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

Abstract

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

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[VOLUME 12, NUMBER 11–12, NOVEMBER–DECEMBER 2015] Innovations in CLINICAL NEUROSCIENCE 21
ABSTRACT
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.
INTRODUCTION
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.
COMMONLY USED NOOTROPICS
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
by FARID TALIH, MD, and JEAN AJALTOUNI, MD
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.
FINANCIAL DISCLOSURES: The authors have
no conflicts of interest relevant to the
content of this article.
ADDRESS CORRESPONDENCE TO:
Farid Talih, MD, American University of Beirut,
3 Dag Hammarskjold Plaza, 8th Floor, New
York, NY 10017-2303 USA;
Email: ft10@aub.edu.lb
KEY WORDS: Nootropics, supplements,
substance abuse, cognitive enhancers,
substance misuse, psychiatric adverse effects
CASE SERIES
Probable Nootropic-
induced Psychiatric
Adverse Effects:
A Series of Four Cases

Innovations in CLINICAL NEUROSCIENCE [VOLUME 12, NUMBER 11–12, NOVEMBER–DECEMBER 2015]
22
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
modafinil.5
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
tremors.10
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-
hydroxy-5-methyl-4-
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
piracetam.17–19
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
NOOTROPIC MODE OF ACTION
DESIRED
PSYCHOTROPIC
EFFECT
ADVERSE SIDE
EFFECTS
Armodafinil •›Glutamate
•›GABA •›Wakefulness
• Headache
• Nasopharyngitis
• Diarrhea
Citicoline
•›Integrity
neuronal
membranes
• Modulation of
acetylcholine
• Dopamine and
glutamate
•›Memory
• Gastrointestinal
discomfort
• Headache
• Insomnia
• Myalgias
• Restlessness
• Fatigue
• Tremors
Piracetam
• Binds to AMPA
receptor
•›Fluidity of
neuronal
membranes
•›Cognition
•›Memory
• Psychomotor
agitation
• Dysphoria
• Dizziness
• Memory loss
• Diarrhea
Ampakines
• Bind to
glutamatergic
AMPA receptor
•›Cognition
•›Memory
•›Learning
•›Alertness
• Spatial memory
impairment
• Possible motor
function
impairment
Cerebrolysin
•› Synaptic
formation
•› Cholinergic fiber
regeneration
•›Cognition
•›Sensory
enhancement
• Vertigo
• Agitation
• Feeling
hot/flushing
›: increase; GABA: gamma-amino butyric acid; AMPA: alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid

[VOLUME 12, NUMBER 11–12, NOVEMBER–DECEMBER 2015] Innovations in CLINICAL NEUROSCIENCE 23
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 REPORTS
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
supplements.
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.
DISCUSSION
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

Innovations in CLINICAL NEUROSCIENCE [VOLUME 12, NUMBER 11–12, NOVEMBER–DECEMBER 2015]
24
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.
CONCLUSION
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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