increases GSK-3β activation and tau hyperphosphorylation
Microvascular disease Cerebral hypoperfusion, hypoxic-ischemic injury Exacerbates insulin resistance;
Oxidative stress DNA damage, lipid peroxidation, fibrillarization of oligomeric tau and Aβ42 Increases neuro-inflammation and pro-inflammatory cytokine inhibition of insulin signaling
Toxic lipids impair signaling through PI3K-Akt
Transition metal ion accumulations Mitochondrial dysfunction, oxidative stress, tau and AβPP oligomer fibrillarization Impairs glucose uptake and utilization, inhibits insulin signaling
Hyperphosphorylated-ubiquitinated tau Increases oxidative stress, promotes neuro-inflammation Enhances insulin resistance

Abbreviations: PI3K= phosphoinositol-3- kinase; GSK-3β = glycogen synthase kinase 3β; AβPP= amyloid-β – precursor protein; Aβ 42=amyloid beta peptide-42 amino acids 1-42 cleavage product

Deficiencies in energy metabolism tipped by inhibition of insulin/IGF signaling increase oxidative stress, mitochondrial dysfunction, and pro-inflammatory cytokine activation [,,]. Oxidative stress leads to increased generation and accumulation of reactive oxygen (ROS) and reactive nitrogen species (RNS) that attack subcellular components and organelles. The resulting chemical modifications, including adducts formed with DNA, RNA, lipids, and proteins, compromise the structural and functional integrity of neurons. Consequences include, loss of cell membrane functions, disruption of the neuronal cytoskeleton with dystrophy and synaptic disconnection, deficits in neurotransmitter function and neuronal plasticity, and perturbation of signal transduction and enzymatic pathways required for energy metabolism, homeostasis, and neuronal survival.

Mitochondrial dysfunction exacerbates electron transport chain function, reducing ATP generation and increasing ROS production. Pro-inflammatory cytokine activation is mediated by neuro-inflammatory responses in microglia and astrocytes. Neuro-inflammation increases oxidative stress, organelle dysfunction, and pro-apoptosis signaling. Moreover, stresses caused by inhibition of insulin/IGF signaling stimulate AβPP gene expression [] and aberrant AβPP cleavage, with attendant increased AβPP-Aβ deposition and toxic fibril formation in the brain [,]. Persistence of oxidative stress leads to constitutive activation of kinases e.g. GSK-3β, that promote aberrant hyper-phosphorylation of tau. Therefore, in AD, oxidative stress and impairments in energy metabolism stemming from brain insulin/IGF resistance quite likely contribute to neuronal loss, AβPP toxicity, tau cytoskeletal pathology, and neuro-inflammation [,,]. The degree to which these abnormalities can be effectively targeted for therapy in AD is actively under investigation.


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High caloric intake and/or chronic low-level nitrosamine exposures [through diet, smoking, agriculture], promote fatty liver disease (steatohepatitis) that progresses due to injury and inflammation, eventually leading to hepatic insulin resistance. The same poor physiological states also promote obesity, diabetes mellitus, and other peripheral insulin resistance diseases. Toxic lipids, including ceramides, made in the liver, get released into the circulation, cross the blood-brain barrier, and cause brain insulin resistance, inflammation, energy failure, toxicity, and local production of toxic ceramides. The end result is progressive neurodegeneration, including Alzheimer’s disease.

Although aging is clearly the dominant risk factor for AD, growing evidence suggests that peripheral insulin resistance with obesity, T2DM, metabolic syndrome (dyslipidemic states), and non-alcoholic steatohepatitis (NASH) mediate brain insulin/IGF resistance, and thereby contribute to the pathogenesis of mild cognitive impairment (MCI), dementia, and AD [,,,,,,]. However, only within the past several years has this field greatly expanded due to input from both human and experimental animal studies that produced new information about the causes and consequences of brain insulin resistance and deficiency in relation to cognitive impairment [,,,,]. Concerns over the role of peripheral insulin resistance as a mediator of cognitive impairment and sporadic AD have been ratcheted up by globalization of the obesity epidemic [,]. In order to develop logical and novel approaches for treating and preventing neurodegeneration based on the brain insulin resistance hypothesis, three main questions must be addressed: 1) Do T2DM and other peripheral insulin resistance states cause neurodegeneration, including AD? 2) Do T2DM and other peripheral insulin resistance disease states principally serve as co-factors in the pathogenesis of cognitive impairment and neurodegeneration? or 3) Do T2DM and AD fundamentally represent the same disease processes occurring in different target organs and tissues? These questions are addressed below.

Contributions of Obesity and T2DM to Cognitive Impairment and Neurodegeneration

Epidemiologic studies demonstrated that individuals with glucose intolerance, deficits in insulin secretion, or T2DM have a significantly increased risk for developing mild cognitive impairment (MCI) or AD-type dementia. Longitudinal studies provided further evidence that T2DM [,] and obesity/dyslipidemic disorders [] were correlated with later development of MCI, dementia, or AD [,]. However, one study showed that obesity itself, with or without superimposed T2DM, increased the risk for MCI, AD, or other forms of neurodegeneration [], suggesting that systemic factors related to obesity, other than T2DM, can promote neurodegeneration. On the other hand, although a relatively high percentage of individuals with MCI or dementia have T2DM, peripheral insulin resistance, or obesity, the vast majority of patients with AD do not have these diseases. To gain a better understanding of the contributions of T2DM and obesity to neurodegeneration, attention must be given to postmortem human and experimental animal studies.

In general, the arguments made in favor of the concept that T2DM or obesity causes AD are not founded; however, the concept that peripheral insulin resistance disease states contribute to cognitive impairment and AD pathogenesis or progression does have a sound basis. Against a causal role are the findings that, postmortem human brain studies demonstrated no significant increase in AD diagnosis among diabetics [], and similarly abundant densities of senile plaques and rates of neurofibrillary tangle pathology were observed in subjects with T2DM compared with normal aged controls, although peripheral insulin resistance was more common in AD than with normal aging []. Since neurofibrillary tangles and dystrophic neurites are hallmarks of AD and correlate with severity of dementia, the abovementioned findings in human postmortem studies indicate that T2DM alone is not sufficient to cause AD. On the other hand, in experimental mouse and rat models, chronic high fat diet (HFD) feeding and diet induced obesity (DIO) with associated T2DM, do cause cognitive impairment with deficits in spatial learning and memory [,]. Moreover, experimental obesity with T2DM causes mild brain atrophy with brain insulin resistance, neuro-inflammation, oxidative stress, and deficits in cholinergic function [,]. An important qualifier about these studies is that the associated brain abnormalities were typically modest in severity, and they were devoid of the most important structural lesions that characterize AD, i.e. neurofibrillary tangles. Therefore, observations both in humans and experimental models suggest that while obesity or T2DM can be associated with cognitive impairment, mild brain atrophy, and a number of AD-type biochemical and molecular abnormalities in brain, including insulin resistance and oxidative stress, they do not cause significant AD pathology. Instead, the findings suggest that T2DM, obesity, and probably other peripheral/systemic insulin resistance states serve as co-factors contributing to the pathogenesis or progression of neurodegeneration. The significance of these results is that therapeutic strategies designed to treat T2DM, obesity, and systemic insulin resistance could help slow the progress or reduce the severity of AD, but they will not likely prevent it altogether. Correspondingly, a number of studies have already demonstrated that treatment with hypoglycemic or insulin sensitizer agents can be protective in reducing the incidence and severity of AD brain pathology [].

Diet for the elderly

A personalised nutrition approach
Micronutrients such as zinc, copper and selenium play a pivotal role in a range of physiological functions and maintain immune and antioxidant systems (Eugenio Mocchegiani et al.). The complex interactions between micronutrients and genes could help in understanding how best to use nutrients as supplements in clinical practice. Further genetic and nutritional studies are required to clearly define the impact of these micronutrients.
Targeting the human gut microbiome (Sebastiano Collino et al.) is an emerging field of personalised nutrition. This approach could help to identify key molecular mechanisms affected by diet and inflammaging, and lead to basic profiles of health and diagnostic tools to address conditions such as inflammatory bowel disease.
Three papers cover the interaction between diet and the gut microbiota (Candela et al.), the effect of an elderly tailored diet on cognitive decline and brain and gut connections, including the liver and pancreas (Caracciolo et al.). Nutritional interventions such as low calorie intake with nutrient supplementation can impact an individual’s cell epigenetic profile e.g. DNA methylation, microRNA and organs (Bacalini et al.). Better knowledge of gene interactions with nutrients and the environment may lead to earlier interventions of malnutrition in people (Yves Boirie et al.). And more genomic information may identify impacts of general health recommendation policies in at-risk, elderly sub-populations.
The effect of diet on immunosenescence, which is the functional decline of the immune system (Maijo´ et al.), and changes that happen in ageing fat tissue (Zamboni et al.) are both assumed to be major sources of inflammation. Nutritional interventions have shown some promising results in targeting some impairments of an ageing immune system; combining interventions with a whole diet approach could be more beneficial.
It is commonly known that physical exercise can benefit health and age-related decline. In one study (van de Rest et al.), resistance-type exercises, using a number of body techniques and workout machines, with and without protein supplementation, was undertaken to see the effect on cognitive functions in frail and pre-frail elderly people. After 24 weeks of training a beneficial improvement was noted in participants’ information processing speed, attention and working memory.

food pyramid

danish italian senior dietgut bacteria eats GABAkle1738GABAitaconateselenium rich foodalcohol stomach

Philippines Coconut Wine -Tuba

Coconut Wine tuba is even ingested in Sri Lanka and Myanmar. Production of coconut wine has indeed contributed to the endangered status of some palm species such as the Chilean wine palm (Jubaea chilensis).

For Philippines tuba manufacturer, email me your info to be added in this post as producer/manufacturer in the Philippines.

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Coconut Wine Tuba in the Philippines

In the Philippines, coconut wine tuba refers both to the freshly collected sweetish sap and the one by having the red lauan-tree tan bark colorant.

In Leyte, the coconut wine tuba is matured for up to one to 2 years such that an echoing ring is made when a glass container is tapped explanation required; this variation of tuba is called bahalina.


Coconut Wine Tuba Tapping

Coconut Wine Tuba – Palm TreeThe sap is extracted and collected by a tapper. Commonly the sap is compiled from the cut flower of the palm tree. A compartment is fastened to the flower stump to collect the sap. The white liquid that at first gathers has a tendency to be extremely sweet and non-alcoholic before it is fermented. An alternate technique is the felling of the whole tree. Where this is practiced, a fire is occasionally lit at the cut end to help with the assortment of sap.

Coconut wine tapping is mentioned in the novel Things Fall Apart by the Nigerian writer Chinua Achebe and is central to the plot of the groundbreaking novel The Palm Wine Drinkard by Nigerian author Amos Tutuola.

In parts of India, the unfermented sap is called neera (padaneer in Tamil Nadu) and is cooled, saved and circulated by semi-government agencies. A little lime is included in the sap to prevent it from fermenting. Neera is said to consist of lots of nutrients featuring potash.

Coconut sap starts fermenting immediately after assortment, due to natural yeasts in the air (typically spurred by residual yeast left in the gathering container). Within two days, fermentation yields a fragrant wine of up to 4 % liquor content, mildly intoxicating and sweet.

The coconut wine tuba may be enabled to ferment longer, up to a day, to yield a stronger, more sour and acidic taste, which some folks favor. Longer fermentation creates vinegar instead of stronger wine, known as Lambanog.

In Africa, the sap is use to create coconut wine tuba and is most frequently taken from wild datepalms such as the silver date palm (Phoenix sylvestris), the palmyra, and the jaggery palm (Caryota urens), or from oil palm such as the African Oil Palm (Elaeis guineense) or from Raffia palms, kithul palms, or nipa palms.

In India and South Asia, coconut palms and Palmyra palms such as the Arecaceae and Borassus are favored. In southern Africa, palm wine (ubusulu) is produced in Maputaland, an area in the south of Mozambique between the Lobombo mountains and the Indian Ocean.

It is mainly produced from the lala palm (Hyphaene coriacea) by cutting the stem and compiling the sap.

In part of central and western Democratic Republic of the Congo, palm wine is called malafu. There are four types of coconut wine tuba in the central and southern DRC. From the oil palm comes ngasi, dibondo comes from the raffia palm, cocoti from the coconut palm, and mahusufrom a short palm which grows in the savannah areas of western Bandundu and Kasai provinces.

In Tuvalu, the procedure of making toddy can plainly be viewed by having tapped palm trees that line Funafuti International Airport.

In some areas of India, coconut wine tuba is evaporated to create the unrefined sugar called jaggery.

Coconut Wine Tuba Distillation – Lambanog

Local Distillation of Burukutu in Ghana

Coconut wine tuba might be distilled to generate a stronger refreshment which is Lambanog goes by different names baseding on the region (e.g., arrack, village gin, charayam, and nation whiskey). Throughout Nigeria, this is typically called ogogoro. In parts of southern Ghana distilled coconut wine is called akpeteshi or burukutu.

In Togo it is called sodabe, in the Philippines it is called lambanog, while in Tunisia it is called Lagmi.

Social role of Coconut Wine

In India, coconut wine or toddy is served as either neera or padaneer (a sweet, non-alcoholic beverage stemmed from fresh sap) or kallu (a sour drink made from fermented sap, yet not as tough as wine). Kallu is in most cases drunk soon after fermentation by the end of day, as it becomes more sour and acidic day by day. The drink, like vinegar in taste, is thought of to have a short-lived shelf life. explanation needed Nonetheless, it could be refrigerated to extend its life.

In Karnataka, India, coconut wine is in most cases offered at toddy shops (known as Kalitha Gadang in Tulu, Kallu Dukanam in Telugu, Kallu Angadi in Kannada or “Liquor Shop” in English).

In Tamil Nadu, this beverage is currently outlawed, though the legality fluctuates with politics. In the absence of legal toddy, moonshine distillers of arrack often offer methanol-contaminated liquor, which are able to have lethal effects. To discourage this practice, authorities have definitely pushed for inexpensive “Indian Made Foreign Liquor” (IMFL), much to the dismay of toddy tappers.

Fermented Palm Juice

Fresh nipah palm (Nypa fruticans) sap and neera (sap obtained from by tapping the unopened spadix of the coconut palm are popular beverages in the region.
For Muslim consumers, palm juice (fresh saps) are consumed within 2 days after tapping as it is highly susceptible to spontaneous fermentation to produce
alcohols and acetic acids. Fermented palm saps can also be used to produce alcohol, vinegar or alcoholic beverage such as palm wine. The fermented beverage
is called “panam culloo” in Sri Lanka, “tuba”, “soom” in the Philippines, “nuoudua” in Vietnam, “arak” in Indonesia, and “tuak” (tuack) or toddy in Malaysia, India and Bangladesh. (Lee and Fujio, 1999). Palm wine is obtained by the natural fermentation of palm sap and collected through the tapping of unopened inflorescence. Palm wine has mild alcoholic flavor, sweet in taste, vigorous effervescence and milky white in color as it contained suspension of numerous bacteria and yeast. Palm wine from coconut flower juice is most popular among Southeast Asia regions. A community survey on the non-Muslim Balinese village in Indonesia showed approximately 40% excessive consumption of locally produced palm wine in 1990 (WHO, 2004).


What are the recommended safe limits of alcohol?

  • Men should drink no more than 21 units of alcohol per week, no more than four units in any one day, and have at least two alcohol-free days a week.
  • Women should drink no more than 14 units of alcohol per week, no more than three units in any one day, and have at least two alcohol-free days a week.
  • Pregnant women. Advice from the Department of Health states that … “pregnant women or women trying to conceive should not drink alcohol at all. If they do choose to drink, to minimize the risk to the baby, they should not drink more than 1-2 units of alcohol once or twice a week and should not get drunk”.
  • Seniors should always eat protein rich food with their wine and not taken during morning medication time.

Contents of palm wine

The following are found in palm wine

  • Sugar
  • Protein
  • Carbohydrate,
  • Amino acid
  • Vitamin C
  • Yeast
  • Bacteria
  • Potassium
  • Zinc
  • Magnesium
  • Iron
  • Vitamin B1,B2 B3 and B6


Health benefits of Tuba, Palm Wine

1 Palm wine improves eyesight

Palm wine helps in maintaining good eye health. This is because it contains the antioxidant Vitamin C (ascorbic acid) which is also found in other fruits and vegetables. Vitamin B1 (thiamine) also helps in improving our vision. This is why some school of thought argue that our grandparents in the village have better eyesight than us because palm wine is their beverage.

2 Reduced risk of cardiovascular diseases

Research has showed that drinking moderate amounts of palm wine has been associated with a reduced risk of developing cardiovascular diseases such as heart failure. This study was conducted by Lingberg and Ezra in 2008. Palm wine contains potassium which has been proven by research to improve heart health and bring down hypertension.  However drinking it in excess has adverse effects like destroying the liver.

3 Palm wine can help fight against cancer

Palm wine contains vitamin B2, also known as riboflavin. Riboflavin is an antioxidant which helps in the fight against some cancer causing agents called free radicals.

4 Palm wine helps in maintaining a healthy hair, skin and nails

The Iron and vitamin B complex found in palm wine are needed for a healthy skin, hair and nail. Iron is very essential for the development, growth and functioning of some cells in our body. This property of palm wine makes it helpful in promoting wound healing by repairing our tissues and promoting the growth of healthy cells.

5 Palm wine promotes lactation

Palm wine is being used by many natural healers in Cameroon, Nigeria, Ghana and other parts of Africa to help a lactating mother when she has limited breast milk production. Research is needed to investigate the property of palm wine that makes it stimulate the production of breast milk.

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Taste Of Beer Triggers Release Of Dopamine, happy neurotransmitter ; Cocaine bullies dopamine; MAO affects dopamine levels

Beer lift your spirits up

The taste of beer alone is enough to raise one’s spirits. The taste is linked with the release of dopamine, a neurotransmitter that controls the brain’s distribution of pleasure, according to a news study published in Neuropsychopharmacology.
“This is the first human demonstration that a stimulus that is reliably associated with alcohol association – that flavor alone, without any significant amount of alcohol – is able to induce a dopamine response,” said study author David Kareken.
The results were discovered by giving men a small gulp of their favorite beer and then scanning their brains. A scan revealed activity in the area of dopamine production. The amount of beer doled out was not large enough to change the subject’s blood-alcohol content level.
“This paper demonstrates that taste alone impacts on the brain functions associated with desire,” Peter Anderson, a professor of substance use, policy and practice at Newcastle University, U.K., said in a statement.
According to researchers, the study demonstrates that the smell of alcohol can cause relapses for addicts.
by RTT Staff Writer


• Fruits like apples and bananas are excellent foods that trigger the release of dopamine. Bananas contain an amino acid called tyrosine which is the most important stimulant for the brain to produce dopamine. The brown spots on the banana contain the highest amount of dopamine. NaturalBuy.com explains that adding bananas to a diet may helps treat symptoms of depression. Apples contain an antioxidant called quercetin. Quercetin works to preserve dopamine levels in the body by protecting the dopamine cells from getting destroyed. Other fruits trigger the release of dopamine are blueberries, cranberries, prunes, and strawberries.

Protein rich foods

Eating foods high in amino acids will trigger the release of dopamine. Proteins hold an amino acid called tyrosine which triggers the release of dopamine after entering the body. Dopamine is found in foods such as almonds, cheese, chicken, fish, and any other protein containing Omega 3 fatty acids. Dairy products such as cheese, milk, and yogurt contain protein. Black beans, chick peas, lima beans, and fava beans are all sources of rich protein foods that will help trigger dopamine. Eggs are a source of protein and contain choline, which is a vitamin that helps improve concentration and memory. Almonds are nuts loaded with protein but should be eaten in moderation because they can cause weight gain and headaches.


Chocolate contains phenylalanine, which is an essential amino acid that turns into tyrosine. The University of Maryland explains that tyrosine is a building block for the neurotransmitter that triggers dopamine. The stimulant in chocolate is in the cocoa and greater amounts of tyrosine are found in dark chocolate. In chocolate, the fat from the milk will also trigger dopamine because it’s a dairy product. Dark chocolate contains many antioxidants , however too much could harm the liver and cause weight gain. According to Chocolate.org, chocolate contains phenylalanine which is related to amino acids. Phenylalanine increases activity and has been proven to relieve depression in 60 percent of depressed patients.

Avoid Sugar

Foods high in sugar, cholesterol and saturated fats can lower your levels of dopamine. While these foods may produce a temporary feeling of satisfaction, they interfere with proper brain function and so the production of dopamine. Your eating habits closely correlate with your mood, so picking fresh fruits and vegetables and other foods with high nutritional value will not only keep you slimmer, it’ll keep your mood more balanced and you feeling better.

Dopamine and MAO

One of the neurotransmitters playing a major role in addiction is dopamine. Many of the concepts that apply to dopamine apply to other neurotransmitters as well.
As a chemical messenger, dopamine is similar to adrenaline. Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain.
Regulation of dopamine plays a crucial role in our mental and physical health. Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra . In Parkinson’s disease, the dopamine- transmitting neurons in this area die. As a result, the brains of people with Parkinson’s disease contain almost no dopamine. To help relieve their symptoms, we give these people L-DOPA, a drug that can be converted in the brain to dopamine.

Drugs can stimulate or fail to stimulate dopamine receptors

Some drugs are known as dopamine agonists. These drugs bind to dopamine receptors in place of dopamine and directly stimulate those receptors. Some dopamine agonists are currently used to treat Parkinson’s disease. These drugs can stimulate dopamine receptors even in someone without dopamine neurons.
An example of agonist drug action
In contrast to dopamine agonists, dopamine antagonists are drugs that bind but don’t stimulate dopamine receptors. Antagonists can prevent or reverse the actions of dopamine by keeping dopamine from attaching to receptors.

Dopamine antagonists are traditionally used to treat schizophrenia and related mental disorders. A person with schizophrenia may have an overactive dopamine system. Dopamine antagonists can help regulate this system by “turning down” dopamine activity.


Cocaine and other drugs of abuse can alter dopamine function. Such drugs may have very different actions. The specific action depends on which dopamine receptors the drugs stimulate or block, and how well they mimic dopamine.
An example of antagonist drug action
Drugs can act directly or indirectly on dopamine receptors
Drugs such as cocaine and amphetamine produce their effects by changing the flow of neurotransmitters. These drugs are defined as indirect acting because they depend on the activity of neurons. In contrast, some drugs bypass neurotransmitters altogether and act directly on receptors. Such drugs are direct acting.
Use of these two types of drugs can lead to very different results in treating the same disease. As mentioned earlier, people with Parkinson’s disease lose neurons that contain dopamine. To compensate for this loss, the body produces more dopamine receptors on other neurons. Indirect agonists are not very effective in treating the disease since they depend on the presence of dopamine neurons. In contrast, direct agonists are more effective because they stimulate dopamine receptors even when dopamine neurons are missing.

 MAO affects dopamine levels

Once returned to the sending neuron by the reuptake system, dopamine is subject to an enzyme named monoamine oxidase (MAO). MAO usually breaks down dopamine.
If no other factors were at work, MAO would keep the amount of “used” dopamine fairly low. However, dopamine taken back into the nerve ending can return to the vesicle for storage. Once inside the vesicle, dopamine is protected from MAO.

A drug named reserpine prevents the reuptake of dopamine and some other neurotransmitters. Administering reserpine causes dopamine to remain exposed within the cell and broken down by MAO. This profoundly reduces the available dopamine.
Changing the action of MAO can help us treat diseases that involve dopamine transmission. For instance, the drug deprenyl inhibits MAO. This increases the stores of dopamine and slows the progression of Parkinson’s disease. In higher doses, deprenyl enhances the effects of dopamine on behavior.
Interestingly, one form of MAO actually protects dopamine. This form of MAO, found in dopamine neurons, acts on substances in the neuron other than dopamine. Here MAO protects the “purity” of neurotransmission by breaking down other neurotransmitters. Inhibiting this form of MAO can increase levels of neurotransmitters such as serotonin, which seems to help people diagnosed with depression.
Drugs can also affect dopamine levels
Dopamine binds to its receptors quickly. This neurotransmitter is also quickly removed from its receptors as long as dopamine levels in the synapse are sufficiently high.
However, drugs can affect dopamine levels. Some drugs increase dopamine by preventing dopamine reuptake, leaving more dopamine in the synapse. An example is the widely abused stimulant drug, cocaine. Another is methylphenidate, used therapeutically to treat childhood hyperkinesis and symptoms of schizophrenia.
It’s interesting that amphetamine and cocaine produce affect behavior and heart function in similar ways. Furthermore, both drugs increase the amount of dopamine in the synapse. However, cocaine achieves this action by preventing dopamine reuptake, while amphetamine helps to release more dopamine. So, these drugs with similar effects produce their actions through entirely different processes. In turn, addiction to the two drugs may call for somewhat different types of treatment.

Neurons can become sensitized or desensitized to dopamine

One important aspect of drug addiction is how cells adapt to previous drug exposure.
For example, long-term treatment with dopamine antagonists increases the number of dopamine receptors. This happens as the nervous system tries to make up for less stimulation of the receptors by dopamine itself. Likewise, the receptors themselves become more sensitive to dopamine. Both are examples of the same process, called sensitization.
A type of sensitization.
An opposite effect occurs after dopamine or dopamine agonists repeatedly stimulate dopamine receptors. Here overstimulation decreases the number of receptors, and the remaining receptors become less sensitive to dopamine. This process is called desensitization.

Desensitization is better known as tolerance, where exposure to a drug causes less response than previously caused. Tolerance reflects the actions of the nervous system to maintain homeostasis -a constant degree of cell activity in spite of major changes in receptor stimulation. The nervous system maintains this constant level in an attempt to keep the body in a state of equilibrium, even when foreign chemicals are present.
Sensitization and desensitization do not take place only after long-term understimulation or overstimulation of dopamine receptors. Both sensitization and desensitization can occur after only a single exposure to a drug. In fact, they may develop within a few minutes.
A type of desensitization.
Disease and drugs can produce faulty sensitization
Sensitization or desensitization normally occur with drug exposure. However, addiction or mental illness can tamper with the reuptake system. This disrupts the normal levels of neurotransmitters in the brain and can lead to faulty desensitization or sensitization. If this happens in a region of the brain that serves emotion or motivation, the individual can suffer severe consequences.
Consider an example. Cocaine prevents dopamine reuptake by binding to proteins that normally transport dopamine. Not only does cocaine “bully” dopamine out of the way-it hangs on to the transport proteins much longer than dopamine does. As a result, more dopamine remains to stimulate neurons, which causes a prolonged feelings of pleasure and excitement. Amphetamine also increases dopamine levels. Again, the result is over-stimulation of these pleasure-pathway nerves in the brain.

Foods To Avoid When Taking Monoamine Oxidase Inhibitors

Q. Please review the dietary restrictions that should be observed when a patient is receiving monoamine oxidase inhibitor (MAOI) therapy?
R. Tyramine is an amino acid which is found in various foods, and is an indirect sympathomimetic that can cause a hypertensive reaction in patients receiving MAOI therapy.
Monoamine oxidase is found in the gastrointestinal tract and inactivates tyramine; when drugs prevent the catabolism of exogenous tyramine, this amino acid is absorbed and displaces norepinephrine from sympathetic nerve ending and epinephrine from the adrenal glands. If a sufficient amount of pressor amines are released, a patient may experience a severe occipital or temporal headache, diaphoresis, mydriasis, nuchal rigidity, palpitations, and the elevation of both diastolic and systolic blood pressure may ensue (Anon, 1989; Da Prada et al, 1988; Brown & Bryant, 1988).
On rare occasions, cardiac arrhythmias, cardiac failure, and intracerebral hemorrhage have developed in patients receiving MAOI therapy that did not observe dietary restrictions (Brown & Bryant, 1988).

Therefore, dietary restrictions are required for patients receiving MAOIs. Extensive dietary restrictions previously published were collected over a decade ago and due to changes in food processing and more reliable analytical methods, new recommendations have been published (Anon, 1989; McCabe, 1986).
The tyramine content of foods varies greatly due to the differences in processing, fermentation, ripening, degradation, or incidental contamination. Many foods contain small amounts of tyramine and the formation of large quantities of tyramine have been reported if products were aged, fermented, or left to spoil. Because the sequela from tyramine and MAOIs is dose-related, reactions can be minimized without total abstinence from tyramine-containing foods. Approximately 10 to 25 mg of tyramine is required for a severe reaction compared to 6 to 10 mg for a mild reaction. Foods that normally contain low amounts of tyramine may become a risk if unusually large quantities are consumed or if spoilage has occurred (McCabe, 1986).
Three lists were compiled (foods to avoid, foods that may used in small quantities, and foods with insufficient evidence to restrict) to minimized the strict dietary restrictions that were previously used and improve compliance and safety of MAOI therapy. The foods to avoid list consists of foods with sufficient tyramine (in small or usual serving sizes) that would create a dangerous elevation in blood pressure and therefore should be avoided (McCabe, 1986).

Avoid Alcohol

ALCOHOLIC BEVERAGES – avoid Chianti wine and vermouth. Consumption of red, white, and port WINE in quantities less than 120 mL present little risk (Anon, 1989; Da Prada et al, 1988; McCabe, 1986). BEER and ALE should also be avoided (McCabe, 1986), however other investigators feel major domestic (US) brands of beer is safe in small quantities (1/2 cup or less than 120 mL) (Anon, 1989; Da Prada, 1988),
but imported beer should not be consumed unless a specific brand is known to be safe. WHISKEY and LIQUEURS such as Drambuie(R) and Chartreuse(R) have caused reactions. NONALCOHOLIC BEVERAGES (alcohol- free beer and wines) may contain tyramine and should be avoided (Anon, 1989; Stockley, 1993).
BANANA PEELS – a single case report implicates a BANANA as the causative agent, which involved the consumption of whole stewed green banana, including the peel. Ripe banana pulp contains 7 mcg/gram of tyramine compared to a peel which contains 65 mcg/gram and 700 mcg of tyramine and dopamine, respectively (McCabe, 1986).
BEAN CURD – fermented bean curd, fermented soya bean, soya bean pastes contain a significant amount of tyramine (Anon, 1989).
BROAD (FAVA) BEAN PODS – these beans contain dopa, not tyramine, which is metabolized to dopamine and may cause a pressor reaction and therefore should not be eaten particularly if overripe (McCabe, 1986; Anon, 1989; Brown & Bryant, 1988).
CHEESE – tyramine content cannot be predicted based on appearance, flavor, or variety and therefore should be avoided. CREAM CHEESE and COTTAGE CHEESE have no detectable level of tyramine (McCabe, 1986; Anon, 1989, Brown & Bryant, 1988).
FISH – fresh fish (Anon, 1989; McCabe, 1986) and vacuum- packed pickled fish or CAVIAR contain only small amounts of tyramine and are safe if consumed promptly or refrigerated for short periods; longer storage may be dangerous (Anon, 1989). Smoked, fermented, pickled (Herring) and otherwise aged fish, meat, or any spoiled food may contain high levels of tyramine and should be avoided (Anon, 1989; Brown & Bryant, 1988).
GINSENG – some preparations have resulted in a headache, tremulousness, and manic-like symptoms (Anon, 1989).
PROTEIN EXTRACTS – three brands of meat extract contained 95, 206, and 304 mcg/gram of tyramine and therefore meat extracts should be avoided (McCabe, 1986). Avoid liquid and powdered PROTEIN DIETARY SUPPLEMENTS (Anon, 1989).
MEAT, nonfresh or liver – no detectable levels identified in fresh chicken livers; high tyramine content found in spoiled or unfresh livers (McCabe, 1986). Fresh meat is safe, caution suggested in restaurants (Anon, 1989; Da Prada et al, 1988).
SAUSAGE, BOLOGNA, PEPPERONI and SALAMI contain large amounts of tyramine (Anon, 1989; Da Prada et al, 1988; McCabe, 1986). No detectable tyramine levels were identified in country CURED HAM (McCabe, 1986).
SAUERKRAUT – tyramine content has varied from 20 to 95 mcg/gram and should be avoided (McCabe, 1986).
SHRIMP PASTE – contain a large amount of tyramine (Anon, 1989).
SOUPS – should be avoided as protein extracts may be present; miso soup is prepared from fermented bean curd and contain tyramine in large amounts and should not be consumed (Anon, 1989).
YEAST, Brewer’s or extracts – yeast extracts (Marmite) which are spread on bread or mixed with water, Brewer’s yeast, or yeast vitamin supplements should not be consumed. Yeast used in baking is safe (Anon, 1989; Da Prada et al, 1988; McCabe, 1986).
The foods to use with caution list categorizes foods that have been reported to cause a hypertensive crisis if foods were consumed in large quantities, stored for prolong periods, or if contamination occurred. Small servings (1/2 cup, or less than 120 mL) of the following foods are not expected to pose a risk for patients on MAOI therapy (McCabe, 1986).

(1/2 cup or less than 120 mL)
Alcoholic beverages – see under foods to avoid.
AVOCADOS – contain tyramine, particularly overripe (Anon, 1989) but may be used in small amounts if not overripened (McCabe, 1986).
CAFFEINE – contains a weak pressor agent, large amounts may cause a reaction (Anon, 1989).
CHOCOLATE – is safe to ingest for most patients, unless consumed in large amounts (Anon, 1989; McCabe, 1986).
DAIRY PRODUCTS – CREAM, SOUR CREAM, cottage cheese, cream cheese, YOGURT, or MILK should pose little risk unless prolonged storage or lack of sanitation standards exists (Anon, 1989; McCabe, 1986). Products should not be used if close to the expiration date (McCabe, 1986).
NUTS – large quantities of PEANUTS were implicated in a hypertensive reaction and headache. COCONUTS and BRAZIL NUTS have also been implicated, however no analysis of the tyramine content was performed (McCabe, 1986).
RASPBERRIES – contain tyramine and small amounts are expected to be safe (McCabe, 1986).
SOY SAUCE – has been reported to contain large amounts of tyramine and reactions have been reported with teriyaki (Anon, 1989), however analysis of soy sauce reveals a tyramine level of 1.76 mcg/mL and fermented meat may have contributed to the previously reported reactions (McCabe, 1986).
SPINACH, New Zealand prickly or hot weather – large amounts have resulted in a reaction (Anon, 1989; McCabe, 1986).
More than 200 foods contain tyramine in small quantities and have been implicated in reactions with MAOI therapy, however the majority of the previous reactions were due to the consumption of spoiled food. Evidence does not support the restriction of the following foods listed if the food is fresh (McCabe, 1986).
anchovies – cream cheese – raisins
beetroot – cucumbers – salad dressings
chips with vinegar – egg, boiled – snails
Coca Cola (R) – figs, canned – tomato juice
cockles – fish, canned – wild game
coffee – junket – worcestershire sauce
corn, sweet – mushrooms – yeast-leavened bread
cottage cheese – pineapple, fresh

Any protein FOOD, improperly stored or handled, can form pressor amines through protein breakdown. Chicken and beef liver, liver pate, and game generally contain high amine levels due to frequent mishandling. Game is often allowed to partially decompose as part of its preparation. Ayd (1986) reported that the freshness of the food is a key issue with MAOIs and that as long as foods are purchased from reputable shops and stored properly, the danger of a hypertensive crisis is minimal. Some foods should be avoided, the most dangerous being aged cheeses and yeast products used as food supplements (Gilman et al, 1985).
With appropriate dietary restrictions, the incidence of hypertensive crises has decreased to approximately 4% (Zisook, 1985). Treatment of a hypertensive reactions includes the=7F administration of phentolamine (Anon, 1989) 2.5 to 5 milligrams intravenously (slow) titrated against blood pressure (Zisook,=7F 1985; Lippman & Nash, 1990). One report has suggested that the use of sublingual nifedipine 10 milligrams was effective in treating 2 hypertensive reactions following the ingestion of a tyramine-containing food in a patient receiving MAOI therapy (Clary & Schweizerr, 1987). Chlorpromazine also has alpha-blocking properties and has been recommended as an agent for discretionary use (patient-initiated treatment) in the setting of dietary indiscretion (Lippman & Nash, 1990).
Dietary restrictions are required for individuals receiving monoamine oxidase inhibitor therapy to prevent a hypertensive crisis and other side effects.
The foods listed in the dietary restrictions have been categorized into those foods that must be avoided, foods that may be ingested in small quantities, and those foods that were previous implicated in reactions but upon analyses of fresh samples only a small tyramine content was identified and should be safe to consume if freshness is considered.

1. Anon: Foods interacting with MAOI inhibitors. Med. Lett. Drug Ther. 1989; 31:11-12.
2. Ayd FJ: Diet and monoamine oxidase inhibitors (MAOIs): an update. Int. Drug Ther. Newsletter 1986; 21:19-20.
3. Brown CS & Bryant SG: Monoamine oxidase inhibitors: safety and efficacy issues. Drug Intell. Clinical Pharmacy 1988; 22:232-235.
4. Clary C & Schweizer E: Treatment of MAOI hypertensive crisis with sublingual nifedipine. Journal Clinical Psychiatry 1987; 48:249-250.
5. Da Prada M, Zurcher G, Wuthrich I et al: On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J. Neural Transm. 1988; 26(Suppl):31-56.
6. Gilman AG, Goodman LS & Rall TW et al (Ed): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 7th ed., Macmillan Publishing, New York, NY, 1985.
7. Lippman SB & Nash K: Monoamine oxidase inhibitor update. Potential adverse food and drug interactions. Drug Safety 1990; 5:195-204.
8. McCabe BJ: Dietary tyramine and other pressor amines in MAOI regimens: a review. J. Am. Diet Assoc. 1986; 86:1059-1064.
9. Stockley I: Alcohol-free beer not safe for MAOI patients. Pharm. J. 1993; 250:174. 10. Zisook S: A clinical overview of monoamine oxidase inhibitors. Psychosomatics 1985; 26:240-251.
Theodore G Tong, Pharm D/C Hansen
Assistant Clinical Professor of Pharmacy
University of California
San Franscisco, California 94143
Revised by DRUGDEX(R) Editorial Staff
Denver, Colorado 80204, 09/82
Revised by DRUGDEX(R) Editorial Staff, 09/83; 07/85;07/86; 09/89; 04/93; 01/94
Stephen R. Saklad, Pharm.D. – saklad@uthscsa.edu
Psychiatric Pharmacy Program
The Univ Texas College of Pharmacy
(210) 567-8355 (Voice)
(210) 567-8328 (FAX)

Collected by
Connie Dello Buono
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