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Probable Nootropic-Induced Psychiatric Adverse Effects: A Series of Four Cases

  • Centre Hospitalier du Valais Romand (CHVR)

Abstract and Figures

Humans have historically attempted to enhance and improve their mental and cognitive abilities. Chemically augmenting the human brain is the basis of nootropic brain enhancement which deals with the development and experimentation with substances that can presumably improve cognition. Nootropics like armodafinil, citicoline, piracetam, ampakines and cerebrolysin are being consumed by young adults for augmentation of alertness, memory and concentration. The evidence on the benefits of nootropics is controversial. The misuse of nootropics can potentially be dangerous and deleterious to the normal human brain. In this report we will briefly describe the common classes of nootropics and describe four cases of probable nootropic induced psychiatric adverse effects. To the best of our knowledge this has not been previously reported in the formal medical literature
Content may be subject to copyright.
The misuse of nootropics—any
substance that may alter, improve, or
augment cognitive performance,
mainly through the stimulation or
inhibition of certain
neurotransmitters—may potentially
be dangerous and deleterious to the
human brain, and certain individuals
with a history of mental or substance
use disorders might be particularly
vulnerable to their adverse effects.
We describe four cases of probable
nootropic-induced psychiatric
adverse effects to illustrate this
theory. To the best of our knowledge
this has not been previously reported
in the formal medical literature. We
briefly describe the most common
classes of nootropics, including their
postulated or proven methods of
actions, their desired effects, and
their adverse side effects, and
provide a brief discussion of the
cases. Our objective is to raise
awareness among physicians in
general and psychiatrists and
addiction specialists in particular of
the potentially dangerous
phenomenon of unsupervised
nootropic use among young adults
who may be especially vulnerable to
nootropics’ negative effects.
Humans have historically sought
to enhance and improve their mental
and cognitive abilities. Chemically
augmenting the human brain is the
basis of nootropic brain
enhancement—the development and
experimentation with substances
that can presumably improve
cognition. A nootropic agent is any
substance that may alter, improve, or
augment cognitive performance,
mainly through the stimulation or
inhibition of certain
neurotransmitters.1Nootropics have
been shown to increase concentration
and memory potential and potentiate
cognitive functioning.2,3 Nootropics
include a wide range of substances,
and the overall mechanisms of action
for most nootropics have not been
well elucidated. In this report, we
describe the most commonly
consumed and easily available
nootropics. We also describe four
cases of nootropic use that potentially
led to unwanted serious adverse
psychiatric effects. To the best of our
knowledge this has not been
previously reported in the formal
medical literature.
The overall evidence regarding the
benefits of nootropics in healthy
individuals seeking mental
enhancement is still controversial.
Additionally, it is important to note
that nootropics are not free of
adverse effects. Table 1 summarizes
Dr. Talih is an assistant professor and Dr. Ajaltouni is a research fellow at the American
University of Beirut Medical Center Department of Psychiatry
Innov Clin Neurosci. 2015;12(11–12):21–25
FUNDING: No funding was received for the
preparation of this manuscript.
no conflicts of interest relevant to the
content of this article.
Farid Talih, MD, American University of Beirut,
3 Dag Hammarskjold Plaza, 8th Floor, New
York, NY 10017-2303 USA;
KEY WORDS: Nootropics, supplements,
substance abuse, cognitive enhancers,
substance misuse, psychiatric adverse effects
Probable Nootropic-
induced Psychiatric
Adverse Effects:
A Series of Four Cases
the mechanisms of action, desired
neuropsychiatric effects, and adverse
effects of the common classes of
nootropics detailed below.
Armodafinil. Armodafinil, a
wakefulness-promoting drug, is the R-
isomer of racemic modafinil. Modafinil
is a compound that produces an
overall neuroexcitatory effect. The
postulated mechanism of action is
increasing the concentration of
glutamate and decreasing gamma-
amino butyric acid (GABA) within the
posterior hypothalamus.4Armodafinil
has been shown to improve
wakefulness in patients with
excessive sleepiness associated with
treated obstructive sleep apnea and
narcolepsy. Despite being the R-
isomer of modafinil, armodafinil has a
different pharmacokinetic profile and
may result in improved wakefulness
throughout the day compared with
Adverse effects. Despite improving
wakefulness, armodafinil’s adverse
effects commonly include headache,
nasopharyngitis, and diarrhea.6
Citicoline. Citicoline, originally
studied for its neuroprotective action
against stroke and dementia,
modulates acetylcholine, dopamine,
and glutamate. It is also involved in
phospholipid metabolism and
enhances the integrity of neuronal
membranes.7Citicoline has been
shown to improve memory in patients
with dementia as well as reduce
damage to the brain after traumatic
brain injury8or stroke.9
Adverse effects. Citicoline has
been found to cause gastrointestinal
discomfort, headache, insomnia,
myalgias, restlessness, fatigue, and
Piracetam. Piracetam, which is
often used in early stages of
Alzheimer’s disease and aging-related
memory impairment,11 is technically
derived from GABA but is functionally
unrelated to this neurotransmitter. It
can act on the alpha-amino-3-
isoxazolepropionic acid (AMPA)
receptor as an allosteric modulator
binding in six different positions12 and
may have an effect on N-methyl- D-
aspartate receptor (NMDA) and
glutamate receptors.13 Piracetam
currently can be purchased online
and is generally used for cognitive
enhancement and memory
improvement.14 Piracetam has also
been found to play a role in restoring
membrane fluidity contributing to
enhanced neuroplasticity15 and
neuroprotective effects.16
Adverse effects. Piracetam users
have reported symptoms of
psychomotor agitation, dysphoria,
tiredness, dizziness, memory loss,
headache, and diarrhea. Many users
reported to have neither felt any
cognitive improvement nor
psychedelic effects after taking
Ampakines. Ampakines are a
class of drugs that bind to the
glutamatergic AMPA receptor,
enhancing its activity20 and potentially
triggering the induction of long-term
potentiation and improvement of
learning, cognition, and alertness.
Adverse effects. Ampakines have
also been found to cause headaches,
somnolence, and nausea.21 Despite the
enhancement of long-term cortical
neural potentiation with the use of
ampakines, shifting cortical neural
plasticity in favor of long-term
potentiation could lead to
TABLE 1. List of common nootropics, mode of action, desirable psychotropic effects, and
adverse side effects
Armodafinil Glutamate
GABA Wakefulness
• Nasopharyngitis
• Diarrhea
Modulation of
Dopamine and
• Gastrointestinal
• Headache
• Insomnia
• Myalgias
• Restlessness
• Fatigue
• Tremors
Binds to AMPA
Fluidity of
• Psychomotor
• Dysphoria
Memory loss
• Diarrhea
Bind to
AMPA receptor
Spatial memory
Possible motor
Cholinergic fiber
• Vertigo
• Agitation
• Feeling
: increase; GABA: gamma-amino butyric acid; AMPA: alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid
impairments in spatial memory and
perhaps motor function.22
Cerebrolysin. Cerebrolysin, a
mixture of low-molecular–weight
peptides and amino acids derived
from porcine brain tissue has been
shown to have neuroprotective and
neurotrophic properties by
ameliorating sensory deficits and
promoting synaptic formation and
cholinergic fiber regeneration.23 It is
currently being used to treat ischemic
strokes in China and Russia.1
Cerebrolysin is reported to be safe
when used in combination with
recombinant tissue-type plasminogen
activator or cholinesterase inhibitors
such as donepezil or rivastigmine.24
Adverse effects. Adverse reactions
to cerebrolysin include vertigo,
agitation, and feeling hot.
Accessibility. Nootropics are
easily accessible via the internet
through online vendors that appear as
pharmacy websites frequently
displaying images of physicians
endorsing the products and
promoting nootropic pharmaceutical
products.25 Nootropics, including
those described above, can be
ordered online without a medical
prescription.26 Nootropics are also
widely available in most health and
nutrition stores in many countries.
Case 1. A 19-year-old male college
student with a history of depression
and attention deficit hyperactivity
disorder (ADHD) presented to the
emergency department with
psychosis and paranoia resulting in
self-injurious behavior. His current
medication was bupropion, and
historically he had been prescribed
methylphenidate but was no longer
taking that medication. His parents
reported a history of cannabis abuse
but he had been abstinent for the past
year. No history of psychosis was
reported. Previously, the patient was
functioning well, in a euthymic state,
and was attending his classes. He
denied any substance abuse, and
urine toxicology was negative. On
further questioning, the patient
revealed that he was taking a
supplement to treat his ADHD. He
reported purchasing it online. The
supplement was found to be
citicoline, and he had been consuming
2 to 3 tablets three times a day for
several weeks. The family had noticed
some insomnia and irritability early
on, but no other concerning behaviors
until now. The patient was admitted
to the psychiatry department, and his
symptoms resolved with olanzapine.
He was discharged home in a stable
condition and instructed to continue
taking olanzapine for one month and
to stop using all supplements.
Case 2. A 24-year-old male body
builder with a history of anxiety
presented to the emergency room
with agitation and several days of
hypomania. Currently, he was not on
any medications, but previously had
been treated with paroxetine for
anxiety. Several years ago, he used
anabolic steroids for a few months,
but has not used them since. He
reported smoking cannabis on
weekends and consuming alcohol
occasionally. Urine toxicology was
negative. On questioning, he reported
recently using cerebrolysin to
enhance his cognitive performance,
consuming two tablets twice daily.
The supplement was obtained from a
local health store. The patient
received diazepam and was observed
overnight. He improved significantly
and was discharged home in stable
condition. Diazepam was discontinued
upon discharge from the hospital. He
was instructed to stop all
Case 3. A 28-year-old female
graduate student presented urgently
to the psychiatry clinic for new onset
insomnia, anxiety, and panic attacks.
She reported a history of depression
that was well controlled with
psychotherapy. Currently, she was
not taking any medications. She
denied any illicit substance use and
did not consume caffeine or smoke
cigarettes. She admitted to being a
casual cannabis smoker, but had not
been using cannabis recently. The
patient reported that she recently
started using armodafinil to help her
cope with her stressful academic
program. Initially, she consumed
armodafinil on an as-needed basis,
and she felt improved performance
and well-being. She then started using
it regularly twice daily. Approximately
one week later, the symptoms of
insomnia, anxiety, and panic attacks
began. The patient reported using
armodafinil upon the suggestion of a
friend, and it was obtained online
from an overseas pharmacy. The
patient was advised to stop
armodafinil and was prescribed
clonazepam twice daily until
symptoms resolved one week later. At
follow-up one week later, up her
symptoms had resolved.
Case 4. A 17-year-old male high
school student with obsessive
compulsive disorder (OCD) and
learning disabilities was admitted to
the emergency room and then to the
psychiatry department for
exacerbation of OCD with akathesia
and paranoia. He had previously been
maintained on fluoxetine with good
control of his OCD. He reported no
substance abuse or caffeine use,
which was confirmed by his parents.
Urine toxicology was negative. No
history of psychosis or paranoia was
reported by the patient or his parents.
Basic medical screening showed no
abnormalities. On further questioning
his parents reported that he had
recently started using a supplement
for memory. Further investigation
revealed that the supplement was
piracetam. The parents had not
objected to him using the supplement
since they perceived it as a safe and
“natural remedy.” The supplements
were obtained online. His symptoms
improved with daily alprazolam and
olanzapine at bedtime. Fluoxetine was
discontinued. He was discharged
home after a short hospital stay in a
stable condition on olanzapine at
bedtime. Piracetam was discontinued.
In addition to being young adults,
all four of the described cases had
some type of psychiatric history.
Three of the four cases had a history
of substance use, mainly cannabis. All
of our cases reported an interest in
maintaining a healthy and natural
lifestyle. They did not perceive
nootropics as harmful, voiced interest
in “natural remedies,” and reported
preferring to use supplements instead
of prescription medications. They
seemed not to be interested in
experiencing euphoria or a
pleasurable sensation, but rather to
enhance their psychological or
cognitive states. All cases improved
rapidly and uneventfully with
symptomatic treatment and
discontinuation of the nootropics.
In our opinion, it is highly likely
that nootropics were responsible for
the psychiatric exacerbation in these
cases, primarily, since they had been
stable at their respective psychiatric
baselines with no new psychosocial
stressors or medication changes,
except the initiation of nootropics.
Additionally, there was no active or
recent substance abuse. There is also
a temporal correlation between
initiating nootropics use and the
psychiatric exacerbations reported.
Limitations. Two of the cases
were taking psychotropic
medications, which may have had
drug interactions with the nootropics,
causing the adverse effects. There is
also the possibility of undisclosed or
undetected substance abuse as a
causal factor. A major limitation is the
inability to definitely determine the
actual composition of the nootropics,
the dosing, and the frequency of use.
Healthcare providers in general,
and specifically those in the mental
health and substance abuse fields,
should keep in mind that nootropic
use is an under recognized and
evolving problem. Nootropic use
should be considered in cases where
there are sudden or unexplained
exacerbations of psychiatric
symptoms in patients who have been
stable and medication adherent. It is
also important to remember that most
nootropics are not detected on
standard drug toxicology screening
tests. We have very little clinical
information on how nootropics may
interact with psychotropics (or other
medications) and potentially cause
adverse physical and psychiatric side
effects. Finally, because nootropics
are often obtained via loosely
regulated sources, such as online
vendors, it is possible that other
psychoactive compounds are
substituted for the advertised
nootropics. Young adults, especially
those with a history of mental health
or substance use disorders, may be at
particular risk of adverse effects from
use of nootropics and should be
educated about the potential for harm
from misuse of nootropics.
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... This manifestation of nootropics is due to the ability to increase the level of cerebral acetylcholine, increase the supply of oxygen to the brain, influence the glutamate and GABA systems [4,5]. Racetam nootropics such as piracetam, oxiracetam, aniracetam, levetiracetam, phenylpiracetam, pramiracetam are commonly used to improve memory [6]. Based on the structural prerequisites for the manifestation of nootropic action, this is facilitated by the introduction of pharmacophore inclusions of various electronic nature in the 1st and 4th positions of pyrrolidin-2-one. ...
... 1H NMR spectra and 13C NMR spectra were recorded on Varian Gemini 400 MHz and Varian Gemini 100 MHz spectrometers. The solvent was dimethyl sulfoxide (DMSO-d 6 ). Chemical shifts are shown on a scale ( ...
In order to search for innovative nootropic agents, new 1-benzyl-4- (4- (R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl) pyrrolidine-2-ones was synthesized by reacting benzylamine with itaconic acid to 1-benzyl-5-oxopyrrolidine-3-carboxylic acid, which was then subjected to hydrazinolysis followed by the addition of substituted isothiacyanate followed by cyclization of intermediate thiosemicarbazides. The structure and purity of the obtained substances were confirmed by elemental analysis, ¹H NMR spectroscopy, ¹³C NMR spectroscopy and LC/MS. Docking studies were performed for the substances synthesized using Autodock 4.2 software. Approximate values of LD50 (in silico determination) are around 870–1000 mg/kg. All synthesized substances were tested for nootropic activity by the passive avoidance test on the scopolamine amnesia model in doses that are about 1/10 of the estimated LD50. Based on the results of docking and pharmacological experiment, the most promising substances 7a, as well as 7e, 7f were identified. The results of molecular docking (hit compound 7a) indicate a positive correlation between the obtained values of docking studies and experimental data.
... Some nootropics interact with food and psychotropics or other routine medications that cause adverse psychiatric side effects. Farid Talih represents the possible interaction and subsequent consequences of nootropics with psychoactive constituents [99] in Table 2. ...
... Possible interaction and subsequent consequences of Nootropics with psychoactive constituents[99]. ...
Ageing comes with degeneration in many biological activities like impairment of cognition, intelligence, attention, and memory. The decline in all those mental capabilities would be due to the abnormal changes in neuronal architecture with increasing age, chronic oxidative stress and inflammatory state of the tissue, nutritional deficiency. Nootropics or smart drugs enhance memory, attention, creativity, and cognitive performance by affecting the synthesis and receptor binding of neurotransmitters in the brain, especially dopamine, serotonin, gamma-aminobutyric acid, glutamate, and acetylcholine. Nootropics have shown their positive effects in parkinson's, autism, alzheimer's, huntington's disorders, where impaired memory is the primary concern. Synthetic class of nootropics has limitations and reported exacerbation of other brain disorders (off label effects) or therapeutic failure in some instances. Nutraceuticals are dietary derived vitamins, minerals, herbal products, proteins, marine products, and probiotics. The health benefits derived from Nutraceuticals are increasing brain blood flow, reducing inflammation in nervous tissues, detoxifying toxins from the brain, balancing neurotransmitter turnover rate, correcting neuronal and receptor damages and facilitating synaptic transmission, good antioxidant properties and power of improving neuroplasticity of the brain that combat neurodegeneration. The demands for effective nootropics will remain high as the number of cases are increased tremendously.
... Furthermore, it has been noticed that while healthy people may not benefit from brain supplements, sick people may. As a result, their use needs to be given additional thought [14][15][16]. ...
Full-text available
Neuropathologies, such as neuroinflammaging, have arisen as a serious concern for preserving the quality of life due to the global increase in neurodegenerative illnesses. Nowadays, neuronutraceuticals have gained remarkable attention. It is necessary to investigate the bioavailability, off-target effects, and mechanism of action of neuronutraceuticals. To comprehend the comprehensive impact on brain health, well-designed randomized controlled trials testing combinations of neuronutraceuticals are also necessary. Although there is a translational gap between basic and clinical research, the present knowledge of the molecular perspectives of neuroinflammaging and neuronutraceuticals may be able to slow down brain aging and to enhance cognitive performance. The present review also highlights the key emergent issues, such as regulatory and scientific concerns of neuronutraceuticals, including bioavailability, formulation, blood–brain permeability, safety, and efficacy.
... Current drugs used to improve learning and memory deficits (nootropics), such as citicoline and piracetam, have minimal efficacy, undesirable side effects and are relatively expensive (Malykh & Sadaie, 2010;Talih & Ajaltouni, 2015). There is, therefore, the need to identify and/or develop other agents with high efficacy and few adverse effects. ...
Full-text available
Background: Cognitive dysfunction, presenting as learning and memory impairment, is a common manifestation in many chronic diseases of the nervous system. Some of these diseases include depression, epilepsy, and Alzheimer's disease. To date, few drugs or medicinal products have shown ability to improve learning and memory deficits. Neuroprotection is one of the mechanisms by which memory could be improved. The extract of Xylopia aethiopica and its kaurene derivative, xylopic acid, have previously demonstrated neuroprotective effects in animal models. The aim of the present study was to investigate the effect of an extract of Xylopia aethiopica fruit and xylopic acid, on learning and memory using murine models. Materials and methods: Unripe Xylopia aethiopica fruits were collected, dried, and extracted using 70% v/v ethanol. Xylopic acid was isolated from the fruits using petroleum ether, concentrated with ethyl acetate and then recrystallized with petroleum ether before purifying with ethanol (96%v/v). Institute of Cancer Research (ICR) mice received oral doses of the extract of Xylopia aethiopica (XAE; 30, 100 and 300 mg/kg), xylopic acid (XA; 30, 100 and mg/kg), citicoline (300 mg/kg), piracetam (300 mg/kg) or ketamine (30 mg/kg) and saline (vehicle). The animals were then taken through the Morris water maze test (MWM), spontaneous alternation Y-maze test (Y-maze), and novel object recognition test (NOR), to assess learning and memory. Results: In the NOR test, XAE (30, 100 and 300 mg/kg) and XA (30, 100 and 300 mg/kg) increased the percentage exploration and recognition index (p = 0.0005 and p < 0.0001, respectively) when compared to both vehicle and ketamine groups. Similarly, doses of XAE and XA as used in the NOR test increased the percentage alternation in the Y-maze test. Although XAE and XA treatments decreased the latencies to find hidden platform in the MWM test, it was not significantly different from the vehicle group. However, this decrease in latency differed significantly when compared to the ketamine group. Interestingly, both XAE and XA treatments increased the percentage frequency to the target quadrant in the probe trial of the MWM. It is noteworthy that in all the three models used, both the extract and xylopic acid performed better than piracetam and citicoline, the reference drugs. Conclusion: The ethanolic extract of Xylopia aethiopica fruit and xylopic acid improved exploratory learning and recognition memory, spatial working, recognition, and reference memories in the behavioral tests.
... The clinical information was scarce on how nootropics may interact with psychotropics or other medications and potentially cause adverse side effects (e.g., psychomotor agitation, memory loss, headache, insomnia, restlessness, and tremors). Therefore, nootropic supplement users should carefully consider the potential for harm from misuse of nootropics (Le et al., 2020;Talih and Ajaltouni, 2015). ...
The Ministry of Food and Drug Safety (MFDS) has identified that numerous dietary supplements contain unapproved (hidden, undeclared, and unauthorized) ingredients that could be unsafe. The aim of this study is to summarize the presence of unapproved ingredients in dietary supplements based on the warning dataset released by the MFDS from 2010 to 2019. The warning data were extracted from the alert system on the MFDS’s website. The highest number (ratio) of products found in the dataset were marketed for sexual enhancement [770 (43.3%)], weight-loss [690 (38.8%)], muscular strengthening [243 (13.7%)], or relaxing [76 (4.3%)]. A total of 1,779 products contained one or more unapproved ingredients. The most common unauthorized compounds were icariin, sildenafil, and tadalafil for sexual enhancement, yohimbine, sibutramine, and sennoside for weight loss, and yohimbine and icariin for muscular strengthening, and melatonin and 5-hydroxytryptophan for relaxing products, respectively. Unapproved ingredients continue to be identified in dietary supplements, especially those marketed for sexual enhancement or weight loss, even after warnings by regulatory authorities. The unauthorized compounds in these dietary supplements have potential adverse health effects on consumers owing to accidental misuse, overuse, interaction with other medications, underlying health conditions, or other pharmaceuticals within the supplement. Our study reviewed potential health issues concerning the main unapproved ingredients to contribute to the understanding of adulteration in dietary supplements. The result of this study can be used to elucidate adulteration trends of unapproved ingredients in dietary supplements.
... Piracetam is a nootropic drug, usually act by enhancing cholinergic neurotransmission (Wurtman et al., 1981). However, frequent use of piracetam results in dysphoria, amnesia, and psychomotor agitation (Talih and Ajaltouni, 2015). Hence, there is a need of safe and effective drugs which can reverse cognitive abnormalities. ...
... The functions of nootropics are: (a) Improving Acetylcholine level in the brain, (b) Improving O 2 supply to the brain, (c) Supplying neurochemicals (e.g.-neurotransmitters, enzymes, hormones) to the brain (Jeon, 2015;Suliman et al., 2016;Crespo-Bujosa and Rodríguez, 2019). To improve memory and mood several nootropic agents are generally used such as Aniracetam, Oxiracetam, Pramiracetam, Piracetam and Choline esterase inhibitors like Donepezil, but the side effects of these agents (Talih and Ajaltouni, 2015;Zaami et al., 2020) have made their applicability limited. ...
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Memory, one of the most vital aspects of the human brain, is necessary for the effective survival of an individual. ‘Memory’ can be defined in various ways but in an overall view, memory is the retention of the information that the brain grasps. Different factors are responsible for the disbalance in the brain’s hippocampus region and the acetylcholine level, which masters the memory and cognitive functions. Plants are a source of pharmacologically potent drug molecules of high efficacy. Recently herbal medicine has evolved rapidly, gaining great acceptance worldwide due to their natural origin and fewer side effects. In this review, the authors have discussed the mechanisms and pharmacological action of herbal bioactive compounds to boost memory. Moreover, this review presents an update of different herbs and natural products that could act as memory enhancers and how they can be potentially utilized in the near future for the treatment of severe brain disorders. In addition, the authors also discuss the differences in biological activity of the same herb and emphasize the requirement for a higher standardization in cultivation methods and plant processing. The demand for further studies evaluating the interactions of herbal drugs is mentioned.
Nootropics (smart drugs) are used by students to enhance cognitive performance which have been reported times in recent years. However, some of the nootropics are central nervous system stimulants which are very likely to lead to addiction or complications such as vomiting and dizziness. Are there nootropics that can improve learning behavior while having potential positive effect on health? Here, we reported that Atomoxetine (ATX) has sex-specific effect on prolonging the life span of female Drosophila melanogaster. Further study indicated that ATX enhanced female resistance to heat stress and their vertical climbing ability, but it did decrease the number of eggs laid. ATX increased food-intake and sleep time both of females and males, and significantly reduced the 24h spontaneous activity of females and males. Our results present the sex dimorphic effect of ATX on life span regulation in Drosophila, and support further research on the beneficial role of ATX and the mechanisms in other animal models.
Memory-enhancing agents have long been required for various reasons such as for obtaining a good score in a test in the young and for retaining memory in the aged. Although many studies have found that several natural products may be good candidates for memory enhancement, there is still a need for better agents. The present study investigated whether rubrofusarin, an active ingredient in Cassiae semen, enhances learning and memory in normal mice. Passive avoidance and Morris water maze tests were performed to determine the memory-enhancing ability of rubrofusarin. To investigate synaptic function, hippocampal long-term potentiation (LTP) was measured. Western blotting was performed to determine protein levels. To investigate neurite outgrowth, DCX immunohistochemistry and cell culture were utilised. Rubrofusarin (1, 3, 10, 30 mg/kg) enhanced memory in passive avoidance and Morris water maze tests. Moreover, rubrofusarin ameliorated scopolamine-induced memory impairment. In the rubrofusarin-treated group, high-frequency stimulation induced higher LTP in the hippocampal Schaffer-collateral pathway compared to the control group. The rubrofusarin-treated group showed a higher number of DCX-positive immature neurons with an increase in the length of dendrites compared to the control group in the hippocampal dentate gyrus region. In vitro experiments showed that rubrofusarin facilitated neurite outgrowth in neuro2a cells through extracellular signal-regulated kinase (ERK). Finally, we found that extracellular signal-regulated kinase (ERK) is required for rubrofusarin-induced enhancement of neurite outgrowth, learning and memory. These results demonstrate that rubrofusarin enhances learning and memory and neurite outgrowth, and these might need activation of ERK pathway.
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Substance abuse affects the central nervous system (CNS) and remains a global health problem. Psychostimulants, such as cocaine and methamphetamine (METH), and opioids affect neuronal function and lead to behavioral impairments via epigenetic modification. Epigenetic changes occur via classical pathways, especially the class III histone deacetylase (HDAC)-sirtuin (SIRT) family, that act as cellular sensors to regulate energy homeostasis and coordinate cellular responses to maintain genome integrity. However, SIRT family (1–7)-associated neurodegeneration has not been elucidated in the context of energy metabolism. The present study examined the effects of psychostimulants, such as cocaine and METH, and opioids, such as morphine, on SIRT family (1–7) [class I, II, III and IV] expression and cellular translocation-mediated dysfunction in astrocytes and microglial cells. The “nootropic” drug piracetam played a preventative role against psychostimulant- and opioid-induced SIRT (1–7) expression in astrocytes. These results indicate that cocaine, METH, and morphine affected deacetylation and cellular function, and these changes were prevented by piracetam in astrocytes.
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Background: Citicoline is a dietary supplement that has been used as a neuroprotective agent for neurological disorders such as stroke and dementia. Citicoline influences acetylcholine, dopamine, and glutamate neurotransmitter systems; serves as an intermediate in phospholipid metabolism; and enhances the integrity of neuronal membranes. Interest has grown in citicoline as a treatment for addiction since it may have beneficial effects on craving, withdrawal symptoms, and cognitive functioning, as well as the ability to attenuate the neurotoxic effects of drugs of abuse. Objectives: To review the literature on citicoline's use in addictive disorders. Methods: Using PubMed we conducted a narrative review of the clinical literature on citicoline related to addictive disorders from the years 1900-2013 using the following keywords: citicoline, CDP-choline, addiction, cocaine, alcohol, substance abuse, and substance dependence. Out of approximately 900 first hits, nine clinical studies have been included in this review. Results: Most addiction research investigated citicoline for cocaine use. The findings suggest that it is safe and well tolerated. Furthermore, citicoline appears to decrease craving and is associated with a reduction in cocaine use, at least at high doses in patients with both bipolar disorder and cocaine dependence. Limited data suggest citicoline may also hold promise for alcohol and cannabis dependence and in reducing food consumption. Conclusions: Currently, there is limited research on the efficacy of citicoline for addictive disorders, but the available literature suggests promising results. Future research should employ larger sample sizes, increased dosing, and more complex study designs.
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Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia. Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation. The pyrrolidine allosteric modulators, piracetam and aniracetam, were among the first of this class of drugs to be discovered. We have determined the structure of the ligand binding domain of the AMPA receptor subtypes GluA2 and GluA3 with piracetam and a corresponding structure of GluA3 with aniracetam. Both drugs bind to GluA2 and GluA3 in a very similar manner, suggesting little subunit specificity. However, the binding sites for piracetam and aniracetam differ considerably. Aniracetam binds to a symmetrical site at the center of the dimer interface. Piracetam binds to multiple sites along the dimer interface with low occupation, one of which is a unique binding site for potential allosteric modulators. This new site may be of importance in the design of new allosteric regulators.
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Cytidine-5'-diphosphate choline (CDP-choline), as an important intermediate for major membrane phospholipids, may exert neuroprotective effects in various neurodegenerative disorders. This longitudinal proton magnetic resonance spectroscopy ((1)H-MRS) study aimed to examine whether a 4-week CDP-choline treatment could alter neurometabolite levels in patients with methamphetamine (MA) dependence and to investigate whether changes in neurometabolite levels would be associated with MA use. We hypothesized that the prefrontal levels of N-acetyl-aspartate (NAA), a neuronal marker, and choline-containing compound (Cho), which are related to membrane turnover, would increase with CDP-choline treatment in MA-dependent patients. We further hypothesized that this increase would correlate with the total number of negative urine results. Thirty-one treatment seekers with MA dependence were randomly assigned to receive CDP-choline (n=16) or placebo (n=15) for 4 weeks. Prefrontal NAA and Cho levels were examined using (1)H-MRS before medication, and at 2 and 4 weeks after treatment. Generalized estimating equation regression analyses showed that the rate of change in prefrontal NAA (p=0.005) and Cho (p=0.03) levels were greater with CDP-choline treatment than with placebo. In the CDP-choline-treated patients, changes in prefrontal NAA levels were positively associated with the total number of negative urine results (p=0.03). Changes in the prefrontal Cho levels, however, were not associated with the total number of negative urine results. These preliminary findings suggest that CDP-choline treatment may exert potential neuroprotective effects directly or indirectly because of reductions in drug use by the MA-dependent patients. Further studies with a larger sample size of MA-dependent patients are warranted to confirm a long-term efficacy of CDP-choline in neuroprotection and abstinence.
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Citicoline is an essential precursor in the synthesis of phosphatidylcholine, a key cell membrane phospholipid, and is known to have neuroprotective effects in acute ischemic stroke. The aim of this study was to determine the efficacy and safety of oral citicoline in Korean patients with acute ischemic stroke. A drug surveillance study was carried out in 4,191 patients with a diagnosis of acute ischemic stroke. Oral citicoline (500-4000 mg/day) was administered within less than 24 h after acute ischemic stroke in 3,736 patients (early group) and later than 24 h after acute ischemic stroke in 455 patients (late group) for at least 6 weeks. For efficacy assessment, primary outcomes were patients' scores obtained with a short form of the National Institutes of Health Stroke Scale (s-NIHSS), a short form of the Barthel Index of activities of daily living (s-BI) and a modified Rankin Scale (mRS) at enrollment, after 6 weeks and at the end of therapy for those patients with extended treatment. All adverse reactions were monitored during the study period for safety assessment. All measured outcomes, including s-NIHSS, s-BI and mRS, were improved after 6 weeks of therapy (P < 0.05). Further improvement was observed in 125 patients who continued citicoline therapy for more than 12 weeks when compared with those who ended therapy at week 6. Improvements were more significant in the higher dose group (> or = 2000 mg/day) (P < 0.001). s-BI scores showed no differences between the early and late groups at the end of therapy. Citicoline safety was excellent; 37 side effects were observed in 31 patients (0.73%). The most frequent findings were nervous system-related symptoms (8 of 37, 21.62%), followed by gastrointestinal symptoms (5 of 37, 13.5%). Oral citicoline improved neurological, functional and global outcomes in patients with acute ischemic stroke without significant safety concerns.
Study objective: To assess the effect of armodafinil on task-related prefrontal cortex activation using functional magnetic resonance imaging (fMRI) in patients with obstructive sleep apnea (OSA) and excessive sleepiness despite continuous positive airway pressure (CPAP) therapy. Methods: This 2-week, multicenter, prospective, randomized, double-blind, placebo-controlled, parallel-group study was conducted at five neuroimaging sites and four collaborating clinical study centers in the United States. Patients were 40 right-handed or ambidextrous men and women aged between 18 and 60 years, with OSA and persistent sleepiness, as determined by multiple sleep latency and Epworth Sleepiness Scale scores, despite effective, stable use of CPAP. Treatment was randomized (1:1) to once-daily armodafinil 200 mg or placebo. The primary efficacy outcome was a change from baseline at week 2 in the volume of activation meeting the predefined threshold in the dorsolateral prefrontal cortex during a 2-back working memory task. The key secondary measure was the change in task response latency. Results: No significant differences were observed between treatment groups in the primary or key secondary outcomes. Armodafinil was generally well tolerated. The most common adverse events (occurring in more than one patient [5%]) were headache (19%), nasopharyngitis (14%), and diarrhea (10%). Conclusions: Armodafinil did not improve fMRI-measured functional brain activation in CPAP-treated patients with OSA and excessive sleepiness. Study registration: Double-Blind, Placebo-Controlled, Functional Neuroimaging Study of Armodafinil (200 mg/Day) on Prefrontal Cortical Activation in Patients With Residual Excessive Sleepiness Associated With Obstructive Sleep Apnea/Hypopnea.
OBJECTIVES: The recent emergence of new psychoactive compounds (novel psychoactive substances (NPS)) has raised prominent challenges in the fields of drug policy, substance use research, public health and service provision. The Recreational Drugs European Network project, funded by the European Commission, was implemented to improve the information stream to young people and professionals about effects/risks of NPS by identifying online products and disseminating relevant information through technological tools. METHODS: Regular multilingual qualitative assessments of websites, drugs fora and other online resources were carried out using the Google search engine in eight languages from collaborating countries. These included the following: the UK, Norway, Belgium, Germany, Hungary, Poland, Italy and Spain. Products were tested and prevention messages were developed and disseminated via technological tools such as interactive websites, SMS alert, social networking (Facebook, Twitter), Multimedia (You Tube), Smartphone applications (iPhone) and virtual learning environments (Second Life). RESULTS: The Recreational Drugs European Network project established itself as the first Europe-wide prevention programme designed for NPS based on the efficacy of novel information and communication technology-based forms of intervention. More than 650 NPS products and combinations were identified; relevant information was disseminated to target population and advice was given to both European Union/international agencies and national policy makers. CONCLUSIONS: Web-monitoring activities are essential for mapping the diffusion of NPS and the use of technological tools can be successfully incorporated in specific prevention programmes. Furthermore, the involvement of multi-disciplinary international partnerships was and continues to be fundamental for responding to such a prominent challenge.
The safety of Cerebrolysin has been shown through many years of clinical use, observations from postmarketing surveillance studies, and safety data from randomized, controlled clinical trials. The reported events showed that adverse reactions to Cerebrolysin were generally mild and transient. Most common adverse events included vertigo, agitation and feeling hot. In the controlled clinical trials analyzed for this report, the incidence of adverse events was similar in Cerebrolysin- and placebo-treated groups. Cerebrolysin seems to be safe when used in combination with recombinant tissue-type plasminogen activator or cholinesterase inhibitors such as donepezil or rivastigmine. To our knowledge, Cerebrolysin was not associated with major changes in vital signs or laboratory parameters.
Losartan, an angiotensin II receptor antagonist (AIIA), is an antihypertensive that has previously been suggested to have cognitive-enhancing potential for older adults. The objective indices for such effects are equivocal, however, and if these drugs do offer dual advantages of hypertension control plus cognitive-enhancing potential, there exists a clear need to establish this directly. This work examines the potential of losartan administered as a single dose to healthy young adults to improve cognitive performance alone or to reverse scopolamine-induced cognitive decrements. In two placebo-controlled, double-blind studies, participants completed a cognitive test battery once before and once after drug absorption. In experiment 1, participants were randomly allocated to receive placebo, losartan 50 mg or losartan 100 mg. In experiment 2, participants were randomly allocated to one of four treatment groups: placebo/placebo, placebo/scopolamine, losartan/scopolamine and losartan/placebo (50 mg losartan p.o. and 1.2 mg scopolamine hydrochloride p.o.). Losartan 50 mg improved performance on a task of prospective memory when administered alone and reversed the detrimental effects of scopolamine both in a standard lexical decision paradigm (p < 0.01) and when the task incorporated a prospective memory component (p < 0.008). The findings highlight a cognitive-enhancing potential for losartan on compromised cognitive systems and emphasise the potential of AIIAs to produce benefits over and above hypertension control.
Armodafinil, a non-amphetamine, wakefulness-promoting medication, is the R- and longer-lasting isomer of racemic modafinil. Armodafinil has been shown to improve wakefulness in patients with excessive sleepiness (ES) associated with treated obstructive sleep apnoea, shift work disorder or narcolepsy. In comparison with modafinil, armodafinil maintains higher plasma concentrations later in the day in healthy subjects. The objective of this analysis was to characterize the pharmacokinetic parameters related to those higher concentrations. Data from three randomized studies in healthy adult subjects receiving single doses of either armodafinil (50, 100, 200, 250, 300 or 400 mg) or modafinil (400 mg) were pooled, and subsequently dose-normalized to a 200 mg dose for each drug. Non-compartmental pharmacokinetic parameters were assessed. Armodafinil and modafinil both had a mean single-dose terminal elimination half-life of approximately 13 hours, with similar mean maximum plasma drug concentration (C(max)) and median time to C(max) values. After reaching C(max), plasma concentrations appeared to decline in a monophasic manner with armodafinil, but in a biphasic manner with modafinil due to the initial rapid elimination of its S-isomer. As a result, mean area under the plasma drug concentration versus time curve (AUC) from time zero to the time of the last measurable concentration (AUC(last)) and AUC from time zero to infinity (AUC(infinity)) values were 33% and 40% higher, respectively, with armodafinil compared with modafinil on a milligram-to-milligram basis. Despite similar half-lives, plasma concentrations following armodafinil administration are higher late in the day than those following modafinil administration on a milligram-to-milligram basis. The different pharmacokinetic profile of armodafinil may result in improved wakefulness throughout the day in patients with ES compared with modafinil.