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The Impact of Caffeine in Triggering Panic Attacks among Adults with Panic Disorder: A Systematic Review and Meta-analysis of Randomized Controlled Trials

January 2020
Canadian Journal of Clinical Nutrition 8(1):69-94

DOI:10.14206/canad.j.clin.nutr.2020.01.06

Authors:

Abdulrahman Buhiji

King Hamad University Hospital

Aram Kassim

East Sussex Healthcare NHS Trust

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Objective: Patients with panic disorder (PD) appear to be at a high-risk for developing a panic attack when consuming caffeine. The purpose of this review was to explore the impact of consumption of caffeine-containing foods in triggering panic attacks among adults diagnosed with PD. Methods: An electronic search of PubMed/Medline and EMBASE databases was conducted. The keywords used for the search were “caffeine”, “energy drink”, “tea”, “coffee”, “caffeinated drinks”, "caffeinated beverages”, “anxiety”, “panic disorder”, ”panic attacks”, and “adenosine receptor agonist”. Studies that reported the experience of caffeine-induced panic attacks among adult patients diagnosed with PD and published in English peer-reviewed journals between January 1950 and December 2018 were included. Each article was reviewed independently by at least two investigators. Panic attacks induced by consuming caffeine-containing foods in PD patients were the primary outcome of interest. Estimates were pooled using random-effects and meta-analysis. Subgroup analysis for sex, age, and country variables was conducted as well. Results: The events of panic attacks among PD patients after caffeine consumption were extracted from fifteen studies across four countries (K=15, N=360). The overall pooled data showed that 48% (173/360 PD patients (95% CI 38.6%–57%) experienced caffeine-triggered panic attacks. Conclusions: In this systematic review and metaanalysis, about half (48%) of adults with PD experienced panic attacks after caffeine consumption. Further research is needed to examine the prevalence of panic attacks on a larger scale among different regions, standardize the dosage of caffeine in the future experiment, as well as identify the potential confounding factors.

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Canadian Journal of Clinical Nutrition, Volume 8, Issue 1, January 2020

ISSN 1927-8942 (Print Edition), ISSN 1927-8950 (Online Edition)

This is an open access article distributed under the terms of the Library and Archives/Government of Canada,

(www.collectionscanada.gc.ca) & The Creative Commons Attribution Non-Commercial License which permits unrestricted non-

commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Review Article

The Impact of Caffeine in Triggering Panic Attacks among Adults with Panic

Disorder: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Abdulrahman Mohamed Buhiji1,2, Mahmood Ahmed Saleh1,2, Aram Kassim3, Aayat

Ebrahim Faraj1,2, Sara Jaafar Mohamed1,2, Kiara Verhagen3, Mo'ez Al-Islam Faris4, Haifa

Mohammad Saleh Algahtani2, Haitham Jahrami*1, 2

1Ministry of Health, Manama, Bahrain.2College of Medicine and Medical Sciences, Arabian Gulf

University, Manama, Bahrain.3King Hamad University Hospital, Bussaitain, Bahrain. 4Department of

Clinical Nutrition and Dietetics, College of Health Sciences/Research Institute of Medical and Health

Sciences (RIMHS), University of Sharjah, Sharjah, UAE

*Correspondence Email Address: hjahrami@health.gov.bh

ABSTRACT

Objective: Patients with panic disorder (PD) appear to be at a high-risk for developing a panic attack

when consuming caffeine. The purpose of this review was to explore the impact of consumption of

caffeine-containing foods in triggering panic attacks among adults diagnosed with PD. Methods: An

electronic search of PubMed/Medline and EMBASE databases was conducted. The keywords used

for the search were “caffeine”, “energy drink”, “tea”, “coffee”, “caffeinated drinks”, "caffeinated

beverages”, “anxiety”, “panic disorder”, ”panic attacks”, and “adenosine receptor agonist”. Studies

that reported the experience of caffeine-induced panic attacks among adult patients diagnosed with

PD and published in English peer-reviewed journals between January 1950 and December 2018 were

included. Each article was reviewed independently by at least two investigators. Panic attacks

induced by consuming caffeine-containing foods in PD patients were the primary outcome of

interest. Estimates were pooled using random-effects and meta-analysis. Subgroup analysis for sex,

age, and country variables was conducted as well. Results: The events of panic attacks among PD

patients after caffeine consumption were extracted from fifteen studies across four countries (K=15,

N=360). The overall pooled data showed that 48% (173/360 PD patients (95% CI 38.6%–57%)

experienced caffeine-triggered panic attacks. Conclusions: In this systematic review and meta-

analysis, about half (48%) of adults with PD experienced panic attacks after caffeine consumption.

Further research is needed to examine the prevalence of panic attacks on a larger scale among

different regions, standardize the dosage of caffeine in the future experiment, as well as identify the

potential confounding factors.

Keywords: Anxiety, Caffeine, Energy drink, Tea, Panic attacks, Panic disorder

Citation: Abdulrahman Mohamed Buhiji, Mahmood Ahmed Saleh, Aram Kassim, Aayat Ebrahim

Faraj, Sara Jaafar Mohamed, Kiara Verhagen, Mo'ez Al-Islam Faris, Haifa Mohammad Saleh

Algahtani, Haitham Jahrami. The Impact of Caffeine in Triggering Panic Attacks among Adults with

Panic Disorder: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Canadian

Journal of Clinical Nutrition 2020; 8 (1): 69-94.

DOI: https://dx.doi.org/10.14206/canad.j.clin.nutr.2020.01.06

Page 69-94

Canadian Journal of Clinical Nutrition, Volume 8, Issue 1, January 2020

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INTRODUCTION

Caffeine is a commonly consumed central nervous system stimulant worldwide (1-3). The

popularity of caffeine stems from the various subjective benefits that individuals experience with

its consumption. This includes increased attentiveness and alertness, improved work

performance (1, 4, 5), enhanced vigilance (6), and delayed sleep onset (4, 5). Nonetheless, when

taken in excessive amounts, caffeine has been reported to have anxiogenic properties (7, 8).

These symptoms appear to be subtle in low volume consumers as compared to frequent

consumers (9). Some studies have suggested that only caffeine doses higher than average

consumption levels can induce significant anxiogenic effects (10, 11). However, anxiety levels

tend to be markedly increased in consumers who suffer from existing anxiety or panic disorder

when compared to the general population (7, 12).

Panic disorder (PD) is defined by the Diagnostic and Statistical Manual of Mental Disorders-5

(DSM-V) as recurrent unexpected panic attacks, whereby at least one of the panic attacks has

been followed by one month or more of one or both of the following: persistent fear or concern

about additional panic attacks or their sequelae, and/or a maladaptive changes of behavior related

to the panic attacks (13). The hallmark of PD is a panic attack, that is defined as an abrupt surge

of intense fear or intense discomfort that reaches a peak within minutes, and during which four

or more of a list of thirteen physical and cognitive symptoms occur (13). The aforementioned

physical symptoms are as follows: palpitations, sweating, shaking, shortness of breath, choking

sensation, chest pain, nausea, abdominal discomfort, dizziness, chills, paresthesia, derealization,

depersonalization, fear of loss of control, and fear of death (13).

A cross-national epidemiological study of PD and panic attacks suggested that the lifetime

prevalence of PD is estimated to be 1.7%, with the median age of onset at 32 years of age (14).

In the United States of America (USA), the median age is thought to be 24 years (13). PD is

considered to be more common in females, with a male to female ratio of 2:1 (13). According to

the diagnostic interview data from National Comorbidity Survey Replication, an estimated 4.7%

of American adults experience PD at sometimes in their lives (15). Currently, clinical practice

guidelines recommend the combination of pharmacotherapy and cognitive behavioral therapy as

Canadian Journal of Clinical Nutrition, Volume 8, Issue 1, January 2020

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the most effective treatment for PD (16). Caffeine abstinence has been proposed in the past as a

method to treat anxiety disorders, including PD (17, 18), but the evidence is scarce.

The purpose of this systematic review and meta-analysis was to explore the role of caffeine in

triggering panic attacks among adults with established PD.

METHODS

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) was used

for this systematic review and meta-analysis as a guideline (19).

Database Searches

An electronic search of PubMed/MEDLINE and EMBASE was conducted by two authors (AB

and MS). The keywords used in the search included: “panic attack” OR “panic disorder” OR

“anxiety” AND “caffeine” OR “energy drink” OR “tea” OR “coffee” OR “caffeinated drink” OR

“caffeinated beverage” OR “adenosine receptor antagonist.” Both authors then screened the

references list of the obtained studies manually to determine if there are additional studies to be

included.

Inclusion and Exclusion Criteria

The inclusion criteria for selecting the studies were: 1) studies that reported PD patients exposed

to caffeine, 2) PD was diagnosed by a psychiatrist, 3) adult PD patients only, 4) studies that

reported the number of panic attack cases after consuming caffeine, and 5) original studies

published in the English language. The exclusion criteria of studies were: 1) PD patients with a

coexisting psychotic disorder, 2) meta-analyses, systemic reviews, or review articles,

commentaries, abstracts, 3) animal experiments, 4) studies that were published in another non-

English language, 5) studies with the full text not found, 6) studies where caffeine is not the

prime focus. See Figure 1 for the flow of study selection.

Main Outcomes and Measures

Estimating caffeine-triggered panic attacks among adult patients with PD was the desired

outcome of this study. Titles and abstracts of the harvested studies were screened by three

authors (AB, MS, and AK), and a fourth author (HJ) solved any disagreement that arose during

screening or extraction. Data were extracted from the included studies by the review team (AB,

MS, AK, AF, SJ, and KV) and involved information about the study’s year of publication,

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sample size, country where the research was conducted, mean age of the sample, proportion of

male subjects, and the primary outcomes following caffeine consumption. Data extraction from

each study was done independently by two members of the review team.

Data Synthesis and Statistical Analyses

The data were combined in this meta-analysis using a random-effects model and the

DerSimonian–Laird method. We reported the proportion of patients who experienced caffeine-

trigged panic attacks the corresponding 95% Confidence Interval (95% CI). Data were also

presented graphically using the Forest plot. An assessment of studies heterogeneity using the I2

statistic was performed; the value of ≥75% was considered to represent high heterogeneity.

Between-study heterogeneity was also assessed in this review by the Cochran (Q) statistic test

and tau square (τ2). A leave-one-out sensitivity analysis was performed by iteratively removing

one study at a time to confirm that any single research did not drive our findings. Subgroup

meta-analysis was conducted to investigate the influence of the country, age, and sex. Meta-

analyses were performed using OpenMetaAnalyst software provided by the Centre for Evidence

Synthesis in Health/Center for Evidence-Based Medicine, the School of Public Health at Brown

University. Other descriptive statistical analyses were performed using Microsoft Excel.

RESULTS

Study Characteristics

Out of seventy-nine studies harvested, fifteen studies involving three hundred sixty PD were

included in the analyses (K=15, N=360). Table 1 presents selected characteristics of studies

examining caffeine-triggered panic attacks among adult patients with PD included in the current

systematic review and meta-analysis.

Out of the 360 patients, 109 were males (30.3%) and 251 were females (69.7 %). Eight studies

were from the USA, three from Brazil, three from Greece, and one from France. These studies

were conducted in the period 1984-2015 and peaked in the mid-nineties. The median sample size

was 23 (range 7-60 PD patients). Adults involved in these studies were with a median age of 35

(range 27- 40 years). The caffeine dose ranged from 200-480 mg per day.

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Caffeine-triggered Panic Attack in Patients with PD

The meta-analytic pooling of data showed that 173 out of 360 PD patients (48%, 95% CI,

38.6%-57.6%) had caffeine-triggered panic attack following caffeine consumption using

random-effects models, Figure 2. Statistically, significant heterogeneity was noted among the

included studies (K=15, I2=62.61%, τ2=0.327, P<0.001). Estimates between studies ranged from

19.0% to 93.7%. The range of point estimate in the sensitivity analysis was 45.4%-50.1%. This

suggests that if one study is removed from the analysis, the overall pooled estimate will change

by approximately 4%. Table 2 presents a systematic summary of studies of examining caffeine-

triggered panic attacks among adults with PD included in the review.

Caffeine-triggered Panic Attack in Patients with PD by their Gender

In this meta-analysis study, males constituted about 30% (N=109) of the population size, and

females were about 70% (N=251). The least percentage of male participants in a study was 18%

from Boulenger et al., (20), while the most rate was 50% from Koenigsberg et al.,(21). The

meta-analysis was conducted to demonstrate the impact of sex (using the proportion of males per

study) in caffeine-induced panic attacks in PD patients. As illustrated in Figure 3, moderator

analysis using the method of moments algorithm meta-regression shows that sex is not

significant predictor (β=1.77 P=0.49).

Caffeine-triggered Panic Attack in Patients with PD by their Age

This study involved adults with PD. The youngest was 27 years old, and the earliest was 40 years

old (median=35). Moderator analysis using meta-regression shows that age is not significant

predictor (β=0.09, P=0.11), Figure 4.

Caffeine-triggered Panic Attacks by Country

Out of the fifteen studies, the majority were from the USA (K=8, N=165), followed equally by

Greece (K=3, N=82) and Brazil (K=3, N=83), and the remaining was from France (K=1, N=30).

Subgroup analysis was performed when three or more studies were available per country. Studies

from the USA showed that 85 out of 165 PD patients, over half of the population, panicked due

to caffeine ingestion (51.9%, 95% C.I.; 33.1%-70.2%). Statistically, significant heterogenicity

was noted among the studies (K=8, I2=74.6%, τ2=0.835, P=0.001).

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Estimates between studies ranged from 19.0%-93.7%. On the other hand, studies from Greece

showed that 30 out of 82 patients experienced a panic attack due to caffeine (36.7%, 95% C.I.,

27.0%-47.8%). The studies did not show statistically significant differences, and no

heterogeneity was noted (K=3, I2=0 %, τ2=0.001, P=0.509). Estimates between studies ranged

from 30.4%-47%. Studies from Brazil showed that 47 out of 83 patients had caffeine-induced

panic attacks (56.6%, 95% C.I., 45.8%-66.8%). The study was not statistically significant, and

no heterogeneity was noted (K=3, I2=0%, τ2=0.001, P=0.856). Estimates between studies ranged

from 52%-58.6%, Figure 5.

DISCUSSION

We were interested in finding the association between panic attacks among adult patients with

PD patients and caffeine consumption. As the exact cause of PD is still unknown, studying the

effect of chemical triggers like caffeine on the disease may impact the treatment strategies or

modalities and the course of PD.

The main findings from our review are that about half (48%) of adults with PD experienced

panic attacks after caffeine consumption. Age and sex did not appear to play a role in influencing

caffeine-trigged panic attacks in adult patients with PD. However, some differences were

obtained between countries which may merit discussion.

This finding can be explained by the main constituent of caffeine, which is a xanthine molecule,

a liposoluble alkaloid, and methylated purine base. During the process of absorption, this

molecule is demethylated by the liver cells, specifically by the actions of cytochrome P450 1A2

(CYP1A2) enzyme, which is responsible for 90% of xenobiotics metabolism. Other enzymes

actively involved in the metabolism of caffeine include CYP2A6, CYP2E1, N-acetyltransferase

(NAT2) and xanthine oxidase (XO). The process is somewhat complicated and yields the

formation of 84% paraxanthine (1,7-dimethylxanthine), 12% theobromine (3,7-

dimethylxanthine), and 4% theophylline (1,3-dimethylxanthine) (22).

Our results also showed a marginal increase in panic attacks with caffeine consumption in older

patients. This, however, did not reach statistical significance. This could be explained by the

chronicity of PD, different metabolism rates; which is faster in younger people (23), higher

sensitivity in older adults to the effects of caffeine, and varying proportions of adipose to lean

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body compartments resulting in higher concentration of caffeine in the plasma and tissue of older

adults (24).

According to the findings of our meta-analysis, male and female patients with PD appear to

metabolize caffeine similarly. Although studies showed different metabolic routes explained by

the differences in steroid hormones among both sexes (25). The plausible explanation to our

findings is that the illness itself alters the metabolism of caffeine in males and females; resulting

in a similar response, providing that the exact etiopathological factor of PD is still not definite.

Caffeine is thought to produce its effects partly by antagonizing adenosine inhibitors in the

central nervous system (26), studies have suggested that polymorphisms of the ADORA2a

adenosine receptor gene (27, 28), and possibly the ADORA1 receptor gene, might explain the

marked individual differences of anxiogenic responses to caffeine (26). Out of the 350

panicogenic genes that have been proposed as candidates to panic disorder (29), there is evidence

suggesting that variations of ADORA2a gene might indeed play an essential role in the

pathogenesis of PD (29, 30).

Subgroup analysis by countries was done and showed that Greece and Brazil had homogenous

outcomes (I2=0%), which is explained by having the same authors (Masdrakis and Nardi,

respectively), hence, using the same labs, caffeine dosages, diagnostic scales. However, the USA

showed heterogeneous outcomes (I2=74.61), which is due to different labs, caffeine dosages, and

scales used in multiple studies conducted by various researchers.

Several systemic reviews were done on the effect of caffeine on PD patients; however, our

analysis is the first meta-analysis done on this topic on a sample of human subjects using clinical

study design. However, the current review entailed several limitations: the meta-analysis was

limited only to English language studies, different diagnostic criteria were used to reach the

diagnosis of PD, the dosage of caffeine varied among studies from 200 mg to 480 mg per day,

the control of psychoactive substances that alter caffeine effects were not fixed (for example

nicotine and alcohol), patients with another medical or psychiatric problems rather than PD were

not excluded, and some factors due to the nature of meta-analysis were not available (including

BMI, smoking, alcohol consumption).

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In future studies, researchers should ensure using a larger sample size, same scales, and same

experimenter design. Clinicians may benefit from this study by using the information in

screening the dietary history of patients, consulting and advising appropriate levels of caffeine,

and tailoring the dose in the treatment plan.

CONCLUSION

In this systematic review and meta-analysis, about half (48%) of adults patients with PD

experienced panic attacks after caffeine consumption. Age and sex did not appear to play a

significant role in influencing the events of caffeine-trigged panic attacks in adult patients with

PD. Further research is needed to examine the prevalence of panic attacks on a larger scale

among different regions, standardize the dosage of caffeine in the future experiment, as well as

identify the potential confounding factors.

Author contribution & Funding

AB and MS contributed to the conception and design of the work. AB, MS, AK, AF, SJ, and KV

coordinated data extraction, data coding, and data preparation. HJ performed data analyses. MF and

HG critically revised the manuscript and provided critical revision. All authors were involved in

writing the paper and approved the final version for publication.

Funding: This research received no specific grant from any funding agency in the public,

commercial, or not-for-profit sectors.

Disclosure of interest

The authors declare no conflict of interest.

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Table 1: Selected characteristics of studies examining caffeine-triggered panic attacks among adults with PD included in

systematic review and meta-analysis

* Mean ± Standard Deviation

NR= Not Reported

Study authors

Year of Publication

Country

Age*

% of Male

Sample Size

Caffeine-triggered cases

Boulenger et.al.

1984

France

38±8.0

18%

Charney et.al.

1985

USA

38±NR

29%

Lee et.al.

1985

USA

34.4±10

37%

Breier et.al.

1986

USA

38±10.0

28%

Klein et.al.

1991

USA

40±9.6

29%

Newman et.al.

1992

USA

36.0±6.2

29%

Beck and Berisford

1992

USA

33.9±NR

24%

Tancer et.al.

1994

USA

32.7±6.6

27%

Koenigsberg et.al.

1998

USA

36.7±8.4

50%

Nardi et.al.

2007

Brazil

34.2±12.3

38%

Masdrakis et.al.

2008

Greece

27±NR

39%

Nardi et.al.

2008

Brazil

33.9±13.0

32%

Masdrakis et.al.

2009

Greece

31.3±8.1955

30%

Nardi et.al.

2009

Brazil

37.48.6

39%

Masdrakis et.al.

2015

Greece

35.0±6.9

21%

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Page80 Page80

Table 2: Systematic summary of studies of examining caffeine-triggered panic attacks among adults with PD included in

systematic review and meta-analysis

Study Authors/year

Materials and Methods

Main Results

Beck and Berisford

1992

A prospective study, double-blinded, placebo design.

Setting at Laboratory.

Patients were referred by local psychotherapists. Exclusion criteria

included: hypertension, pregnancy, and use of prescription

medications that contained caffeine.

Panic symptom ratings were derived from DSM-III-R and were

modeled after the Acute Panic Inventory. Caffeine dose was 250

mg/day.

Psychophysiological measures:

Systolic and diastolic blood pressure was measured by remote-

controlled Grass 7P8 sphygmomanometer. Skin conductance

measured using Beckman Ag-AgC1 electrodes and a Grass 7P1

preamplifier. Heart rate was measured using a Grass 7P3

preamplifier and was converted from a raw EKG signal to a beats-

per-minute expression using a Grass 7P44B tachograph. All were

then recorded on a Grass 7D polygraph

Subjective anxiety:

A potentiometer attached to a mechanical calibrated on a 0-100

scale. Subjects were instructed to use the dial to rate their level of

anxiety

Panic symptom ratings: Subjects were asked to rate on a 0-3 scale,

each of 12 panic symptoms, derived from DSM-III-R.

19% (n=4) of PD patients reported an

increase in panic symptoms in both

caffeine and placebo conditions.

They also reported a more significant

increase in severity of anxiety.

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Page81 Page81

Boulenger et al. 1984

A questionnaire designed by the investigators to assess the

consumption of various caffeinated beverages, foods, or drugs and

the effects of caffeine on various somatic and psychologic

symptoms.

Subjects were outpatients involved in various research programs at

the National Institute of Mental Health.

Exclusion criteria: notable medical problems

PD patients were based on the Research Diagnostic Criteria

Daily caffeine consumption was calculated according to the

quantities of caffeine suggested by Gilbert for different beverages.

Spielberger State-Trait Anxiety Inventory, the Beck Depression

Inventory, and the Hopkins Symptom Checklist (SCL-90) were

administered. Several subscales were derived from the SCL-90 as

described by its authors.

In participants with PD, 11 out of 16

psychopathologic measures were

significantly and positively correlated with

the daily caffeine intake level – including

levels of anxiety.

11 out of 20 patients with PD reported

giving up coffee because of CNS

stimulation (nervousness, tension, anxiety,

insomnia).

The consumption of one cup of coffee was

associated with notably more intense

ratings of anxiety, alertness, and insomnia -

but not of well-being- in the patients with

PDs s than in their controls.

Breier et al. 1986

Face to face interview using the Schedule for Affective Disorders

and Schizophrenia (SADS) and a semi-structured interviewing

guide, looking at age of onset of symptoms, duration of symptoms

and symptom free periods, as well as estimating the frequency and

type of panic attacks that predominated in each year (spontaneous,

non-spontaneous or mixed). Caffeine consumption and the patient’s

report of its effect on generalized anxiety and panic anxiety were

documented.

The setting was at outpatient clinical research treatment program

for agoraphobia and PD.

Subjects were referred from self-referrals in response to a

newspaper articles are describing the anxiety disorders clinic,

private psychiatrists, and other mental health professionals, non-

psychiatric physicians, general hospital clinics, and community

mental health center clinics.

Inclusion criteria: the history of spontaneous panic attacks, a

current Research Diagnostic Criteria diagnosis of agoraphobia,

mixed phobia, and/or PDPD, age between 18 and 65 years, good

54% (n=26) of patients who drank

caffeinated beverages reported worsening

of anxiety symptoms following caffeine

consumption.

17% (n=8) indicated that caffeine

consumption precipitated panic attacks.

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Page82 Page82

physical health as determined by physical and laboratory

examinations, no history of psychotic disorders or current

substance abuse.

PD was diagnosed using the Research Diagnostic Criteria.

An intensive, face-to-face interview that consisted of structured and

semi-structured components was used to collect the data It was 4

hours, in 2 settings.

The interviews were done by three clinicians with experience in the

treatment of anxiety disorders.

The data collected were mostly dependent on patient recall of

historical information; the diagnostic determinations in the study

must be considered "estimates" and therefore subject to

inaccuracies.

Charney et al. 1985

Placebo-controlled, double-blind clinical trial.

It is done at the anxiety disorder clinic of the Ribicoff Research

Facilities of the Connecticut Mental Health Center.

Patients were self-referred either by word of mouth or articles in

local newspapers or referred by clinicians familiar with the

treatment program. An initial screening interview was done,

followed by a structured interview by a research psychiatrist

utilizing the Schedule for Affective Disorders and Schizophrenia.

Exclusion criteria: lack of diagnostic clarity or presence of medical

problems.

PD diagnosis was established using the Diagnostic and Statistical

Manual of Mental Disorders-III.

Each patient participated in two test days, and the time interval

between test days ranged from one day to three weeks.

Blood was sampled from an intravenous cannula in a forearm vein

that was kept patent with a normal saline solution. Samples

collected at 15 and 0.5 minutes before the caffeine dose and 60,

120, 180, and 240 minutes after the caffeine dose. Additional

samples for cortisol and caffeine levels were drawn 30 and 90

71% (n=15) of the patients experienced

increased anxiety, nervousness, nausea,

palpitations, restlessness, and tremors

following caffeine consumption.

These symptoms were correlated with the

plasma caffeine levels in the patients.

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Page83 Page83

minutes.

Plasma cortisol level was determined by radioimmunoassay.

Quantitation of the plasma free 3-methoxy-4-

hydroxyphenylethylenglycol (MHPG) was carried out by selected

ion monitoring, using a quadrupole mass spectrometer equipped

with a gas chromatographic inlet system.

Serum caffeine and paraxanthine levels were determined using

reverse-phase high-pressure liquid chromatography.

The sequence of administering placebo followed by active caffeine

was fixed to allow subjects to accommodate to test procedures.

Klein et al. 1991

A double-blind study between a single oral dose of meta-

chlorophenyl piperazine, caffeine, and placebo.

It is done in the section on Anxiety and Affective Disorders of the

National Institute of Mental Health.

Patients were referred by local psychiatrists and were then screened

by two clinicians.

Panic attacks were assessed based on the Diagnostic and Statistical

Manual of Mental Disorders-III criteria.

Caffeine dose was fixed at 480 mg per day.

The meta-chlorophenylpiperazine (m-CPP) dose was 0.5 mg/kg

Oral single-dose drug or placebo was used on separate days with at

least 72hr between procedures.

An indwelling intravenous (IV) catheter was placed in a forearm

vein. Between 9 and 10:30 AM, identical unmarked capsules of

placebo, m-CPP, or caffeine were administered.

Baseline blood samples collected at 15 minutes before and at +90,

+ 120, + 150, + 180, and +210 mm after drug administration.

Blood pressure and pulse were measured using an automated

monitor.

Plasma prolactin was measured using double-antibody

radioimmunoassay kits.

Plasma cortisol was measured using a double-antibody

70% (n=5) of those who received caffeine

experienced a panic attack.

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Page84 Page84

radioimmunoassay kit.

The behavioral rating scales were Zung Anxiety rating scale,

Hamilton Depression rating scale, NIMH panic attack inventory,

NIMH rating scales for anxiety, depression, and global impairment.

To avoid any biasing effect on the m-CPP or placebo responses

resulting from caffeine's anxiogenic effects, caffeine was always

given as the last study drug, whereas m-CPP and placebo were

randomly assigned.

Koenigsberg et.al 1998

PD diagnosis was made using Diagnostic and Statistical Manual of

Mental Disorders-III-R criteria.

Inclusion criteria: good physical health, not pregnant, and meeting

Diagnostic and Statistical Manual of Mental Disorders-III criteria

for PD with or without agoraphobia.

Exclusion criteria: abnormal thyroid function, history of

arrhythmia, seizure disorder, or sleep apnea. Also, those with other

psychiatric disorders were excluded.

Subjects participated in either a 2-night or a 3-night protocol.

Subjects retired at their usual bedtime and polysomnographic

recordings were obtained each night.

Behavior was monitored using an infrared video system.

Once stage 3–4 sleep had been maintained for 3 min, the caffeine

dose was infused through an intravenous catheter over a 3 min

period.

If a subject awakened and appeared fully alert following infusion,

the investigator entered and administered the Acute Panic

Inventory.

A response was rated as a full panic if Diagnostic and Statistical

Manual of Mental Disorders-III-R criteria for the panic attack were

met. If three or more panic symptoms were present, but full attack

criteria were not met, the episode was rated as a subclinical

response.

25% (n=2) of the subjects had a panic

attack.

25% (n=2) had subclinical response.

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Lee et al. al 1985

Subjects were outpatient meeting Diagnostic and Statistical Manual

of Mental Disorders-III criteria for anxiety disorder. They

completed the Hopkins Symptom Checklist (SCL-90-R) and a

caffeine questionnaire designed by one of the authors, assessing

amount of daily consumption of caffeine-containing beverages and

drugs, symptom profiles in response to drinking a cup of coffee,

and use of minor tranquilizers and other medications.

Amount of daily caffeine consumption from approximately 25

sources was calculated.

Correlations between caffeine consumption and subscale scores on

the SCL-90-R were examined.

76.7% (n=23) of patients were anxious

following a cup of coffee.

Frequency of developing anxiety was not

different between the groups, but somatic

symptoms were more in patients who

consume <100 mg/day.

Masdrakis et al. 2008

Randomized, double-blind, crossover experiment.

Subjects recruited from the Outpatient Clinic of their Department.

The diagnosis was established by two Associate Professors of

Psychiatry, using the Diagnostic and Statistical Manual of Mental

Disorders-IV criteria, and a third psychiatrist through a Structured

Clinical Interview for Diagnostic and Statistical Manual of Mental

Disorders-III-R.

Inclusion criteria: PD with or without agoraphobia, free of

psychotropic drugs for one month at least, normal blood tests, and

free from any cardiovascular problems.

Exclusion criteria: any other mental illness, substance abuse

disorder (except smoking), any significant medical disease or

medication that may interfere with the study, and pregnancy.

A dose of caffeine = 200 and 400 mg/day in 2 days, 3–7 days apart,

in the form of instant coffee, produced by a multinational company.

Psychometric evaluations through Hamilton Depression Rating

Scale, State-Trait Anxiety Inventory, Diagnostic and Statistical

Manual of Mental Disorders-IV symptoms of Panic Attack,

Symptom Checklist-90-Revised, ‘Declaration of Panic’ which is a

subjective statement, and Daily Caffeine Consumption

questionnaire.

30% (n=7) of patients presented with panic

attack after at least one caffeine challenge

test.

Patients with PD who experienced a panic

attack presented with a higher baseline of

non-specific general psychopathology

(SCL-90-R) and a shorter breath-holding

duration than those with PD and did not

experience a panic attack after caffeine

challenge.

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Psychophysiological evaluations through voluntary breath-holding

and heartbeat perception.

Breath Holding duration measured by electronic chronometer

Heartbeat perception performed using the ‘mental tracking’

procedure, and an electrocardiogram was performed concurrently.

Masdrakis et al. 2009

Patients were in the acute phase of PD and were waiting for therapy

(they were drug-free).

Panic attack symptoms were diagnosed by Diagnostic and

Statistical Manual of Mental Disorders-IV.

Caffeine administration dose was 400-mg/day. Administered in the

form of instant coffee, produced by a multinational

Company.

Patients completed the State-Trait Anxiety Inventory-State form,

visual analog scales of the 13 Diagnostic and Statistical Manual of

Mental Disorders-IV ‘panic attack’ symptoms, and they obtained a

subjective statement form to "do you have a panic attack?"

An electronic chronometer measured BH duration.

35% (n=14) of patients panicked after the

caffeine challenge.

The study showed that caffeine

administration increases lactate levels and

that has been associated with caffeine-

induced panic attacks.

Also, those with a lower baseline breath-

holding duration were more vulnerable to

the effects of caffeine as a panic inducer;

through the accumulation of CO2.

Masdrakis et al. 2015

Randomized, double-blind, cross-over experiment.

Patients were referred from the Department's Outpatient Clinic.

Inclusion criteria: Diagnostic and Statistical Manual of Mental

Disorders-IV-TR PD with or without agoraphobia; current

exacerbation of panic/agoraphobic symptoms; psychotropic drug-

free for at least one month before baseline evaluation.

Exclusion criteria: concurrent medical/psychiatric comorbidity;

major medical/psychiatric disorders in the past; currently on

medication or psychotherapy; score in the Hamilton Depression

Rating Scale (17-item) 410; substance abuse disorder except

smoking; pregnancy

Panic was diagnosed using the Diagnostic and Statistical Manual of

Mental Disorders-IV-TR.

Caffeine dose was 400-mg/day, given with a placebo-challenge,

twice 3–7 days apart, administered in the form of caffeinated and

47.3% (n=9) panicked after the caffeine

challenge.

No patients panicked after placebo-

challenge.

Eleven subjects consumed low amounts of

caffeine (<100mg daily) and eight

moderate amounts (100– 300 mg/day).

Panic attack after caffeine administration

was observed in 6 low and three moderate

daily consumers.

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Page87 Page87

decaffeinated-instant coffee respectively.

A blood sample was taken for baseline Adrenocorticotropic

hormone (ACTH) and cortisol evaluation.

Patients completed the visual analog scales of the 13 Diagnostic

and Statistical Manual of Mental Disorders-IV ‘panic attack’

symptoms, and they obtained a subjective statement form to ‘do

you have a panic attack?

ACTH and cortisol levels were estimated using commercial

radioimmunoassay kits.

Nardi et.al 2007

Randomized double-blinded experiment

Setting in Laboratory of Panic and Respiration from the Federal

University of Rio de Janeiro.

Patients spontaneously presented themselves, received a clinical

diagnosis by a study psychiatrist, then a second diagnosis by a

second clinician.

Inclusion criteria: 18 to 55 years of age, occurrence of at least three

panic attacks in 2 weeks before the first challenge test day for the

PD patients, no use of any antipsychotic, antidepressant,

benzodiazepine or nonbenzodiazepine anxiolytic medication for at

least 4 weeks, or fluoxetine for 5 weeks, before the first test by any

subject, and a negative urine test for benzodiazepines and other

medications just before each challenge test.

Exclusion criteria were: unstable medical condition, cognitive-

behavior psychotherapy during the study, the presence of suicidal

risk, smokers, or a history of respiratory disease.

PD was diagnosed using the Diagnostic and Statistical Manual of

Mental Disorders-IV.

Caffeine dose was 480 mg/day, given on two occasions seven days

apart, administered in the form of instant coffee.

The 35% CO2 test was always done. First, the patients inhaled

either 35% CO2 mixture or atmospheric compressed air, and then

the other gas after 20 minutes.

58.6% (n = 17) of patients with PD

developed panic attack.

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Caffeine challenge test was done one week after the respiratory

examination.

Anxiety level measurement was done by Subjective Units of

Disturbance Scale, A semiquantitative evaluation method, and the

Diagnostic Symptom Questionnaire adapted for Diagnostic and

Statistical Manual of Mental Disorders-IV.

Nardi et.al

2008

(Same as Nardi 2007).

Amount of caffeine in the solution was calculated by their local

biochemical laboratory.

In the first session, subjects received the oral dose of caffeine or

caffeine-free solution, and in the second session, the same

procedure was performed using the drug that had not been

administered in the previous session.

Anxiety level measurement was done by Subjective Units of

Disturbance Scale, A semiquantitative evaluation method, and the

Diagnostic Symptom Questionnaire adapted for Diagnostic and

Statistical Manual of Mental Disorders-IV.

52.0% (n = 13) PD patients experienced a

panic attack after the test.

Nardi et.al

2009

(Same as Nardi 2007)

Anxiety level measurement was done by Subjective Units of

Disturbance Scale, A semiquantitative evaluation method, and the

Diagnostic Symptom Questionnaire adapted for Diagnostic and

Statistical Manual of Mental Disorders-IV.

Family history data were collected during the interview with the

patient.

An interview of a first-degree relative done to compare and check

information.

60.7% (n=17) of panic disease patients

developed a panic attack.

Newman et al. 1992

A randomized, double-blind, placebo-controlled trial.

All subjects were attending the outpatient department of the

National Institute.

of the Mental Health Clinical Center

Panic was diagnosed using the Diagnostic and Statistical Manual of

14% (n=1) patient experienced panic

attack. Caffeine, but not placebo,

significantly increased Zung anxiety scores

among all subjects. PD patients were more

sensitive than normal control subjects to

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Page89 Page89

Mental Disorders-III-R criteria.

Caffeine dose was 7mg/day base/kg body weight.

Subjects received caffeine drink or identical tasting placebo.

All Electroencephalograms (EEG) were recorded by a registered

EEG technician.

Fifteen minutes of EEG activity recorded at baseline, 30-45

minutes after ingestion of caffeine or placebo, and 75-90 minutes

after.

Ratings on the Zung Anxiety Scale were made at baseline and at 90

minutes; a visual analog subjective scale for anxiety was completed

at baseline and 90 minutes.

Caffeine levels were measured by high-pressure liquid

chromatography from venous blood drawn at 90 minutes.

caffeine’s effects (P < 0.05) visual analog

scales for anxiety reflected an anxiogenic

effect of caffeine (p < 0.01) increased

sensitivity of patients with PD (p < 0.05).

The two groups did not differ in their EEG

responses to caffeine.

Tancer et al. 1994

Double-blinded study with 480 mg/day caffeine base or placebo

capsules.

The subjects were outpatients treated at the Section on Anxiety and

Affective Disorders, National

Institute of Mental Health.

PD was diagnosed using the Diagnostic and Statistical Manual of

Mental Disorders-III –R criteria

Caffeine dose was 480 mg/day.

All subject received both caffeine and placebo on separate days.

Blood pressure and pulse were monitored every five minutes using

an automated recorder

Behavioral rating: Spielberger State Anxiety Inventory, and a

clinician-rated Zung Anxiety Inventory.

Blood samples for cortisol and lactic acid were drawn before the

pills were administered and at +90 minutes.

Lactate analyzed using an enzymatic oxidation assay.

Cortisol was measured using radioimmunoassay.

27% (n=3) of PD patients reported a panic

attack during the caffeine study day.

Greater increase in lactate levels was a

consistent finding in PD patients.

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Page90 Page90

Figure 1: Flow Diagram of Study Inclusion

Screening

Eligibility

68 Records identified through database

searching

11 Additional records identified

through other sources

79 Records screened

Titles, abstract and full-text screening

25 Full-text articles assessed

for eligibility

15 Studies included in

qualitative synthesis

15 Studies included in

quantitative synthesis

(meta-analysis)

Identification

Included

10 Full-text articles excluded,

due to reason.

6 did not report caffeine-

triggered panic attacks rate in

patients with PD

4 reviews (no original data)

54 records were duplicates or

wrong sample.

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Page91 Page91

Figure 2: Caffeine-triggered panic attacks among adult patients with panic disorder

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Page92 Page92

Figure 3: The association between caffeine-triggered panic attacks among adult

patients with panic disorder and gender

Regression of %Male on Logit event rate

%Male

Logit event rate

0.15 0.19 0.22 0.26 0.30 0.34 0.38 0.42 0.46 0.49 0.53

3.00

2.50

2.00

1.50

1.00

0.50

0.00

-0.50

-1.00

-1.50

-2.00

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Page93 Page93

Figure 4: The association between caffeine-triggered panic attacks among adult

patients with panic disorder and age

Regression of Age on Logit event rate

Age

Logit event rate

25.70 27.26 28.82 30.38 31.94 33.50 35.06 36.62 38.18 39.74 41.30

3.00

2.50

2.00

1.50

1.00

0.50

0.00

-0.50

-1.00

-1.50

-2.00

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Figure 5: Caffeine-triggered panic attacks among adult patients with panic disorder

by country

Nutrition and Anxiety Disorders

Chapter

Oct 2022

Ramli Musa

Food and anxiety are interrelated to each other in various relationships. Food may worsen the anxiety symptoms; hence, modification of food intake would certainly help in alleviating some of the anxiety symptoms at a certain degree. Certain foods, particularly organic in nature, are also effective in helping the patients to go through the treatment course and fasten the recovery process. It may not be the only key solution or main treatment, but modification in dietary intake would help the sufferers. In this chapter, we outline how anxiety and types of food are interrelated and different types of food could help or worsen the anxiety symptoms. Also, at the end of this chapter, we outline the effects of microbiome on human guts and anxiety symptoms.KeywordsAnxietyDepressionDietaryPanicogenicModification

Caffeine alters emotion and emotional responses in low habitual caffeine consumers

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Caffeine reliably increases emotional arousal, but it is unclear whether and how it influences other dimensions of emotion such as emotional valence. These experiments documented whether caffeine influences emotion and emotion regulation choice and success. Low to abstinent caffeine consumers (maximum 100 mg/day) completed measures of state anxiety, positive and negative emotion, and salivary cortisol before, 45 min after, and 75 min after consuming 400 mg caffeine or placebo. Participants also completed an emotion regulation choice task, in which they chose to employ cognitive reappraisal or distraction in response to high and low intensity negative pictures (Experiment 1), or a cognitive reappraisal task, in which they employed cognitive reappraisal or no emotion regulation strategy in response to negative and neutral pictures (Experiment 2). State anxiety, negative emotion, and salivary cortisol were heightened both 45 and 75 min after caffeine intake relative to placebo. In Experiment 1, caffeine did not influence the frequency with which participants chose reappraisal or distraction, but reduced negativity of the picture ratings. In Experiment 2, caffeine did not influence cognitive reappraisal success. Thus, caffeine mitigated emotional responses to negative situations, but not how participants chose to regulate such responses or the success with which they did so.

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Full-text available

Feb 2016

Caffeine is the most widely-consumed psychoactive drug in the world, but our understanding of how caffeine affects our brains is relatively incomplete. Most studies focus on effects of caffeine on adenosine receptors, but there is evidence for other, more complex mechanisms. In the fruit fly Drosophila melanogaster, which shows a robust diurnal pattern of sleep/wake activity, caffeine reduces nighttime sleep behavior independently of the one known adenosine receptor. Here, we show that dopamine is required for the wake-promoting effect of caffeine in the fly, and that caffeine likely acts presynaptically to increase dopamine signaling. We identify a cluster of neurons, the paired anterior medial (PAM) cluster of dopaminergic neurons, as the ones relevant for the caffeine response. PAM neurons show increased activity following caffeine administration, and promote wake when activated. Also, inhibition of these neurons abrogates sleep suppression by caffeine. While previous studies have focused on adenosine-receptor mediated mechanisms for caffeine action, we have identified a role for dopaminergic neurons in the arousal-promoting effect of caffeine.

Mechanisms of the psychostimulant effects of caffeine: Implications for substance use disorders

Article

Full-text available

May 2016
PSYCHOPHARMACOLOGY

Sergi Ferré

Background: The psychostimulant properties of caffeine are reviewed and compared with those of prototypical psychostimulants able to cause substance use disorders (SUD). Caffeine produces psychomotor-activating, reinforcing, and arousing effects, which depend on its ability to disinhibit the brake that endogenous adenosine imposes on the ascending dopamine and arousal systems. Objectives: A model that considers the striatal adenosine A2A-dopamine D2 receptor heteromer as a key modulator of dopamine-dependent striatal functions (reward-oriented behavior and learning of stimulus-reward and reward-response associations) is introduced, which should explain most of the psychomotor and reinforcing effects of caffeine. Highlights: The model can explain the caffeine-induced rotational behavior in rats with unilateral striatal dopamine denervation and the ability of caffeine to reverse the adipsic-aphagic syndrome in dopamine-deficient rodents. The model can also explain the weaker reinforcing effects and low abuse liability of caffeine, compared with prototypical psychostimulants. Finally, the model can explain the actual major societal dangers of caffeine: the ability of caffeine to potentiate the addictive and toxic effects of drugs of abuse, with the particularly alarming associations of caffeine (as adulterant) with cocaine, amphetamine derivatives, synthetic cathinones, and energy drinks with alcohol, and the higher sensitivity of children and adolescents to the psychostimulant effects of caffeine and its potential to increase vulnerability to SUD. Conclusions: The striatal A2A-D2 receptor heteromer constitutes an unequivocal main pharmacological target of caffeine and provides the main mechanisms by which caffeine potentiates the acute and long-term effects of prototypical psychostimulants.

Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?

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Full-text available

Apr 2015

Caffeine use is increasing worldwide. The underlying motivations are mainly concentration and memory enhancement and physical performance improvement. Coffee and caffeine-containing products affect the cardiovascular system, with their positive inotropic and chronotropic effects, and the central nervous system, with their locomotor activity stimulation and anxiogenic-like effects. Thus, it is of interest to examine whether these effects could be detrimental for health. Furthermore, caffeine abuse and dependence are becoming more and more common and can lead to caffeine intoxication, which puts individuals at risk for premature and unnatural death. The present review summarizes the main findings concerning caffeine’s mechanisms of action (focusing on adenosine antagonism, intracellular calcium mobilization, and phosphodiesterases inhibition), use, abuse, dependence, intoxication, and lethal effects. It also suggests that the concepts of toxic and lethal doses are relative, since doses below the toxic and/or lethal range may play a causal role in intoxication or death. This could be due to caffeine’s interaction with other substances or to the individuals&apos preexisting metabolism alterations or diseases.be due to caffeine’s interaction with other substances or to individuals’ pre-existing diseases or metabolism alterations.

Caffeine improves reaction time, vigilance and logical reasoning during extended periods with restricted opportunities for sleep

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Full-text available

Dec 2014

Various occupational groups are required to maintain optimal physical and cognitive function during overnight periods of wakefulness, often with less than optimal sleep. Strategies are required to help mitigate the impairments in cognitive function to help sustain workplace safety and productivity. To test the effectiveness of repeated 200 mg doses of caffeine on cognitive function and live-fire marksmanship with soldiers during three successive nights of sustained wakefulness followed by 4-h afternoon sleep periods. Twenty Special Forces personnel (28.6 ± 4.7 years, 177.6 ± 7.5 cm and 81.2 ± 8.0 kg) were randomly assigned to receive four 200-mg doses of caffeine (n = 10) or placebo (n = 10) during the late evening and early morning hours during three successive days. An afternoon 4-h sleep period followed. The psychomotor (PVT) and field (FVT) vigilance, logical reasoning (LRT) tests and a vigilance monitor assessed cognitive function throughout the study. Live-fire marksmanship requiring friend-foe discrimination was assessed. Caffeine maintained speed on the PVT (p < 0.02), improved detection of events during FVT (p < 0.001), increased number of correct responses to stimuli as assessed by the vigilance monitor (p < 0.001) and increased response speed during the LRT (p < 0.001) throughout the three overnight testing periods. Live-fire marksmanship was not altered by caffeine. A total daily dose of 800 mg caffeine during successive overnight periods of wakefulness is an effective strategy to maintain cognitive function when optimal sleep periods during the day are not available.

Caffeine Use Disorder: A Review of the Evidence and Future Implications

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Full-text available

Sep 2014

Merideth A Addicott

The latest edition of the Diagnostic and Statistical Manual of Mental Disorders (5th edition; DSM-5) has introduced new provisions for caffeine-related disorders. Caffeine withdrawal is now an officially recognized diagnosis, and criteria for caffeine use disorder have been proposed for additional study. Caffeine use disorder is intended to be characterized by cognitive, behavioral, and physiological symptoms indicative of caffeine use despite significant caffeine-related problems, similar to other substance use disorders. However, since non-problematic caffeine use is so common and widespread, it may be difficult for some health professionals to accept that caffeine use can result in the same types of pathological behaviors caused by alcohol, cocaine, opiates, or other drugs of abuse. Yet there is evidence that some individuals are psychologically and physiologically dependent on caffeine, although the prevalence and severity of these problems is unknown. This article reviews the recent changes to the DSM, the concerns regarding these changes, and some potential impacts these changes could have on caffeine consumers.

Caffeine Use Disorder: A Comprehensive Review and Research Agenda

Article

Full-text available

Sep 2013

Caffeine is the most commonly used drug in the world. Although consumption of low to moderate doses of caffeine is generally safe, an increasing number of clinical studies are showing that some caffeine users become dependent on the drug and are unable to reduce consumption despite knowledge of recurrent health problems associated with continued use. Thus, the World Health Organization and some health care professionals recognize caffeine dependence as a clinical disorder. In this comprehensive literature review, we summarize published research on the biological evidence for caffeine dependence; we provide a systematic review of the prevalence of caffeine dependence and rates of endorsement of clinically meaningful indicators of distress and functional impairment among habitual caffeine users; we discuss the diagnostic criteria for Caffeine Use Disorder-a condition for further study included in the Diagnostic and Statistical Manual of Mental Disorders (5(th) ed.); and we outline a research agenda to help guide future clinical, epidemiological, and genetic investigations of caffeine dependence. Numerous controlled laboratory investigations reviewed in this article show that caffeine produces behavioral and physiological effects similar to other drugs of dependence. Moreover, several recent clinical studies indicate that caffeine dependence is a clinically meaningful disorder that affects a nontrivial proportion of caffeine users. Nevertheless, more research is needed to determine the reliability, validity, and prevalence of this clinically important health problem.

Cross-national epidemiology of panic disorder and panic attacks in the world mental health surveys

Article

Oct 2016
DEPRESS ANXIETY

Context: The scarcity of cross-national reports and the changes in Diagnostic and Statistical Manual version 5 (DSM-5) regarding panic disorder (PD) and panic attacks (PAs) call for new epidemiological data on PD and PAs and its subtypes in the general population. Objective: To present representative data about the cross-national epidemiology of PD and PAs in accordance with DSM-5 definitions. Design and setting: Nationally representative cross-sectional surveys using the World Health Organization Composite International Diagnostic Interview version 3.0. Participants: Respondents (n = 142,949) from 25 high, middle, and lower-middle income countries across the world aged 18 years or older. Main outcome measures: PD and presence of single and recurrent PAs. Results: Lifetime prevalence of PAs was 13.2% (SE 0.1%). Among persons that ever had a PA, the majority had recurrent PAs (66.5%; SE 0.5%), while only 12.8% fulfilled DSM-5 criteria for PD. Recurrent PAs were associated with a subsequent onset of a variety of mental disorders (OR 2.0; 95% CI 1.8-2.2) and their course (OR 1.3; 95% CI 1.2-2.4) whereas single PAs were not (OR 1.1; 95% CI 0.9-1.3 and OR 0.7; 95% CI 0.6-0.8). Cross-national lifetime prevalence estimates were 1.7% (SE 0.0%) for PD with a median age of onset of 32 (IQR 20-47). Some 80.4% of persons with lifetime PD had a lifetime comorbid mental disorder. Conclusions: We extended previous epidemiological data to a cross-national context. The presence of recurrent PAs in particular is associated with subsequent onset and course of mental disorders beyond agoraphobia and PD, and might serve as a generic risk marker for psychopathology.

Adolescent caffeine consumption increases adulthood anxiety-related behavior and modifies neuroendocrine signaling

Article

Feb 2016

Caffeine is a commonly used psychoactive substance and consumption by children and adolescents continues to rise. Here, we examine the lasting effects of adolescent caffeine consumption on anxiety-related behaviors and several neuroendocrine measures in adulthood. Adolescent male Sprague-Dawley rats consumed caffeine (0.3 g/L) for 28 consecutive days from postnatal day 28 (P28) to P55. Age-matched control rats consumed water. Behavioral testing for anxiety-related behavior began in adulthood (P62) 7 days after removal of caffeine. Adolescent caffeine consumption enhanced anxiety-related behavior in an open field, social interaction test, and elevated plus maze. Similar caffeine consumption in adult rats did not alter anxiety-related behavior after caffeine removal. Characterization of neuroendocrine measures was next assessed to determine whether the changes in anxiety were associated with modifications in the HPA axis. Blood plasma levels of corticosterone (CORT) were assessed throughout the caffeine consumption procedure in adolescent rats. Adolescent caffeine consumption elevated plasma CORT 24 h after initiation of caffeine consumption that normalized over the course of the 28-day consumption procedure. CORT levels were also elevated 24 h after caffeine removal and remained elevated for 7 days. Despite elevated basal CORT in adult rats that consumed caffeine during adolescence, the adrenocorticotropic hormone (ACTH) and CORT response to placement on an elevated pedestal (a mild stressor) was significantly blunted. Lastly, we assessed changes in basal and stress-induced c-fos and corticotropin-releasing factor (Crf) mRNA expression in brain tissue collected at 7 days withdrawal from adolescent caffeine. Adolescent caffeine consumption increased basal c-fos mRNA in the paraventricular nucleus of the hypothalamus. Adolescent caffeine consumption had no other effects on the basal or stress-induced c-fos mRNA changes. Caffeine consumption during adolescence increased basal Crf mRNA in the central nucleus of the amygdala, but no additional effects of stress or caffeine consumption were observed in other brain regions. Together these findings suggest that adolescent caffeine consumption may increase vulnerability to psychiatric disorders including anxiety-related disorders, and this vulnerability may result from dysregulation of the neuroendocrine stress response system.

Effects of caffeine on the human circadian clock in vivo and in vitro

Article

Sep 2015
Sci Transl Med

Caffeine’s wakefulness-promoting and sleep-disrupting effects are well established, yet whether caffeine affects human circadian timing is unknown. We show that evening caffeine consumption delays the human circadian melatonin rhythm in vivo and that chronic application of caffeine lengthens the circadian period of molecular oscillations in vitro, primarily with an adenosine receptor/cyclic adenosine monophosphate (AMP)–dependent mechanism. In a double-blind, placebo-controlled, ~49-day long, within-subject study, we found that consumption of a caffeine dose equivalent to that in a double espresso 3 hours before habitual bedtime induced a ~40-min phase delay of the circadian melatonin rhythm in humans. This magnitude of delay was nearly half of the magnitude of the phase-delaying response induced by exposure to 3 hours of evening bright light (~3000 lux, ~7 W/m2) that began at habitual bedtime. Furthermore, using human osteosarcoma U2OS cells expressing clock gene luciferase reporters, we found a dose-dependent lengthening of the circadian period by caffeine. By pharmacological dissection and small interfering RNA knockdown, we established that perturbation of adenosine receptor signaling, but not ryanodine receptor or phosphodiesterase activity, was sufficient to account for caffeine’s effects on cellular timekeeping. We also used a cyclic AMP biosensor to show that caffeine increased cyclic AMP levels, indicating that caffeine influenced a core component of the cellular circadian clock. Together, our findings demonstrate that caffeine influences human circadian timing, showing one way that the world’s most widely consumed psychoactive drug affects human physiology.