Mortimer Mamelak

Gammahydroxybutyrate: An endogenous regulator of energy metabolism

Gammahydroxybutyrate is a naturally occurring metabolite of many mammalian tissues. Although its administration produces a wide range of pharmacological effects, its normal function has never been clearly defined. GHB can induce NREM and REM sleep, anaesthesia, hypothermia, and a trance-like state which has been considered a model for petit mal epilepsy. It markedly increases brain dopamine levels. It has been touted as a central neurotransmitter or neuromodulator, and high affinity brain receptors, as well as central mechanisms for its synthesis, uptake and release have been demonstrated in support of this. But GHB is also found in many peripheral tissues and in some of these in higher concentrations than in the brain. No explanation has been offered for its presence in these tissues. A number of studies indicate that GHB can reduce energy substrate consumption in both brain and peripheral tissues, and that it can protect these tissues from the damaging effects of anoxia or excessive metabolic demand. Indeed there is some evidence to suggest that endogenous GHB levels rise under these circumstances. GHB appears to act through the endogenous opioid system, since in the brain, at least, GHB raises dynorphin levels and its metabolic and pharmacological effects can be blocked by naloxone. These, and other observations detailed in this review, suggest that GHB may function naturally in the induction and maintenance of physiological states, like sleep and hibernation, in which energy utilization is depressed. GHB may also function naturally as an endogenous protective agent when tissue energy supplies are limited.

Alzheimer’ s disease, oxidative stress and gammahydroxybutyrate

Although the cause of Alzheimers disease is unknown, oxidative stress, energy depletion, excitotoxicity and vascular endothelial pathology are all considered to play a part in its pathogenesis. In reaction to these adverse events, the Alzheimer brain appears to deploy a highly conserved biological response to tissue stress. Oxidative metabolism is turned down, the expression of antioxidative enzymes is increased and intermediary metabolism is shifted in the direction of the pentose phosphate shunt to promote reductive detoxification, repair and biosynthesis. Gathering evidence suggests that the release of beta-amyloid and the formation of neurofibrillary tangles, the two hallmarks of Alzheimers disease, are components of this protective response. Gammahydroxybutyrate (GHB), an endogenous short chain fatty acid, may be able to buttress this response. GHB can reduce glucose utilization, shift intermediary metabolism in the direction the pentose phosphate shunt and generate NADPH, a key cofactor in the activity of many antioxidative and reductive enzymes. GHB has been shown to spare cerebral energy utilization, block excitotoxicity and maintain vascular integrity in the face of impaired perfusion. Most important, GHB has repeatedly been shown to prevent the tissue damaging effects of oxidative stress. It may therefore be possible to utilize GHB to strengthen the brains innate defences against the pathological processes operating in the Alzheimer brain and, in this way, stem the advance of Alzheimers disease.

Psychological, topographic EEG, and CT scan correlates of frontal lobe function in schizophrenia

This study examined frontal lobe function in a group of 20 patients with schizophrenia, on and off medication, compared to 20 normals matched for age, sex, handedness, intelligence, and educational level. Schizophrenic patients generally did not perform as well as normals on the Wisconsin Card Sorting Test (WCST). Patients off medication performed less well on this test than those on medication. Those on medication did not perform as well as those off medication on the design and word fluency tests, which suggested that medications may affect various aspects of frontal lobe function differently. During the WCST, normal subjects demonstrated an increase in beta mean frequency of the electroencephalogram in frontal and centrotemporal regions which was not statistically significant in either schizophrenic group. This shift in beta mean frequency was found to correlate positively with performance on the WCST in normals, but not in patients. Patients with more negative symptoms tended to show a smaller increase in beta mean frequency during the WCST. Performance on the WCST was correlated negatively with ventricle-brain ratio in all subjects, suggesting that frontal lobe function might be related to computed tomographic measures in the normal population as well as in schizophrenic patients. There was no correlation with performance on the WCST and length of illness.

Narcolepsy and depression and the neurobiology of gammahydroxybutyrate.

A voluminous literature describes the relationship between disturbed sleep and depression. The breakdown of sleep is one of the cardinal features of depression and often also heralds its onset. Frequent arousals, periods of wakefulness and a short sleep onset REM latency are typical polysomnographic features of depression. The short latency to REM sleep has been attributed to the combination of a monoaminergic deficiency and cholinergic supersensitivity and these irregularities have been proposed to form the biological basis of the disorder. A similar imbalance between monoaminergic and cholinergic neurotransmission has been found in narcolepsy, a condition in which frequent awakenings, periods of wakefulness and short sleep onset REM latencies are also characteristic findings during sleep. In many cases of narcolepsy, this imbalance appears to result from a deficiency of hypocretin but once established, whether in depression or narcolepsy, this disequilibrium sets the stage for the dissociation or premature appearance of REM sleep and for the dissociation of the motor inhibitory component of REM sleep or cataplexy. In the presence of this monoaminergic/cholinergic imbalance, gammahydroxybutyrate (GHB) may acutely further reduce the latency of REM sleep and induce cataplexy, in both patients with narcolepsy or depression. On the other hand, the repeated nocturnal application of GHB in patients with narcolepsy improves the continuity of sleep, prolongs the latency to REM sleep and prevents cataplexy. Evidence to date suggests that GHB may restore the normal balance between monoaminergic and cholinergic neurotransmission. As such, the repeated use of GHB at night and the stabilization of sleep over time makes GHB an effective treatment for narcolepsy and a potentially effective treatment for depression.

Sporadic Alzheimer's Disease: The Starving Brain

A reduction in cerebral glucose utilization is one of the earliest signs of Alzheimers disease. Although the exact cause of this reduction is not known, gathering evidence suggests that it is part of a complex metabolic adaptation to oxidative stress during which glycolysis and oxidative phosphorylation are turned down, glucose metabolism is shifted to the pentose phosphate pathway to generate antioxidant reducing factors such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, and the gamma-aminobutyric acid (GABA) shunt is activated to provide glutamate as an alternate source of energy. In the face of these adaptive metabolic changes, the Alzheimer brain runs short of energy and begins to digest itself. The very early induction of macroautophagy attests to the search for nutrients. In clinical trials, antioxidants alone have not been effectively able to influence the course of the disease as these agents do not meet the energy and nutritional requirements of the brain. Evidence is presented that gammahydroxybutyrate, a natural product of the GABA shunt, can provide the necessary energy, carbon, and antioxidant power and that its use may be able to delay the onset and progress of Alzheimers disease.

Neurodegeneration, Sleep, and Cerebral Energy Metabolism: A Testable Hypothesis

Varying degrees of metabolic arrest are used by many living species to survive in a harsh environment. For example, in hibernating mammals, neuronal activity and cerebral metabolism are profoundly depressed in most regions of the brain and limited energy resources are deployed to maintain vital cell functions. Gathering evidence suggests that energy resources are also limited in both Alzheimers and Parkinsons diseases, and that this promotes metabolic stress and the degenerative process. Key steps in this process are energy requiring, and this further compromises cell energy reserves. It may be possible to slow the progress of these diseases by inducing slow-wave sleep (SWS) at night with gammahydroxybutyrate. Patients with these diseases sleep poorly and generate little SWS. SWS and hibernation are thought to be on a continuum of energy conservation. Thus, the induction of SWS may retard the degenerative process by depressing cell metabolism and by directing energy utilization to vital cell functions. In this way, GHB-induced SWS may duplicate the effects of hibernation and extend biologic time.

Frontal spectral EEG findings in acutely Ill schizophrenics

Recent topographic electroencephalographic (EEG) studies have suggested that compared to normal controls, schizophrenics have more slow activity in frontal regions and either increased or decreased fast activity postcentrally (Morihisa et al. 1983; Morstyn et al. 1983; Guenther and Breitling 1985). These findings were correlated with cerebral blood flow and positron emission tomography studies, which suggested decreased metabolic activity in the frontal regions of the brain in some schizophrenics (Ingvar and Franzen 1974; Buchsbaum et al. 1982). However, these studies have largely examined chronic patients, without regard to the symptomatology at the time of assessment. The present pilot study examined the spectral EEG from six locations in schizophrenic patients who were in an acute exacerbation of their illness prior to, during, and after their treatment as compared to normal controls. Our aim was to determine whether signs of hypofrontality might be seen with acute symptomatology or were limited to a more chronic residual state.

A comparative study on the effects of brotizolam and flurazepam on sleep and performance in the elderly.

This study was undertaken to compare the effects of 0.25 mg of brotizolam, 15 mg of flurazepam, and placebo on the sleep and performance of elderly subjects with chronic insomnia during a 2-week period of administration. Thirty-six male and female subjects who ranged in age from 60-72 years were divided into three treatment groups. All groups received placebo on the first three study nights, the active drug or placebo on the next 14 nights, and placebo again on the two following withdrawal nights. Sleep was assessed by means of questionnaires, and residual effects during the day were studied by means of the multiple sleep latency test and a variety of memory, performance, and vigilance tests. Sleep improved with all treatments. Rebound insomnia was noted on brotizolam withdrawal; flurazepam withdrawal had a milder impact. At the end of this 19-night study, only the placebo-treated group was sleeping significantly longer than at baseline. Both drug treatments increased daytime sleepiness and impaired performance on the first day after their administration. These effects waned after 2 weeks of treatment with brotizolam, but not flurazepam. The results of this study affirm the increased sensitivity of elderly subjects to benzodiazepine hypnotics and their indication for acute or intermittent insomnia, rather than for the more chronic forms of this disorder.

A Comparative 25‐Night Sleep Laboratory Study on the Effects of Quazepam and Triazolam on Chronic Insomniacs

Abstract: The short‐ and intermediate‐term actions, as well as the carryover and withdrawal effects, of quazepam, a new benzodiazepine hypnotic with a half‐life of 60 to 100 hours, were compared with those of triazolam, a triazolodiazepine hypnotic with a half‐life of 2 to 3 hours. Both the subjective effects of these drugs as well as their objective actions on the sleep EEG were sought. The study was conducted on two groups of six subjects with chronic insomnia who ranged in age from 32 to 56 years. Each subject was studied for 25 consecutive nights. Placebo was administered at bedtime on the first four nights, followed by 30 mg quazepam or 0.5 mg triazolam on the next 14 nights and by placebo again on the ensuing seven withdrawal nights. Both drugs increased the total sleep time during their administration and improved the subjective quality of sleep. Major differences, however, were observed on withdrawal. A significant and marked decrease in the total sleep time occurred with triazolam on the first withdrawal night. With quazepam, rebound insomnia was not observed at any time during the seven‐day withdrawal period.

Spectral EEG Correlates of Dream Recall

Recent studies have shown that dreaming is not limited to rapid eye movement (REM) sleep, but can be found to varying degrees in any stage of sleep. This study attempted to quantify the EEG correlations of dreaming during Stage 2 sleep. Six normal volunteers were studied for 24 nights in the sleep laboratory. Electroencephalogram (EEG) recording prior to awakening from Stage 2 sleep and from other stages without awakening were subjected to computer spectral analysis. Although awakenings associated with dream recall tended to have lower total power, mean frequency in the beta band proved to be the best correlate of mental activity in Stage 2 sleep. Mean frequency had its highest values in REM sleep and wakefulness and declined in Stage 2 and Stage 4 sleep, in keeping with the decline in mental activity reported from these stages. Implications of these findings are discussed with regard to models of dream recall and clinical states.