Acute Hypoglycemia Presenting as Methamphetamine psychosis

[Quercetin]

This thread intend to present the theory that acute hypoglycemia present itself as acute psychosis while under the intoxication of methamphetamine. The unusual presentation creating a diagnostic dilemma was repeatedly observed and attributed to the adrenergic attribute of the substance; anorectic activity, obsessive-compulsive behavior, etc.

Reediting is needed, acute psychosis is glutamate mediated.

I am writing this as we speak. Please be part of the project and ask question!


I am also active in
http://www.bluelight.ru/vb/threads/...research-on-cessation?p=10750516#post10750516
http://www.bluelight.ru/vb/threads/...oxicity-and-Tolerance-Reduction-Prevention-II

A study on methamphetamine psychosis in a psychiatric clinic
This study compares patients with acute methamphetamine psychosis to those with chronic methamphetamine psychosis and it investigates how the two groups differ in terms of psychosomatic findings, social background, and so on. The subjects consisted of 100 outpatients diagnosed at our clinic as having methamphetamine-induced psychosis over a period of sixteen years (1979 to 1995). Of these patients, 73 were of the acute type (currently using the drug or totally abstinent for less than 3 months), and 27 were of the chronic type (totally abstinent from the drug from 2 to 38 years). Psychosomatic Findings Ninety five patients (68 acute-type and 27 chronic-type) were classified into six clinical clusters, depending on which of the following states was dominant: paranoid-hallucinatory state, schizophrenia-like state, short-tempered and impulsive state, manic-depression-like state, neurosis-like state, and permanent-encephalopathic state. In the clinical cluster of paranoid-hallucinatory state, all 32 patients were of the acute-type. On the other hand, of those patients in the clinical cluster of neurosis-like state, the majority (N = 25) were of the chronic-type. Social Background The social background of 99 patients (72 acute-type and 27 chronic-type) was investigated under the three headings of: gangsters, criminal records and broken families. Of 19 patients who are gangsters, 18 cases were acute and the remaining case was chronic. Of 64 patients with criminal records, 51 were acute and 13 were chronic. Of 24 patients who come from broken families, 20 were acute and 4 were chronic. In all of these three items, the rate of acute-type patients was significantly higher than that of chronic-type patients. Based on the results obtained, the medical treatment and the prognosis of the patients, the author refers to preventive measures for stimulant-drug abuse.

 

[panic in paradise]

thanks

that is common with many substances and hardly ever mentioned.


if someone has it with out knowing in the first place their blood sugar can get low enough to be far worse then behavioral symptoms.

 

[Quercetin]

Insulin, glucose sensing, counterregulation

Methamphetamine-induced insulin release.
Administration of methamphetamine or amphetamine to rats and mice produces a rapid increase in the level of immunoassayable plasma insulin not attributable to hyperglycemia. While in the mouse this release of insulin is followed consistently by a profound hypoglycemia, in the rat this response is variable. Studies in vitro demonstrate that insulin is released by a direct effect of methamphetamine on the pancreas.

Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia.
An impaired ability to sense and appropriately respond to insulin-induced hypoglycemia is a common and serious complication faced by insulin-treated diabetic patients. This study tests the hypothesis that insulin acts directly in the brain to regulate critical glucose-sensing neurons in the hypothalamus to mediate the counterregulatory response to hypoglycemia. To delineate insulin actions in the brain, neuron-specific insulin receptor knockout (NIRKO) mice and littermate controls were subjected to graded hypoglycemic (100, 70, 50, and 30 mg/dl) hyperinsulinemic (20 mU/kg/min) clamps and nonhypoglycemic stressors (e.g., restraint, heat). Subsequently, counterregulatory responses, hypothalamic neuronal activation (with transcriptional marker c-fos), and regional brain glucose uptake (via (14)C-2deoxyglucose autoradiography) were measured. Additionally, electrophysiological activity of individual glucose-inhibited neurons and hypothalamic glucose sensing protein expression (GLUTs, glucokinase) were measured. NIRKO mice revealed a glycemia-dependent impairment in the sympathoadrenal response to hypoglycemia and demonstrated markedly reduced (3-fold) hypothalamic c-fos activation in response to hypoglycemia but not other stressors. Glucose-inhibited neurons in the ventromedial hypothalamus of NIRKO mice displayed significantly blunted glucose responsiveness (membrane potential and input resistance responses were blunted 66 and 80%, respectively). Further, hypothalamic expression of the insulin-responsive GLUT 4, but not glucokinase, was reduced by 30% in NIRKO mice while regional brain glucose uptake remained unaltered. Chronically, insulin acts in the brain to regulate the counterregulatory response to hypoglycemia by directly altering glucose sensing in hypothalamic neurons and shifting the glycemic levels necessary to elicit a normal sympathoadrenal response.

Hypothalamic nitric oxide in hypoglycemia detection and counterregulation: a two-edged sword.
Hypoglycemia is the main complication for patients with type 1 diabetes mellitus receiving intensive insulin therapy. In addition to the obvious deleterious effects of acute hypoglycemia on brain function, recurrent episodes of hypoglycemia (RH) have an even more insidious effect. RH impairs the ability of the brain to detect and initiate an appropriate counterregulatory response (CRR) to restore euglycemia in response to subsequent hypoglycemia. Knowledge of mechanisms involved in hypoglycemia detection and counterregulation has significantly improved over the past 20 years. Glucose sensitive neurons (GSNs) in the ventromedial hypothalamus (VMH) may play a key role in the CRR. VMH nitric oxide (NO) production has recently been shown to be critical for both the CRR and glucose sensing by glucose-inhibited neurons. Interestingly, downstream effects of NO may also contribute to the impaired CRR after RH. In this review, we will discuss current literature regarding the molecular mechanisms by which VMH GSNs sense glucose. Putative roles of GSNs in the detection and initiation of the CRR will then be described. Finally, hypothetical mechanisms by which VMH NO production may both facilitate and subsequently impair the CRR will be discussed.

Neuropeptide PACAP contributes to the glucagon response to insulin-induced hypoglycaemia in mice.
The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide in the autonomic nerves innervating the pancreatic islets and previous studies have shown that it stimulates insulin and glucagon secretion. It is known that autonomic nerve activation contributes to the glucagon response to hypoglycaemia. In the present study, we evaluated whether PACAP is involved in this glucagon response by examining the glucagon response to insulin-induced hypoglycaemia in mice genetically deleted of the specific PACAP receptor, the PAC1 receptor. We found that insulin (1 U kg-1 ip) reduced circulating glucose to a hypoglycaemic level of approximately 2.5 mmol L-1 in PAC1R-/- mice and their wild-type counterparts with no difference between the groups. However, the glucagon response to this hypoglycaemia was markedly impaired in the PAC1R-/- mice. Thus, after 120 min, plasma glucagon was 437 +/- 79 ng L-1 in wild-type mice vs. only 140 +/- 36 ng L-1 in PAC1R-/- mice (P=0.004). In contrast, the glucagon response to intravenously administered arginine (0.25 g kg-1) was the same in the two groups of mice. We conclude that PACAP through activation of PAC1 receptors contribute to the glucagon response to insulin-induced hypoglycaemia. Therefore, the glucagon response to hypoglycaemia is dependent not only on the classical neurotransmitters but also on the neuropeptide PACAP.


Glucose sensing neurons
Our laboratory studies the function of specialized glucose sensing neurons, which may enable the brain to sense and respond to the metabolic status of the body. We have shown that the glucose sensitivity of these neurons follows changes in peripheral energy status in both health and diabetes. Our long-term goal is to understand the cellular mechanisms allowing these neurons to sense glucose and respond to the metabolic state of the body in health, obesity and diabetes.

We have only to read the news or look around us to know that obesity and Type 2 diabetes mellitus are serious health issues. In fact, obesity and its associated co-morbidities (e.g., heart disease, hypertension, stroke, and cancer) are the second leading cause of death in the United States. Poor dietary habits and a sedentary lifestyle contribute to this epidemic. However, it is also clear that obesity and Type 2 diabetes mellitus are preceded by an underlying dysfunction in the regulation of energy homeostasis. One of the earliest indications of disease is peripheral insulin resistance combined with impaired insulin secretion in response to glucose. While most people probably do not suspect that their brain is at fault for their increasing waistline or diabetes, there is no doubt that the brain plays a major role in regulating energy homeostasis. Moreover, growing evidence indicates that dysfunction in the way that the brain senses nutrients contributes strongly to the development of peripheral insulin resistance. However, the mechanism wherein the brain actually senses and responds to the metabolic status of the body remains a mystery.

Glucose regulates specialized neurons. These “glucose sensing neurons” reside in a number of brain regions associated with energy homeostasis, including the ventromedial hypothalamus (VMH). We hypothesize that VMH glucose sensing neurons enable the brain to sense and respond to the body’s metabolic status. Moreover, aberration of these neurons impairs the brain’s regulation of energy homeostasis. Dr. Zhentao Song, a member of our research team, and I were the first to characterize glucose sensing neurons using glucose levels which would be seen in the living brain during normal daily fluctuations, as well as during diabetes. In the brain of a fed rat, glucose concentration is ~1.5 mM. After the equivalent of a day-long fast in humans, glucose concentration in the rat brain is 0.7 mM. During severe uncompensated diabetes, where glucose concentrations in the blood can reach 20 mM (360 mg/dl), brain glucose concentrations are 4.5 mM. There are two types of glucose sensing neurons which respond directly to changes in extracellular glucose concentration within this range. Glucose-inhibited (GI) neurons decrease, while glucose-excited (GE) neurons increase their activity as extracellular glucose levels increase. Their response to glucose is steeply linear from 0.5 to 1.5 mM, after which it begins to plateau, showing no further response above 5 mM. Therefore, GI and GE neurons are exquisitely sensitive to glucose concentrations seen in the brain under normal physiological conditions. Since glucose sensing neurons were originally studied in 10 or 20 mM glucose, it was not until we established that they respond to normal brain glucose levels that they could be seriously considered as mediators of the brain’s response to metabolic status.
A Control B Diabetic
Figure 1. Fluorescence of the nitric oxide (NO)-sensitive dye, diaminofluorescein
(DAF-FM) in glucose-inhibited (GI) neurons from the ventromedial hypothalamus (VMH). DAF-FM fluorescence increases when NO is produced. The presence of DAF-FM fluorescence in control rats indicates that VMH GI neurons produce nitric oxide under steady state conditions. DAF-FM fluorescence (NO production) increases in these neurons as extracellular glucose concentration decreases. In contrast, VMH GI neurons from diabetic rats do not produce nitric oxide under steady state conditions or in response to decreased glucose. Canabal et al., AJP 2007.

GI neurons sense glucose by AMP-activated protein kinase (AMPK) mediated regulation of a chloride channel (the cystic fibrosis transmembrane regulator, CFTR). Dr. Debra Canabal, a recent graduate from our laboratory who is now at Research Diets, showed that the gaseous messenger, nitric oxide (NO), is also involved in the glucose response of GI neurons. Like pancreatic beta cells, the effects of glucose in GE neurons are transduced by the ATP-sensitive potassium (KATP) channel. Victoria Cotero, a PhD candidate in our laboratory, discovered that insulin regulates the glucose sensitivity of GE neurons.

The glucose sensitivity of VMH glucose sensing neurons is related to the metabolic status of the body. For example, Beth Murphy, a PhD candidate in our laboratory, recently discovered that the glucose sensitivity of VMH GI neurons differs in the fed and fasted state; in fed mice glucose concentrations must decrease further to elicit the same response seen in GI neurons from fasted mice. This suggests that VMH GI neurons respond more strongly to decreased blood glucose when peripheral energy stores are depleted by a fast. Interestingly, when VMH GI neurons are exposed to “diabetic” levels of brain glucose (5 mM), they no longer alter their activity and NO production in response to glucose or insulin. Furthermore, NO production in VMH GI neurons is absent in rats with Type 1 diabetes mellitus (Figure 1). Both changes in GI neurons’ activity and NO production are restored when AMPK is re-activated. Alterations in GI and GE neurons may also lead to the development of Type 2 diabetes mellitus. We have shown that VMH GI and GE neurons, as well as VMH KATP channels are dysfunctional in pre-diabetic rats that Dr. Barry Levin (see next article) selectively bred for the genetic tendency to develop obesity and Type 2 diabetes mellitus after eating a diet frighteningly similar to the standard American diet.

Finally, hypoglycemia, the major limiting factor in intensive insulin therapy used for Type 1 and advanced Type 2 diabetes mellitus, prevents the brain from detecting future hypoglycemic episodes and generating protective responses that restore blood glucose levels to normal. Dr. Song’s work revealed that VMH GI and GE neurons from rats subjected to insulin-hypoglycemia are less sensitive to decreased glucose. Impaired NO production in GI neurons may be responsible. Dr. Xavier Fioramonti, a postdoctoral fellow in our laboratory, discovered that blocking VMH NO production also prevented the brain from generating the full protective response to hypoglycemia.

Thus, our data strongly suggest that VMH GI and GE neurons enable the brain to sense and respond to changes in metabolic status. Moreover, glucose sensitivity of VMH GI and GE neurons is reduced by diabetic hyperglycemia and insulin-induced hypoglycemia. Since the brain does not detect and respond normally to hypoglycemia under these conditions, it suggests that dysfunction in VMH GI and GE neurons underlies impaired brain glucose sensing. Finally, dysfunctional glucose sensing by VMH GI and GE neurons may play a role in the development of obesity and Type 2 diabetes mellitus. It is our long-term goal to understand the cellular mechanisms by which glucose sensing neurons sense glucose and how these mechanisms become dysfunctional during obesity and diabetes.

http://www.umdnj.edu/research/publications/fall07/index.htm

 

[Quercetin]

The diagnosis of Psychosis
Hypoglycaemia may produce a wide variety of mental state derangements via neuroglycope-nia, and this includes psychosis and focal neurological deficit, as well as the typical features of acute neuroglycopenia (anxiety, agitation including violence, sweating, tremor, tachycardia, hunger, parenthesis, confusion, fatigue, speech and visual disturbances) and subacuteneuroglycopenia (decreased activity, somnolence, poor concentration, personality change,amnesia) both of which can progress to coma and death. Sympathetic overactivity is usually present as a compensatory mechanism, but may be attenuated by drugs that block adrenergic or cholinergic function, or by disease. Tose with a history of frequent hypoglycaemia may lose awareness of the early symptoms and develop subacuteneuroglycopenia. Te cause of hypoglycaemia is usually exogenous insulin or oral hypogly-caemic drugs taken in excess of food (acutely or sometimes chronically), reactive hypogly-caemia (hypoglycaemia secondary to insulin release following a dietary carbohydrate load,though this is rarely severe enough to cause severe neuroglycopenic symptoms), or poison-ing (e.g. alcohol, typically 2–16 hours after heavy consumption), and less commonly endog-enous insulin excess (e.g. insulinoma), a deficiency in glucose synthesis or mobilization(e.g. adrenal insufciency, hypothyroidism, liver failure), serious infections (e.g. malaria),prolonged starvation, and a wide range of other causes. Initial diagnosis of hypoglycaemia should be obvious if fingerprint glucose testing is undertaken along withclinical history and examination; hypoglycaemia is usually defined as a glucose level below 3 mM. Emergency treatment with oral or intravenous glucose (according to level of consciousness) is required, with oxygen if necessary. Hypoglycaemia requires explanation: if the cause is not obvious, it should be hunted for thoroughly.

http://www.scribd.com/doc/69900216/The-Diagnosis-of-Psychosis

Acute Hypoglycemia Presenting as Acute Psychosis
We are presenting a unique case of acute hypoglycemia presenting as acute psychosis with an unusual presentation creating a diagnostic dilemma. Medline search was done using the search words hypoglycemia and psychosis and to the best of our knowledge this is the first reported case of hypoglycemia presenting as acute psychosis. Unsuspected hypoglycemia may masquerade as neurologic, psychiatric, traumatic, or toxicologic disorders. Hypoglycemia has been misdiagnosed as cerebrovascular accident, transient ischemic attack, seizure disorder, brain tumor, narcolepsy, multiple sclerosis, psychosis, sympathomimetic drug ingestion, hysteria, and depression and also can masquerade as traumatic head injury with varying degrees of altered mentation, as well as cardiac arrhythmia with bradycardia. Our case provides a unique look at how a simple abnormality when overlooked can present as a difficult diagnostic challenge for both medicine and psychiatry services. Particular care should be exercised when dealing with psychiatric patients with these entities so that hypoglycemia is not missed. Significant medical harm to the patient and medicolegal risks for the emergency physician are issues to consider in cases involving misdiagnosis, incorrect therapy, and inappropriate disposition.

Introduction:
Almost 7% patients presenting with altered mental status to the ED are in fact hypoglycemic. In addition to the diabetic patient, numerous other clinical scenarios may involve hypoglycemia, including toxicologic, infectious, psychiatric, and metabolic syndrome presentations. (4)(5) The patient’s clinical presentation and history, however, may lead the provider to attribute the signs and symptoms to other conditions such as a cerebrovascular accident, status epilepticus, intoxication, sepsis, traumatic injury or severe psychotic agitation. (6-10) rather than to hypoglycemia Patients with hypoglycemia may present to the ED with a range of signs and symptoms that can be divided into two broad categories: neuroglycopenic and hyperepinephrinemic. As glucose is the main energy source for the CNS, it is not surprising that most episodes of symptomatic hypoglycemia present with neurologic dysfunction. When there is a decline in serum sugar, the brain quickly exhausts its reserve supply of carbohydrate fuel, thus resulting in CNS dysfunction, which is manifested most commonly as alteration in consciousness such as lethargy, confusion, and unresponsiveness. More importantly, for the psychiatrist, the patients may present with agitation and combativeness. Other neuroglycopenic manifestations include convulsive activity and the development of focal neurologic deficits. A review of 125 cases of hypoglycemia presenting to an urban ED showed that the neuroglycopenic findings predominated. (4) Depressed sensorium was noted in 52% of cases, with other mental status changes (e.g., agitation and combativeness) found in 30% of patients. Described less frequently, seizure activity and focal neurological findings were encountered in 7% and 2% of of patients, respectively. (4) In the absence of neuronal damage, these neurologic deficits should reverse with the administration of glucose and do not require aggressive evaluation such as a computed tomography (CT) scan of the head.

Case Report:
Mr. X is a 56-year-old African American male with history of schizoaffective disorder and multiple prior psychiatric admissions, resident of a community residence who was brought in by police to the psychiatric emergency room secondary to agitation and combative behavior at his residence. Medical history was significant for diet-controlled hypertension; old Apical MI and GI bleed in 1992. In the ER Mr. X was calm and cooperative and claimed that other residents were bothering him at the community residence. Mr. X was admitted to the psychiatric ward and put on his usual medications which included:

Depakote 500 mg orally BID
Seroquel 200 mg orally BID
Haldol 5 mg orally BID
Trilafon 16mg orally in am and 32 mg orally at bedtime
Ativan 0.5 mg orally BID

Once on the psychiatric unit Mr. X immediately became extremely agitated. He was yelling, screaming, making animal sounds, banging his head against the wall and his speech was incoherent. His eyes were rolled back and he became very combative which prompted the physician on call to restrain the patient for his own safety. He was given cogentin 2mg IM secondary to his EPS like presentation as he was on high doses of multiple psychotropics however there was no change in his condition. While on restraints the patient had streaks of red dried blood coming out of his mouth. Because of severe agitation patient was given 6 mg of ativan in divided doses, which controlled his agitation for only a brief period of time before he became combative again. Stat neurological and medical consultations were sought. According to the neurologist a seizure was unlikely as patient was conscious and neurological exam was non-focal. Medical consult could not identify any obvious cause for this unusual presentation and decided to transfer the patient to medical intensive care unit for further management. The initial investigations revealed:

Vitals: T 98.8F, P 107,R 18, BP
Urine toxicology- negative
CBC- WNL
CMP- Blood glucose of 10mg/dL, Electrolytes WNL
CT scan head- Negative for any bleed

Mr. X was given 50% IV glucose and repeat blood sugar was done which was 22mg/dL. Patient’s condition started to improve and after two hours the blood glucose was 210mg/dL. By that time there was marked change in Mr. X’s condition and his only complaint was hunger. He was transferred to medical floor and psychiatric and endocrinology consult were sought. Psychiatric consult did not believe that sudden change in the blood glucose was due to any psychotropic medications. Endocrinology workup was negative for any obvious cause of hypoglycemia including insulinoma and extra pancreatic neoplasms. All three specialties agreed that patient’s low blood sugar could have been a result of exogenous insulin or oral hypoglycemic administration most likely due to medication error at the community residence. Mr. X was discharged to the community residence in stable condition.

Research in healthy adults shows that mental efficiency measurably declines as blood glucose falls below 65mg/dL. The actual level of blood glucose that causes CNS deprivation and produces symptoms is highly individual. The glucose level may be influenced by factors such as age, sex, weight, dietary history, physical activity, emotion, and coexisting disease. Many reports exist of asymptomatic individuals with plasma glucose levels of 35 mg/dL or lower and of individuals who are symptomatic with glucose levels in the normal range. The actual value of plasma glucose that defines hypoglycemia is somewhat arbitrary. The clinical state of the patient must be correlated with the glucose determination. Hypoglycemic symptoms and manifestations can be divided into those produced by the counterregulatory hormones (adrenaline and glucagon) triggered by the falling serum glucose, and the neuroglycopenic effects produced by the reduced brain sugar.

Adrenergic Manifestations
• Shakiness, anxiety, nervousness, tremor
• Palpitations, tachycardia
• Sweating, feeling of warmth
• Pallor, coldness, clamminess
• Dilated pupils
Glucagon Manifestations
• Hunger, borborygmus
• Nausea, vomiting, abdominal discomfort
Neuroglycopenic Manifestations
• Abnormal mentation, impaired judgment
• Nonspecific dysphoria, anxiety, moodiness, depression, crying, fear of dying
• Negativism, irritability, belligerence, combativeness, rage
• Personality change, emotional lability
• Fatigue, weakness, apathy, lethargy, daydreaming, sleepiness
• Confusion, amnesia, dizziness, delirium
• Staring, "glassy" look, blurred vision, double vision
• Automatic behavior
• Difficulty speaking, slurred speech
• Ataxia, incoordination, sometimes mistaken for "drunkenness"
• Focal or general motor deficit, paralysis, hemiparesis
• Paresthesias, headache
• Stupor, coma, abnormal breathing
• Generalized or focal seizures

Not all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by the severity. In young children, vomiting often accompanies morning hypoglycemia with ketosis. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects. The symptoms of a single person do tend to be similar from episode to episode

Plasma glucose levels should be determined in all patients who are comatose, have a seizure, have a disturbance of sensorium, have taken a drug overdose, smell of alcohol, or have funny spells that are undefined. Random glucose levels should be determined in all diabetic patients with clinically significant complaints who come to the psychiatric ED.

Hypoglycemia may present without classic symptoms especially in elderly patients and may imitate every neurological symptom. Our case illustrates the importance of considering hypoglycemia in every case of change in mental status, acute neurological deficits, acute psychosis, acute agitation even when clinical findings seem to be explained by other causes. An immediate blood glucose test should be done to exclude hypoglycemia.

Acute psychotic disorder and hypoglycemia.
A variable array of neuroglycopenic symptoms are frequently encountered in the hypoglycemic stage, but acute psychotic disorders are quite rare. A fifty five year old female presented with an acute psychosis following oral sulfonylurea induced hypoglycemia without preceding features of adrenomedullary stimulation. This case report suggests that an acute and transient psychotic disorder may be an important neuroglycopenic feature and its early recognition protects the patient from severe hypoglycemic brain damage in a state of hypoglycemia unawareness.

Insulinoma: A commonly misdiagnosed pancreatic tumour
Insulinomas are rare tumors of the neuroendocrine variety. Importantly, insulinomas are seldom malignant; if metastatic disease is not found at the time of initial diagnosis, it is unlikely to develop in the future (albeit rare metachronous metastases and local recurrence at the surgical site have been reported). Symptoms due to excessive insulin secretion can mimic psychoses and misdiagnosis is common. We report the case of a twenty five year old man who was treated for four years as a case of psychosis. It was only when one of the physicians got a fasting blood sugar level done that the diagnosis of insulinoma was suspected. He had a three centimeter tumour in the uncinate process which was enucleated and the patient was cured. Thus, accurate diagnosis is essential for this potentially curable condition.

Episodic confusional state: Due to insulinoma
This case report deals with 45-year-old male who came for consultation in the psychiatry department for the persisting symptoms, after consulting various departments with no relief. He had episodes of confusion with disorganized behavior, restlessness, and symptoms like talking irrelevantly once a week lasting up to 10-30 min in the preceding six months. Investigations like computerized tomography scan, electroencephalogram were not contributory. While under observation in our ward for evaluation and diagnosis, one such episode with intense sweating and clouding of consciousness was witnessed and helped in clinching the diagnosis of insulinoma. The case is reported for its rarity and as one of the causes of episodic confusional state. Most of the patients present with neuropsychiatric symptoms and are often misdiagnosed as dissociative disorder psychosis.

Hypoglycemia induced behavioural deficit and decreased GABA receptor, CREB expression in the cerebellum of streptozoticin induced diabetic rats.
http://www.ncbi.nlm.nih.gov/pubmed/20851745
Intensive glycemic control during diabetes is associated with an increased incidence of hypoglycemia, which is the major barrier in blood glucose homeostasis during diabetes therapy. The CNS neurotransmitters play an important role in the regulation of glucose homeostasis. In the present study, we showed the effects of hypoglycemia in diabetic and non- diabetic rats on motor functions and alterations of GABA receptor and CREB expression in the cerebellum. Cerebellar dysfunction is associated with seizure generation, motor deficits and memory impairment. Scatchard analysis of [(3)H]GABA binding in the cerebellum of diabetic hypoglycemic and control hypoglycemic rats showed significant (P<0.01) decrease in B(max) and K(d) compared to diabetic and control rats. Real-time PCR amplification of GABA receptor subunit GABA(Aα1) and GAD showed significant (P<0.001) down-regulation in the cerebellum of hypoglycemic rats compared to diabetic and control rats. Confocal imaging study confirmed the decreased GABA receptors in hypoglycemic rats. CREB mRNA expression was down-regulated during recurrent hypoglycemia. Both diabetic and non-diabetic hypoglycemic rats showed impaired performance in grid walk test compared to diabetic and control. Impaired GABA receptor and CREB expression along with motor function deficit were more prominent in hypoglycemic rats than hyperglycemic which showed that hypoglycemia is causing more neuronal damage at molecular level. These molecular changes observed during hypo/hyperglycemia contribute to motor and learning deficits which has clinical significance in diabetes treatment.

 

[panic in paradise]

well done, a lot of 'problem drinking' could be explained this way also.

 

[Quercetin]

well done, a lot of 'problem drinking' could be explained this way also.

Ethanol-induced Alterations of Glucose Tolerance, Postglucose Hypoglycemia, and Insulin Secretion in Normal, Obese, and Diabetic Subject
Ethanol at an average blood concentration of 1 mg. per milliliter enhanced the immediate (first-phase) and prolonged (second-phase) insulin response to an intravenous glucose load in nonfasting normal human subjects. Simultaneously, the glucose disposal rate was increased and the postglucose hypoglycemia was accentuated, resulting in definite hypoglycemic symptoms in some individuals. Oral glucose tolerance was not changed by ethanol administration, but the thirty-minute blood glucose and plasma insulin values were increased, suggesting that alcohol might accelerate the absorption of glucose from the gut. Ethanol given orally during evening hours (1.5 gm. per kilogram) caused a nocturnal hyperinsulinemia and a decrease of blood glucose, but not an actual hypoglycemia. Oral glucose tolerance and plasma insulin response tested the next morning, when ethanol had disappeared from the blood, were not influenced by drinking the previous evening. The K-value of intravenous glucose was increased at this time, however. When alcohol was administered for one week at a dose corresponding to 25 per cent of daily calories and substituting for fat, both the oral and intravenous glucose tolerances were impaired in each subject but the insulin response remained unchaged.In obese nondiabetic subjects, ethanol did not potentiate the early insulin response to intravenous glucose but it increased the second phase of insulin secretion in response to sustained hyperglycemia. In contrast to conditions in nonobese subjects, the glucose disposal rate was not incresed and postglucose hypoglycemia was not accentuated by ethanol in overweight subjects. In insulin-deficient diabetic patients the absent early insulin response could not be restored by ethanol, and the late component of insulin release was little increased by alcohol infusion. Ethanol did not improve the glucose utilization of diabetic patients.

Ethanol will not cause hyperglycemia like methamphetamine.

 

[Wizzle]

Slightly OT, but in regards to Mr. X: Is it common for patients to be prescribed three different antipsychotics? I work in the psychiatric field and the tendency is to use only one AP, although sometimes two are used, usually one typical and one atypical.

 

[IndustrialStrength]

I for one am. So yes please do. I don't post much in this forum but I enjoy the reading material immensely.
Thanks for the time you've spent on the subject & any further time you may spend.
Any additional information I believe is usually valued by the community here.

 

[Epsilon Alpha]

I was gonna write more.. but is anybody interested?

Keep up the good work! I've been reading intently, but my question to you is do you think amphetamine's effects on thyroid hormone levels plays a significant role in this phenomenon?

 

[Quercetin]

Keep up the good work! I've been reading intently, but my question to you is do you think amphetamine's effects on thyroid hormone levels plays a significant role in this phenomenon?

UCP3 and thyroid hormone involvement in methamphetamine-induced hyperthermia.
Here, we determined the extent of hypothalamic-pituitary-thyroid (HPT) axis and uncoupling protein-3 (UCP3) involvement in methamphetamine (METH)-induced hyperthermia. Sprague-Dawley rats treated with METH (40mg/kg, s.c.) responded with a hyperthermic response that peaked 1h post-treatment and was sustained through 2h. After METH treatment, thyroparathyroidectomized (TX) animals developed hypothermia that was sustained for the 3h monitoring period. In TX animals supplemented for 5 days with levothyroxine (100microg/kg, s.c.), METH-induced hypothermia was eliminated and the hyperthermic response was restored. Thyroid hormone levels (T3 and T4), measured in euthyroid animals 1h after METH, remained unchanged. As seen in rats, 1h post-METH (20mg/kg, i.p.) treatment, wild-type (WT) mice developed profound hyperthermia that was sustained for 2h. In marked contrast, UCP3-/- animals developed a markedly blunted hyperthermic response at 1h compared to WT animals. Furthermore, UCP3-/- mice could not sustain this slight elevation in temperature. Two hours post-METH treatment, UCP3-/- animal temperature returned to baseline temperatures. UCP3-/- mice were also completely protected against the lethal effects of METH, whereas 40% of WT mice succumbed to the hyperthermia. These findings suggest that thyroid hormone plays a permissive role in the thermogenic effects induced by METH. Furthermore, the findings indicate that UCP3 plays a major role in the development and maintenance of the hyperthermia induced by METH. The relationship of these results to the hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is also discussed.

Acute and prolonged effects of insulin-induced hypoglycemia on the pituitary-thyroid axis in humans.
Secretory activity of the pituitary-thyroid axis and thyroid hormone metabolism show characteristic changes in response to different stressors often referred to as the euthyroid sick syndrome. Hypoglycemia is an acute metabolic stressor inducing various neuroendocrine responses, the effects of which on pituitary-thyroid secretory activity so far have been entirely neglected. We performed stepwise hypoglycemic and euglycemic clamps each lasting 6 hours in 30 healthy men. To assess the potential influence of hyperinsulinemia on pituitary-thyroid hormone release, 2 different rates of insulin infusion were used for the clamps. During the hypoglycemic clamps, serum thyroid-stimulating hormone (TSH) concentration decreased in comparison to the euglycemic condition on average by 28% +/- 4% (P <.001), while serum concentration of free triiodothyronine (fT3), free thyroxine (fT4), and thyroxine-binding globulin (TBG) remained unchanged. The effect did not depend on the rate of insulin infusion. To assess the prolonged effect of acute hypoglycemia on pituitary-thyroid secretory activity, serum TSH and thyroid hormone concentrations were subsequently measured in another 15 healthy men before and 18 hours after 2 consecutive hypoglycemic clamps together lasting about 270 minutes. Compared with values before the hypoglycemic clamps, serum levels of TSH, fT3, and fT4 were found to be still reduced (by 44% +/- 6%, 12% +/- 2%, and 10% +/- 1%, respectively) 18 hours after the last hypoglycemic episode (P <.001 for all comparisons). The observed hormonal changes after hypoglycemia were not accompanied by any change in resting energy expenditure (REE). Data indicate acute as well as prolonged inhibitory influences of hypoglycemia on pituitary-thyroid secretory activity. The pattern of changes suggests that hypoglycemia exerts its influence primarily at a central, ie, pituitary and/or hypothalamic, site of the axis.

Thyroid hormone pay a major role in many neurological and metabolic function.

 

[Epsilon Alpha]

I will be experimenting this weekend. Thyroid hormone T3 50mcg and Methamphetamine 100mg will be consumed orally every 6h for 144h.

Be careful, unless you've got a severe thyroid deficiency you could seriously hurt yourself. T3/4 are well known to upregulate B1 adrenoreceptors in addition to its vasoconstrictive, metabolism boosting, and glycogen depleting effects. I personally suggest you don't attempt, or if you do at least have a beta blocker and a cold shower on hand.

For those who are unfamiliar with B1 agonists, they are responsible for epinephrine's effects on heart rate.
http://www.jbc.org/content/266/24/15863.short

 

[RR279]

Be careful, unless you've got a severe thyroid deficiency you could seriously hurt yourself. T3/4 are well known to upregulate B1 adrenoreceptors in addition to its vasoconstrictive, metabolism boosting, and glycogen depleting effects. I personally suggest you don't attempt, or if you do at least have a beta blocker and a cold shower on hand.

For those who are unfamiliar with B1 agonists, they are responsible for epinephrine's effects on heart rate.
http://www.jbc.org/content/266/24/15863.short

Agreed. Hyperthyroidism(or thyroid storm, rather) present almost exactly the same as stimulant OD. Mixing T3/4 with meth just seems like mixing nitro and glycerin(which you just may very well come to need if the cardiac vasoconstriction becomes symptomatic.)

 

[Limpet_Chicken]

If you are determined to try this, 100mg of meth seems grossly excessive. I wouldn't go with any more than 10-15mg.

 

[P A]

Inb4 "Are you still alive, OP?"

 

[Quercetin]

Neuroglycopenia

Neuroglycopenia is a medical term that refers to a shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia. Glycopenia affects the function of neurons, and alters brain function and behavior.

Signs and symptoms of neuroglycopenia
Abnormal mentation, impaired judgement
Nonspecific dysphoria, anxiety, moodiness, depression, crying, fear of dying, suicidal thoughts
Negativism, irritability, belligerence, combativeness, rage
Personality change, emotional lability
Fatigue, weakness, apathy, lethargy, daydreaming, sleep
Confusion, amnesia, dizziness, delirium
Staring, "glassy" look, blurred vision, double vision
Automatic behavior
Difficulty speaking, slurred speech
Ataxia, incoordination, sometimes mistaken for "drunkenness"
Focal or general motor deficit, paralysis, hemiparesis
Paresthesia, headache
Stupor, coma, abnormal breathing
Generalized or focal seizures

Not all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by the severity of the hypoglycemia. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects or a hard-to-define malaise. The symptoms of a single person do tend to be similar from episode to episode.

Most neurons have the ability to use other fuels besides glucose (e.g., lactic acid, ketones). Our knowledge of the "switchover" process is incomplete. The most severe neuroglycopenic symptoms occur with hypoglycemia caused by excess insulin because insulin reduces the availability of other fuels by suppressing ketogenesis and gluconeogenesis.

A few types of specialized neurons, especially in the hypothalamus, act as glucose sensors, responding to changing levels of glucose by increasing or decreasing their firing rates. They can elicit a variety of hormonal, autonomic, and behavioral responses to neuroglycopenia. The hormonal and autonomic responses include release of counterregulatory hormones. There is some evidence that the autonomic nervous system can alter liver glucose metabolism independently of the counterregulatory hormones.

Compensatory responses to neuroglycopenia
Adjustment of efficiency of transfer of glucose from blood across the blood–brain barrier into the central nervous system represents a third form of compensation which occurs more gradually. Levels of glucose within the central nervous system are normally lower than the blood, regulated by an incompletely understood transfer process. Chronic hypoglycemia or hyperglycemia seems to result in an increase or decrease in efficiency of transfer to maintain CNS levels of glucose within an optimal range.

Neuroglycopenia without hypoglycemia
In both young and old patients, the brain may habituate to low glucose levels, with a reduction of noticeable symptoms, sometimes despite neuroglycopenic impairment. In insulin-dependent diabetic patients this phenomenon is termed hypoglycemia unawareness and is a significant clinical problem when improved glycemic control is attempted. Another aspect of this phenomenon occurs in type I glycogenosis, when chronic hypoglycemia before diagnosis may be better tolerated than acute hypoglycemia after treatment is underway.
Neuroglycopenia without hypoglycemia.

 

[Quercetin]

Blood-brain barrier & Methamphetamine

Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction.
Methamphetamine (METH), an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB) function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB) to date.In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM) increased the expression of glucose transporter protein-1 (GLUT1) in primary human brain endothelial cell (hBEC, main component of BBB) without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB) aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function.Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

Methamphetamine inhibits the glucose uptake by human neurons and astrocytes: stabilization by acetyl-L-carnitine.
Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 µM increased the uptake while 200 µM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial β-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers.

Methamphetamine disrupts blood-brain barrier function by induction of oxidative stress in brain endothelial cells.
Methamphetamine (METH), a potent stimulant with strong euphoric properties, has a high abuse liability and long-lasting neurotoxic effects. Recent studies in animal models have indicated that METH can induce impairment of the blood-brain barrier (BBB), thus suggesting that some of the neurotoxic effects resulting from METH abuse could be the outcome of barrier disruption. In this study, we provide evidence that METH alters BBB function through direct effects on endothelial cells and explore possible underlying mechanisms leading to endothelial injury. We report that METH increases BBB permeability in vivo, and exposure of primary human brain microvascular endothelial cells (BMVEC) to METH diminishes the tightness of BMVEC monolayers in a dose- and time-dependent manner by decreasing the expression of cell membrane-associated tight junction (TJ) proteins. These changes were accompanied by the enhanced production of reactive oxygen species, increased monocyte migration across METH-treated endothelial monolayers, and activation of myosin light chain kinase (MLCK) in BMVEC. Antioxidant treatment attenuated or completely reversed all tested aspects of METH-induced BBB dysfunction. Our data suggest that BBB injury is caused by METH-mediated oxidative stress, which activates MLCK and negatively affects the TJ complex. These observations provide a basis for antioxidant protection against brain endothelial injury caused by METH exposure.

Methamphetamine transiently increases the blood-brain barrier permeability in the hippocampus: role of tight junction proteins and matrix metalloproteinase-9.
Methamphetamine (METH) is a powerful stimulant drug of abuse that has steadily gained popularity worldwide. It is known that METH is highly neurotoxic and causes irreversible damage of brain cells leading to neurological and psychiatric abnormalities. Recent studies suggested that METH-induced neurotoxicity might also result from its ability to compromise blood-brain barrier (BBB) function. Due to the crucial role of BBB in the maintenance of brain homeostasis and protection against toxic molecules and pathogenic organisms, its dysfunction could have severe consequences. In this study, we investigated the effect of an acute high dose of METH (30mg/kg) on BBB permeability after different time points and in different brain regions. For that, young adult mice were sacrificed 1h, 24h or 72h post-METH administration. METH increased BBB permeability, but this effect was detected only at 24h after administration, being therefore a transitory effect. Interestingly, we also found that the hippocampus was the most susceptible brain region to METH, comparing to frontal cortex and striatum. Moreover, in an attempt to identify the key players in METH-induced BBB dysfunction we further investigated potential alterations in tight junction (TJ) proteins and matrix metalloproteinase-9 (MMP-9). METH was able to decrease the protein levels of zonula occludens (ZO)-1, claudin-5 and occludin in the hippocampus 24h post-injection, and increased the activity and immunoreactivity of MMP-9. The pre-treatment with BB-94 (30mg/kg), a matrix metalloproteinase inhibitor, prevented the METH-induced increase in MMP-9 immunoreactivity in the hippocampus. Overall, the present data demonstrate that METH transiently increases the BBB permeability in the hippocampus, which can be explained by alterations on TJ proteins and MMP-9.

Methamphetamine alters blood brain barrier permeability via the modulation of tight junction expression: Implication for HIV-1 neuropathogenesis in the context of drug abuse.
The pathogenesis of human immunodeficiency virus (HIV) associated encephalopathy is attributed to infiltration of the central nervous system (CNS) by HIV-1 infected mononuclear cells that transmigrate across the blood brain barrier (BBB). The endothelial tight junctions (TJ) of the blood brain barrier (BBB) play a critical role in controlling cellular traffic into the CNS. Neuropathogenesis of HIV-1 is exacerbated by drugs of abuse such as methamphetamine (Meth) which are capable of dysregulating BBB function. HIV-1 viral proteins like gp120 are both neurotoxic and cytotoxic and have been implicated in the development of HIV-1 dementia (HAD). We hypothesize that gp120 in synergy with Meth can alter BBB permeability via the modulation of tight junction expression. We investigated the effect of Meth and/or gp120 on the basal expression of TJ proteins ZO-1, JAM-2, Occludin, Claudin-3 and Claudin-5, using in vitro cultures of the primary brain microvascular endothelial cells (BMVEC). Further, the functional effects of TJ modulation were assessed using an in vitro BBB model, that allowed measurement of BBB permeability using TEER measurements and transendothelial migration of immunocompetent cells. Our results show that both Meth and gp120 individually and in combination, modulated TJ expression, and these effects involved Rho-A activation. Further, both Meth and gp120 alone and in combination significantly decreased transendothelial resistance across the in vitro BBB and the enhanced transendothelial migration of immunocompetent cells across the BBB. An understanding of the mechanisms of BBB breakdown that lead to neurotoxicity is crucial to the development of therapeutic modalities for Meth abusing HAD patients.

 

[Quercetin]

Metabolism & L-Carnitine

To treat symptoms of hyperthyroidism: L-Carnitine is a peripheral antagonist of thyroid hormone
It inhibits the entry of triiodo thyronine and thyroxine into the cell nuclei. Through a randomized trial, Benvenga et al. showed that 2–4 g of oral L-carnitine per day could reverse hyperthyroid symptoms even in the most serious form of hyperthyroidism: thyroid storm. They suggest that since hyperthyroidism impoverishes the tissue deposits of carnitine, there is a rationale for using L-carnitine at least in certain clinical settings. Incidentally, the fact that carnitine failed to prevent relapses of hyperthyroidism further supports the concept that carnitine action is in the periphery and not in the thyroid gland.

Role of carnitine esters in brain neuropathology.
L-Carnitine (L-C) is a naturally occurring quaternary ammonium compound endogenous in all mammalian species and is a vital cofactor for the mitochondrial oxidation of fatty acids. Fatty acids are utilized as an energy substrate in all tissues, and although glucose is the main energetic substrate in adult brain, fatty acids have also been shown to be utilized by brain as an energy substrate. L-C also participates in the control of the mitochondrial acyl-CoA/CoA ratio, peroxisomal oxidation of fatty acids, and the production of ketone bodies. Due to their intrinsic interaction with the bioenergetic processes, they play an important role in diseases associated with metabolic compromise, especially mitochondrial-related disorders. A deficiency of carnitine is known to have major deleterious effects on the CNS. Several syndromes of secondary carnitine deficiency have been described that may result from defects in intermediary metabolism and alterations principally involving mitochondrial oxidative pathways. Mitochondrial superoxide formation resulting from disturbed electron transfer within the respiratory chain may affect the activities of respiratory chain complexes I, II, III, IV, and V and underlie some CNS pathologies. This mitochondrial dysfunction may be ameliorated by L-C and its esters. In addition to its metabolic role, L-C and its esters such as acetyl-L-carnitine (ALC) poses unique neuroprotective, neuromodulatory, and neurotrophic properties which may play an important role in counteracting various disease processes. Neural dysfunction and metabolic imbalances underlie many diseases, and the inclusion of metabolic modifiers may provide an alternative and early intervention approach, which may limit further developmental damage, cognitive loss, and improve long-term therapeutic outcomes. The neurophysiological and neuroprotective actions of L-C and ALC on cellular processes in the central and peripheral nervous system show such effects. Indeed, many studies have shown improvement in processes, such as memory and learning, and are discussed in this review.

The protective role of L-carnitine against neurotoxicity evoked by drug of abuse, methamphetamine, could be related to mitochondrial dysfunction.
There is growing evidence that suggests that brain injury after amphetamine and methamphetamine (METH) administration is due to an increase in free radical formation and mitochondrial damage, which leads to a failure of cellular energy metabolism followed by a secondary excitotoxicity. Neuronal degeneration caused by drugs of abuse is also associated with decreased ATP synthesis. Defective mitochondrial oxidative phosphorylation and metabolic compromise also play an important role in atherogenesis, in the pathogenesis of Alzheimer's disease, Parkinson's disease, diabetes, and aging. The energy deficits in the central nervous system can lead to the generation of reactive oxygen and nitrogen species as indicated by increased activity of the free radical scavenging enzymes like catalase and superoxide dismutase. The METH-induced dopaminergic neurotoxicity may be mediated by the generation of peroxynitrite and can be protected by antioxidants selenium, melatonin, and selective nNOS inhibitor, 7-nitroindazole. L-Carnitine (LC) is well known to carry long-chain fatty acyl groups into mitochondria for beta-oxidation. It also plays a protective role in 3-nitropropioinc acid (3-NPA)-induced neurotoxicity as demonstrated in vitro and in vivo. LC has also been utilized in detoxification efforts in fatty acid-related metabolic disorders. In this study we have tested the hypothesis that enhancement of mitochondrial energy metabolism by LC could prevent the generation of peroxynitrite and free radicals produced by METH. Adult male C57BL/6N mice were divided into four groups. Group I served as control. Groups III and IV received LC (100 mg/kg, orally) for one week. Groups II and IV received 4 x 10 mg/kg METH i.p. at 2-h intervals after one week of LC administration. LC treatment continued for one more week to groups III and IV. One week after METH administration, mice were sacrificed by decapitation, and striatum was dissected to measure the formation of 3-nitrotyrosine (3-NT) by HPLC/Coularry system. METH treatment produced significant formation of 3-NT, a marker of peroxynitrite generation, in mice striatum. The pre- and post-treatment of mice with LC significantly attenuated the production of 3-NT in the striatum resulting from METH treatment. The protective effects by the compound LC in this study could be related to the prevention of the possible metabolic compromise by METH and the resulting energy deficits that lead to the generation of reactive oxygen and nitrogen species. These data further confirm our hypothesis that METH-induced neurotoxicity is mediated by the production of peroxynitrite, and LC may reduce the peroxynitrite levels and protect against the underlying mechanism of METH toxicity, which are models for several neurodegenerative disorders like Parkinson's disease.

Valproate and acetyl-L-carnitine prevent methamphetamine-induced behavioral sensitization in mice.
This study deals with the possible inhibitory role played by acetyl-l-carnitine (ALC) against methamphetamine (METH)-induced behavioral sensitization. Because valproate (VAL) inhibits the behavioral sensitization exerted by different psychostimulants, we investigated ALC's potential to prevent the amplification of METH-mediated psychomotor effects. We therefore evaluated the locomotor effects of VAL or ALC alone or in combination with METH after acute (day 1) as well as repeated (day 7) drug challenge. Finally, to assess the induction of behavioral sensitization, we also recorded the METH-mediated locomotor response after 7 days of drug suspension (day 15). Results showed that both VAL and ALC prevented the METH-induced sensitization. Another interesting observation was the significantly higher METH-induced hyperactivity at day 15 (after a 7-day drug-free period), indicating that behavioral sensitization developed during the washout period. Results also showed that both the acute and repeated coadministration of METH with either VAL or ALC inhibited METH-induced hyperactivity. We present different hypotheses concerning similar but also peculiar mechanisms that might underlie the preventive action of VAL and ALC. These data add to a growing body of literature that illustrates the potential of ALC in protecting against the insult of dysfunctional mitochondrial metabolism and psychostimulant-mediated neurotoxicity. By demonstrating an in vivo action against one of the most abused drugs, these results raise the possibility of beneficial effects of ALC in abuse behavior.

Sensitization
Addiction may also be related to increased (sensitized) drug craving when environmental stimuli associated with drug taking, or drug cues, are encountered. This process may contribute to the risk for relapse in addicts attempting to quit. Such sensitization involves changes in brain mesolimbic dopamine transmission, as well as a molecule inside mesolimbic neurons called delta FosB.

 

[Quercetin]

Hypoglycemic unawareness

Although one expects hypoglycemic episodes to be accompanied by the typical symptoms (e.g., tremor, sweating, palpitations, etc.), this is not always the case. When hypoglycemia occurs in the absence of such symptoms it is called hypoglycemic unawareness. Especially in people with long-standing type 1 diabetes and those who attempt to maintain glucose levels which are closer to normal, hypoglycemic unawareness is common.

In patients with type 1 diabetes mellitus, as plasma glucose levels fall, insulin levels do not decrease - they are simply a passive reflection of the absorption of exogenous insulin. Also, glucagon levels do not increase. Therefore, the first and second defenses against hypoglycemia are already lost in established type 1 diabetes mellitus. Further, the epinephrine response is typically attenuated, i.e., the glycemic threshold for the epinephrine response is shifted to lower plasma glucose concentrations, which can be aggravated by previous incidents of hypoglycemia.

The following factors contribute to hypoglycemic unawareness:
a) there may be autonomic neuropathy
b) the brain may have become desensitized to hypoglycemia
c) the person may be using medicines which mask the hypoglycemic symptoms

a) Autonomic neuropathy: During hypoglycemia, the body normally releases epinephrine [more commonly known as adrenalin] and related substances. This serves two purposes: The β-effect of epinephrine is responsible for the palpitations and tremors, giving the patient warning that hypoglycemia is present. The β-effect of epinephrine also stimulates the liver to release glucose (gluconeogenesis and glycogenolysis). In other words, the epinephrine warns the patient that hypoglycemia is present and signals the liver to release glucose to reverse it. In the absence of epinephrine release, or when it is attenuated (reduced) during hypoglycemia, the patient may not be aware that his/her glucose level is low. This is termed 'hypoglycemic unawareness'. The problem is compounded since, in the absence of an appropriate epinephrine response, the usual responses of glycogenolysis and gluconeogenesis may also be lost or blunted.

Since epinephrine release is a function of the autonomic nervous system, the presence of autonomic neuropathy (i.e., a damaged autonomic nervous system) will cause the epinephrine release in response to hypoglycemia to be lost or blunted. Unfortunately, damage to the autonomic nervous system in the form of autonomic neuropathy is a common complication of long-standing diabetes (especially type 1 diabetes), so the presence of hypoglycemic unawareness may be a sign of autonomic neuropathy, although the autonomic response to hypoglycemia is already impaired in patients with type 1 diabetes mellitus even in the absence of autonomic neuropathy.

Because the autonomic response is, in effect, the body's backup system for responding to hypoglycemia, patients with type 1 diabetes are forced to rely almost exclusively on a backup system for protection, which can unfortunately, deteriorate over time. The reduced autonomic response (including the sympathetic neural norepinephrine and acetylcholine as well as the adrenomedullary epinephrine response) causes the clinical syndrome of hypoglycemia unawareness — loss of the largely neurogenic warning symptoms of developing hypoglycemia.

b) Brain desensitization to hypoglycemia: If a person has frequent episodes of hypoglycemia (even mild ones), the brain becomes "used to" the low glucose and no longer signals for epinephrine to be released during such times. More specifically, there are glucose transporters located in the brain cells (neurons). These transporters increase in number in response to repeated hypoglycemia (this permits the brain to receive a steady supply of glucose even during hypoglycemia). As a result, what was once the hypoglycemic threshold for the brain to signal epinephrine release becomes lower. Epinephrine is not released, if at all, until the blood glucose level has dropped to even lower levels. Clinically, the result is hypoglycemic unawareness.

c) Beta blocker drugs: These medicines are designed to blunt the β-effect of adrenalin and related substances. Hence, if hypoglycemia occurs in someone who is using this type of drug, he/she may not experience the typical adrenergic warning symptoms such as tremor and palpitations. Again, the result is hypoglycemic unawareness. As noted above, beta blockers will also prevent adrenalin from stimulating the liver to make glucose, and therefore may make the hypoglycemia more severe and/or more protracted. Of all the hypoglycemia symptoms, sweating is typically not blocked by beta blockers.
Since repeated hypoglycemia is common in people with diabetes who strive to keep their glucose levels near normal, the incidence of hypoglycemic unawareness becomes more prevalent in patients who follow 'intensive treatment' protocols.

The most common treatment for this condition is to liberalize the patient's target glucose levels, in an attempt to decrease the frequency of hypoglycemic episodes. Hypoglycemic unawareness will sometimes disappear when the frequency of hypoglycemic episodes has declined, but this is not always the case.

 

[RR279]

I haven't read much of the info, but has anyone ever checked their BGL after a speed binge to get an idea of the general range? I have a glucometer around here somewhere, I'll see if I can find it.

 

[Quercetin]

I haven't read much of the info, but has anyone ever checked their BGL after a speed binge to get an idea of the general range? I have a glucometer around here somewhere, I'll see if I can find it.

Adaptation in brain glucose uptake following recurrent hypoglycemia
Brain glucose metabolism is impaired during hypoglycemia, but, if sustained, brain metabolism reverts to normal in animal models--data in man are lacking. We tested the hypothesis that adaptations occur to allow maintenance of normal rates of brain glucose uptake (BGU) following recurrent hypoglycemia in man. Twelve normal humans were studied over 4 days. On the initial day, arterial plasma glucose concentrations were decreased from 4.72 to 2.50 mmol/liter in five 0.56 mmol/liter steps. Cerebral blood flow, brain arteriovenous glucose difference, BGU, and cognitive function were quantitated at each step. BGU was initially impaired at the 3.61 mmol/liter glucose step (P = 0.04) and was antedated by increments in epinephrine that began at 4.16 mmol/liter (P = 0.03). The onset of hypoglycemic symptoms occurred during the 3.61 mmol/liter glucose step (P = 0.02), whereas tests of cognitive function generally deteriorated at the 3.05 mmol/liter step (P < 0.05). During the next 56 hr, mean glucose concentrations were kept at 2.9 +/- 0.1 mmol/liter and reached normal only during meals. The stepped clamp protocol was repeated beginning at 4.16 mmol/liter on the last day. No decrement in BGU was observed at any step; cognitive function was preserved until significantly lower glucose concentrations on the final day relative to the first (P = 0.04). Subjects remained asymptomatic of hypoglycemia until they reached a glucose concentration of 2.50 mmol/liter (P < 0.001 vs. day 1), while initial increments in all counterregulatory hormones were forestalled to lower glucose steps than on day 1. Therefore, adaptations occur that allow normal BGU and cerebral function to be maintained during recurrent systemic hypoglycemia. Counterregulatory events that should result in symptoms of hypoglycemia and increments in endogenous glucose production are prevented until extremely subnormal glucose concentrations.

Its not so much hypoglycemia alone, neuroglycopenia is the problem. I am under the impression that dysfunction within glucose uptake transporter, Dentate gyrus and blood-brain-barrier are the root of the problem. Metabolic changes occur as a result of hypoglycemic episodes.