Interaction between psychological and pharmacological treatment in cognitive impairment. Can the pattern of neuropsychological improvement obtained with cholinergic drugs be used to infer a cholinergic mechanism in other nootropic drugs? Acute tryptophan depletion reduces kynurenine levels: implications for treatment of impaired visuospatial memory performance in irritable bowel syndrome Cognitive effects of l-deprenyl in Alzheimer's disease Pharmacologic probes of neurotransmitter systems in tardive dyskinesia: implications for clinical management. Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans Piracetam combined with lecithin in the treatment of Alzheimer's disease Pharmaco-electroencephalographic and clinical effects of the cholinergic substance--acetyl-L-carnitine--in patients with organic brain syndrome. Modulation of memory and visuospatial processes by biperiden and rivastigmine in elderly healthy subjects Selegiline versus oxiracetam in patients with Alzheimer-type dementia. Treatment trial of oxiracetam in Alzheimer's disease. Long‐term and high‐dose piracetam treatment of Alzheimer's disease Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential [L-acetylcarnitine treatment on fragile X patients hyperactive behaviour]. The effects of acute scopolamine in geriatric depression.
In contrast to other kinds of psychotropic drugs , nootropics or cognition enhancing drugs may be indicated , not for the direct treatment of the pathology itself , but for improving or restoring the remaining brain functions . Brain functions are normally trained during various kinds of non-medical therapy , such as physiotherapy , speech therapy , occupational therapy , memory training etc ... In research little attention has been paid to the combination of both kinds of therapeutic approaches , probably because of the important method ological difficulties . This combination however , offers various interesting perspectives : L. ISRAEL examined in two placebo-controlled studies the effects of either 160 mg/d of ginkgo biloba extractum ( GBE ) or piracetam 2.4 or 4.8 g/d , combined with a memory training program , in nondemented patients complaining of memory problems . The results of both studies suggest that nootropic drug treatment and memory training have each an effect on different cognitive functions and , hence , are complementary . Some functions , like attention/perception in the GBE study and learning in the piracetam study , seem to benefit from both treatments , suggesting a mutually potentiating effect of drug treatment and training . This potentiation is very clear in the treatment of dyslexic children : in a placebo-controlled study piracetam 3.3 g/d , in combination with normal school teaching and more specific logopedic therapy , allowed a normal progression during the full school year in reading accuracy and reading comprehension , while the placebo treated children getting a similar training progressed only with 50 % . Recently promising results were obtained in the treatment of dysphasic patients with a combination of speech therapy and piracetam 4.8 g/d , especially when given during the first months after the stroke , or otherwise in combination with an intensive speech training . In both double-blind studies the piracetam treated group improved about 60 % more than the group who only got speech therapy and placebo . All these data may be explained by the restorative or enhancing influence of nootropic drugs on neurotransmitter systems closely related to learning and memory functions . E.g. piracetam restores the availability and function of muscarinic and NMDA receptors in aging animals , most probably through a modulation of the psychico-chemical properties of the neuronal membrane such as the membrane fluidity 1 . Enhancement of episodic memory and reduction of intrusion errors are considered as the most characteristic outcome of cholinergic drugs administration in AD patients . 2 . Since the nootropic drugs Piracetam and Oxiracetam are deemed to act through a cholinergic mechanism , we checked whether AD patients treated with these drugs would show the same pattern of neuropsychological improvement . 3 . Results were negative , since ( a ) episodic memory showed a similar degree of improvement both in patients treated with these drugs and in patients treated with placebo ; ( b ) the number of intrusions tended to increase , rather than to decrease , after the treatment period Rationale A visuospatial episodic memory impairment has recently been identified in irritable bowel syndrome . Increased tryptophan metabolism along the kynurenine pathway has also been reported in irritable bowel syndrome , which may play a role in altered cognitive performance as peripheral kynurenine can cross the blood brain barrier and lead to the production of neuroactive metabolites , which modulate glutamatergic and cholinergic signalling , key neurotransmitter systems involved in cognitive function . Objectives Utilising the acute tryptophan depletion ( ATD ) protocol , the aim of this study was to examine if manipulating peripheral levels of tryptophan regulates cognitive performance in irritable bowel syndrome and also to determine for the first time if the ATD protocol alters kynurenine supply to the central nervous system . Methods In this double-blind , placebo-controlled , crossover design study , nine female patients with irritable bowel syndrome and 14 matched female healthy controls participant completed a range of tests from the CANTAB ® following ATD and placebo .  Plasma tryptophan and kynurenine , self-report measures of gastrointestinal symptoms , mood and arousal were determined pre- and post-treatment on each study day . Results Following placebo ( p = 0.016 ) but not ATD ( p > 0.05 ) , patients with irritable bowel syndrome exhibited impaired visuospatial memory performance ( Paired Associates Learning ( PAL ) test ) . In addition , ATD significantly decreased ( p < 0.001 ) and placebo significantly increased ( p < 0.001 ) plasma kynurenine levels in both groups . Conclusions Manipulating peripheral tryptophan and kynurenine levels using ATD modulates hippocampal-mediated cognitive performance in irritable bowel syndrome but not healthy controls . These data may have important implication s for reducing cognitive impairment in irritable bowel syndrome Monoamine neurotransmitter systems , along with cholinergic systems , are known to play important roles in cognition , and are disrupted in at least some patients with dementia of the Alzheimer type ( DAT ) . This suggests that monoamine-enhancing drugs might ameliorate cognitive symptoms in certain patients with DAT .  l-Deprenyl is a monoamine oxidase ( MAO ) inhibitor which may selectively inhibit MAO-B at low doses , while at high doses it nonselectively inhibits MAO-A as well as MAO-B. We studied its effects on several types of cognitive function in 17 patients with DAT . Two doses of l-deprenyl ( 10 mg/day and 40 mg/day ) and placebo were compared in a double-blind , serial treatment design . Episodic learning and memory , knowledge memory , attention , recognition , and performance on a continuous performance task were assessed at baseline and under these drug and placebo conditions . Statistically significant improvement was noted in performance on an episodic memory and learning task requiring complex information processing and sustained conscious effort during treatment with l-deprenyl 10 mg/day . Knowledge memory , intrusions , and other cognitive functions relevant to DAT were not altered by l-deprenyl at either dose Despite the plethora of clinical drug trials in tardive dyskinesia , few consistent findings have emerged . One possible reason for this is that there have been no serious attempts to define the role of major neurotransmitter systems ( dopamine , norepinephrine , acetylcholine , serotonin , GABA ) in one specific population of tardive dyskinesia patients . This study reports a series of five controlled drug trials in a population of patients with persistent tardive dyskinesia ; each drug probed one of four neurotransmitter systems . The intra- and interpatient responses are analyzed and the implication s of the pharmacologic response profiles for the clinical management of tardive dyskinesia are discussed Rationale One of the most often reported cognitive deficits of acute cannabis administration is an impaired recall of previously learned information . Objective The aim of the present study was to determine whether cannabis-induced memory impairment in humans is mediated via glutamatergic or cholinergic pathways . Methods Fifteen occasional cannabis users participated in a double-blind , placebo-controlled , six-way cross-over study . On separate test days , subjects received combinations of pretreatment ( placebo , vardenafil 20 mg or rivastigmine 3 mg ) and treatment ( placebo or 1,376 mg cannabis/kg body weight ) . Cognitive tests were administered immediately after inhalation of treatment was finished and included measures of memory ( visual verbal learning task , prospect i ve memory test , Sternberg memory test ) , perceptual-motor control ( critical tracking task ) , attention ( divided attention task ) and motor impulsivity ( stop signal task ) . Results The results of this study demonstrate that subjects under the influence of cannabis were impaired in all memory tasks , in critical tracking , divided attention and the stop signal task . Pretreatment with rivastigmine attenuated the effect of cannabis on delayed recall and showed a trend towards significance on immediate recall . When cannabis was given in combination with vardenafil , there were no significant interaction effects in any of the tasks . Conclusions The present data therefore suggest that acetylcholine plays an important role in cannabis-induced memory impairment , whereas similar results for glutamate have not been demonstrated in this study Nootropics , a new class of drugs believed to activate mental functions , have been proposed as a treatment for clinical disorders in which cognition is impaired . We therefore administered the nootropic drug piracetam , alone and in combination with phosphatidylcholine ( PC ) , to 18 patients with Alzheimer 's disease ( AD ) , and measured the effects of treatment on a broad range of cognitive functions .  Piracetam was administered according to three double-blind crossover protocol s and a replication study that differed in piracetam dose ( 2.4 to 9.9 g/day ) and whether PC ( 18 g/day ) was administered concurrently . The drug was well tolerated , and there were not toxic side effects . Plasma choline levels rose significantly during piracetam and PC administration ; monoamine metabolites in cerebrospinal fluid were unaffected by treatment . Piracetam , either alone or in combination with PC , did not significantly affect cognition in the AD group as a whole , nor did it improve test performance in any single patient In two double-blind , placebo-controlled clinical studies of the nootropic compound acetyl-L-carnitine on the electroencephalogram ( EEG ) and impaired brain functions of elderly out patients with mild to moderate cognitive decline of the organic brain syndrome , statistically significant effects could be detected after eight weeks ( on the EEG ) , and after 12 weeks of treatment ( on the physician 's clinical global impression and the patient-rated level of activities of daily living ) . Side-effects of acetyl-L-carnitine were generally minor and overall rare . Longer treatment periods and further specifications with regard to the aetiopathology and degree of cognitive impairment are recommended for further clinical studies of this promising compound Rationale The central cholinergic system is implicated in cognitive functioning . The dysfunction of this system is expressed in many diseases like Alzheimer 's disease , dementia of Lewy body , Parkinson 's disease and vascular dementia . In recent animal studies , it was found that selective cholinergic modulation affects visuospatial processes even more than memory function . Objective In the current study , we tried to replicate those findings . In order to investigate the acute effects of cholinergic drugs on memory and visuospatial functions , a selective anticholinergic drug , biperiden , was compared to a selective acetylcholinesterase-inhibiting drug , rivastigmine , in healthy elderly subjects . Methods A double-blind , placebo-controlled , r and omised , cross-over study was performed in 16 healthy , elderly volunteers ( eight men , eight women ; mean age 66.1 , SD 4.46 years ) . All subjects received biperiden ( 2 mg ) , rivastigmine ( 3 mg ) and placebo with an interval of 7 days between them . Testing took place 1 h after drug intake ( which was around Tmax for both drugs ) . Subjects were presented with tests for episodic memory ( wordlist and picture memory ) , working memory tasks ( N-back , symbol recall ) and motor learning ( maze task , pursuit rotor ) . Visuospatial abilities were assessed by tests with high visual scanning components ( tangled lines and Symbol Digit Substitution Test ) . Results Episodic memory was impaired by biperiden . Rivastigmine impaired recognition parts of the episodic memory performance . Working memory was non-significantly impaired by biperiden and not affected by rivastigmine .  Motor learning as well as visuospatial processes were impaired by biperiden and improved by rivastigmine . Conclusions These results implicate acetylcholine as a modulator not only of memory but also of visuospatial abilities The efficacy and tolerability of the monoamine oxidase B inhibitor selegiline and of the nootropic agent oxiracetam were compared in a single-blind , controlled , parallel study . The trial involved 22 men and 18 women with mild-to-moderate senile and presenile dementia of the Alzheimer type . The treatments were administered for 90 consecutive days as follows : one 10-mg selegiline tablet once daily and one 800-mg oxiracetam tablet twice daily . Efficacy was evaluated by means of a complex battery of neuropsychological tests , administered monthly for three months , starting from baseline . Safety was evaluated by monitoring adverse drug reactions as well as any pathological changes in hematology , blood chemistry , or liver and kidney function , measured at baseline and again at the conclusion of the study . Analysis of the results demonstrates that , at the dosage used , selegiline is more effective than oxiracetam in improving higher cognitive functions and reducing impairment in daily living . In particular , short- and long-term memory , sustained concentration , attention , verbal fluency , and visuospatial abilities were , for the most part , positively affected by selegiline .  Gastroenteric and systemic tolerability of both drugs was also very good Twenty-four carefully assessed patients with probable Alzheimer 's disease were enrolled in a double-blind , placebo-controlled treatment study of oxiracetam , a nootropic agent reported to improve memory performance in patients with dementia . A broad battery of neuropsychological tests failed to reveal any improvement in the treated group or in any treated patient when individual test scores were analyzed . These findings indicate that oxiracetam is ineffective in reducing cognitive impairment due to Alzheimer 's disease Pre clinical research suggests that piracetam ( a nootropic drug ) may improve cognitive functions , but previous studies have failed to demonstrate a clear benefit for the treatment of Alzheimer 's disease ( AD ) . We report a 1-year , double-blind , placebo-controlled , parallel-group study with a high dose of piracetam ( 8 g/d per os ) in 33 ambulant patients with early probable AD . Thirty subjects completed the 1-year study . No improvement occurred in either group , but our results support the hypothesis that long-term administration of high doses of piracetam might slow the progression of cognitive deterioration in patients with AD . The most significant differences concerned the recall of pictures series and recent incident and remote memory . The drug was well-tolerated ABSTRACT Introduction :  Chronic breathlessness  is a common and distressing symptom of advanced disease with few effective treatments . Central nervous system mechanisms are important in respiratory sensation and control . Consequently , drugs which may modify processing and perception of afferent information in the brain may have a role . Antidepressants have been proposed ; however , current evidence is limited . Of potentially suitable antidepressants , mirtazapine is an attractive option given its tolerability profile , low cost , and wide availability , along with additional potential benefits . Areas covered : The paper provides an overview of the physiology of breathlessness , with an emphasis on central mechanisms , particularly the role of fear circuits and the associated neurotransmitters . It provides a potential rationale for how mirtazapine may improve chronic breathlessness and quality of life in patients with advanced disease . The evidence was identified by a literature search performed in PubMed through to October 2018 . Expert opinion : Currently , there is insufficient evidence to support the routine use of antidepressants for chronic breathlessness in advanced disease . Mirtazapine is a promising c and i date to pursue , with definitive r and omized controlled trials required to determine its efficacy and safety in this setting Hyperactivity is a significant problem for almost all young males affected by fragile X syndrome ( FXS ) , the most common inherited disease causing mental retardation . Therapeutical approaches are actually based on Central Nervous System ( CNS ) stimulants lacking a well defined rationale and efficacy while they further decrease the patient 's limited attention span . A pilot study on 17 fragile X male treated with L-acetylcarnitine ( LAC ) over one year , showed a significant reduction of their hyperactivity behaviour tested by the Conners Abbreviated Parent-Teacher Question naire . LAC use in FXS patients derives from the hypothesis that the biochemical and physiological properties this substance has may preserve brain activity . LAC is a small , hydrosoluble molecule that easily diffuses in the extracellular space and enters any cell in the nervous system through specific transporters . Different cerebral areas use this molecule differently to metabolize glucose and lipids to provide for ATP and neurotrasmitters synthesis . The acetyl group LAC carriers represents a key metabolic signaling element possibly mediating its effect in the CNS . The exogenous administration of LAC may affect brain activity in FXS by : I ) modulation of fuel partitioning for energy production , which at the mithocondrial level is associated with the Kreb 's cycle metabolic role in neurotransmitter synthesis ; II ) remodelling of lipid membrane in terms of LAC actively determining the production of polyunsaturated fatty acids ; III ) preferential effect on the attention component of the cholinergic system which relies on its peculiar modality of communication in the CNS . Based on the above premises an explorative , double-blind , placebo controlled , multicenter study is ongoing . A total population of 160 children from nine European centers will be enrolled . The objective of this study is to determine the effect of LAC on the hyperactive behaviour of FXS children as evaluated by the administration of the Conners Abbreviated Parent Question naire In an intensive multidrug , multidose study , nine elderly depressed patients were administered 0.1 , 0.25 , and 0.5 mg of scopolamine hydrobromide , 1 mg of oral lorazepam , and placebo in a double-blind investigation aim ed at assessing the status of the central cholinergic nervous system in geriatric depression . Significant cognitive and behavioral effects of scopolamine were observed only at the high dose ( 0.5 mg ) , while lower doses and lorazepam showed no significant differences from placebo .  Cognitive deficits caused by scopolamine were in the areas of new learning , access to semantic memory , vigilance , and continuous performance . Behavioral effects consisted of activation , restlessness , and anxiety , but there was no significant effect on depressed mood . These results suggest that elderly depressed patients with mild to moderate cognitive impairment seem to be more similar to previously studied elderly controls rather than to patients with Alzheimer 's disease in their reaction to short-term cholinergic blockade , and suggest that the cognitive and mood changes often seen in geriatric depression may involve factors other than disturbed muscarinic cholinergic mechanisms
From the data reported in the literature , it emerges that nootropics may be an effective alternative for strengthening and enhancing cognitive performance in patients with a range of pathologies .
Although nootropics , and specifically the cholinergic precursors , already have a long history behind them , according to recent renewal of interest , they still seem to have a significant therapeutic role .
Drugs with regulatory indications for symptomatic treatment of Alzheimer 's disease , such as cholinesterase inhibitors and memantine , often have transient effects in dementia disorders .
Nootropics represent probably the first " smart drugs " used for the treatment of cognitive deficits .
The aim of this paper is to verify , by a systematic analysis of the literature , the effectiveness of nootropics in this indication .
The analysis was limited to nootropics with cholinergic activity , in view of the role played by acetylcholine in learning and memory .
Acetylcholine was the first neurotransmitter identified in the history of neuroscience and is the main neurotransmitter of the peripheral , autonomic , and enteric nervous systems .