Manage PTSD, TBI, and Gulf War Illness

For more information visit: www.tmedpharma.com

Med

osttraumatic Stress

Rev 1.1 November 201 2

PTSD, TBI, GWI and the Autonomic Nervous System

PTSD, TBI, and Gulf War Illness: Autonomic Dysfunction

related to Neurotransmitter Depletion

The objective of this pamphlet is to provide healthcare professionals with information regarding the physiological impact that chronic stress can have on the human body and the co-morbid factors associated with exposure to traumatic events, traumatic brain injury, and neurotoxic chemicals. This pamphlet will provide information on the following items:

ALLOSTASIS

The delicate chemical balance of the human body can be seriously altered when exposed to extreme stress, injury or exposure to toxic chemicals. The alterations in chemical synthesis and signaling as a result of these factors yield a host of

allostasis and allostatic load put forward by Sterling and Eyer in 1988 link the protective and survival values of the acute response to stress to the adverse consequences that result if the acute response persists.

NEUROTRANSMITTER DEPLETION

The neurobiological response to stress, toxic chemicals and brain injury can result in a host of co-morbidities such as Myocardial Infarction, depression, and Parkinsons Disease, all of which seriously alter the course of a patients life and

There are a number of neurotransmitters, neuropeptides and hormones involved in the acute stress response. These chemicals have important functions throughout the regulatory central and autonomic nervous systems. The structural changes in the brain as a result of exposure to combat stress, neurotoxic chemicals, or traumatic brain injury alter the function of these regulatory systems ultimately resulting in complex clinical conditions. Due to the complex nature of

at managing symptoms related to these exposures as they do not address the

The common use of antidepressants, NSAIDs, opiate pain relievers, and hypnotic sleep medications to treat these complex clinical cases often result in a host of

management of pain, sleep and cognitive disorders associated with autonomic dysfunction.

Physiologic Symptoms of PostTraumatic Stress Disorder

Autonomic Nervous System FunctionHeart Rate VariabilityNeurobiology of PTSD

Medical Food Management of PTSD, TBI and GWI

Sleep DisturbancesChronic PainHyperarousalIrritable Bowel SyndromeDepressed Heart Rate VariabilityMental FatigueMemory DysfunctionIrritabilityDepression

Physiologic Symptoms ofTraumatic Brain Injury

FatigueHeadachesMemory DysfunctionCognitive DysfunctionSleep disturbancesDizziness/Loss of BalanceIrritability-emotional disturbancesFeelings of depressionDepressed Heart Rate Variability

Physiologic Symptoms of GulfWar Illness

FatigueMusculoskeletal PainNeuropathic PainCognitive DisordersGastrointestinal DisordersSleep DisordersLoss of Balance


Autonomic Nervous System Dysfunction

Amino Acids and Neurotransmitters

The existing body of evidence indicates that many psychosocial stressors appear to have multiple different biological risk factors, reflecting links to most of the known major regulatory systems (e.g., cardiovascular, immune, HPA, SNS) Initial empirical work based on various cumulative indices of physiological risk has provided evidence that greater cumulative dysregulation is associated with significantly greater risks for subsequent disease (cardiovascular disease), declines in physical and cognitive functioning and overall mortality (Seeman et al, 1997; Seeman et al, 2001; Karlamangla et al, 2002; Geronimus et al, 2006). Cumulative indices of allostatic load have also been positively related to measures of psychosocial stress in young adolescents (Evans et al, 2007) as well as symptoms of post-traumatic stress disorder (PTSD) in mothers of pediatric cancer survivors (Glover et al, 2006) and adverse perinatal outcomes (Shannon et al, 2007).

Exposure to stress elicits adaptive physiological responses in regulatory systems including the hypothalamic pituitary axis (HPA), the sympathetic (SNS) and parasympathetic (PNS) branches of the autonomic nervous system, and the cardiovascular and immune systems. As these systems become increasingly dysregulated, they begin to exhibit imbalances in the primary neural mediators of the stress response, such as glucocorticoids, catecholamines, proinflammatory cytokines and alterations in other neurotransmitter pathways. Autonomic dysregulation is evidenced in both basal levels of system parameters, including circulating baseline levels of specific hormones, changes in patterns of dynamic response to stimuli, and changes in heart rate variability (HRV). Chronic dysregulation is believed to confer cumulative physiological risk for disease and disability by causing damage to tissues and major organ systems.

Active service men and women who are exposed to psychological stressors, neuro-toxic chemicals or who suffer traumatic brain injury are at high risk for sustained autonomic nervous system dysregulation. Suppressed parasympathetic activity and consistently elevated sympathetic activity, as measured by HRV, adversely affects the physiology of the human body. The long term effects of this imbalance are profound and can explain onset of early cardiovascular disease, proliferation of sleep disorders, and development of depression among our nations active and inactive military personnel.

Diseases with pathologies that involve imbalances in neurotransmitters will increase the requirements for certain amino acids and other dietary precursors to restore homeostasis (Bazzichi et al. 2006). For most of these amino acids and dietary precursors, uptake by target neurons is a concentration-driven process; therefore, intakes must be sufficient to increase the extracellular to intracellular concentrations to levels high enough to drive a rapid rate of uptake (Fernstrom, 1981). The rate of precursor uptake by target neurons is important to neurotransmitter synthesis because the enzymes involved are found only in these neurons and thus the amount of substrate available is the limiting factor in neurotransmitter production (Wurtman et al. 1993).

As blood levels of dietary precursors rise in response to increased intakes, the concentration-driven rate of precursor uptake by target neurons is increased, making more substrate available for neurotransmitter production and subsequent release (Fernstrom, 1994). Changes in intakes of the dietary precursors of these neurotransmitters will therefore influence physiological responses by affecting neurotransmitter availability (Szymusiak et al. 1993).

When the body is stressed and sympathetic nervous system activity is elevated the rate at which amino acids are consumed increases. Sustained sympathetic response can deplete the body of vital neurotransmitter precursors needed for the maintenance of non-sympathetic functions. For example, increased utilization of GABA and Acetylcholine to manage the stress response can leave the autonomic nervous system depleted of these chemicals, essentially crippling its ability to restore balance.

Disease and Neurotransmitter Deficiency

The nutritional requirements of most interest to patients with chronic disorders associated with muscle pain, fatigue, sleep disturbances, loss of memory, and poor concentration are nutrients and dietary factors that support the effects of acetylcholine on neuromuscular , neurocognitive, and neuroendocrine functions. The concept that nutrient requirements are modified by disease has been recognized for more than 30 years, and is supported by studies which have shown changes in plasma, urinary, and tissue levels of nutrients associated with abnormalities in physiological endpoints reflective of specific pathologies.


Heart Rate Variability: Diagnosing

Autonomic Dysfunction

Traumatic Brain Injury and HRV

Heart rate variability (HRV) is a measure of the autonomic nervous system functioning and reflects an individual’s ability to adaptively cope with stress. Heart rate variability (HRV) has been used as an indicator of autonomic nervous system function in many settings (Appelhans and Luecken 2006). HRV can be measured by both instantaneous heart rate and beat-to-beat alterations (R–R intervals) in heart rate (Appelhans and Luecken 2006). Heart rate (HR) does not remain constant but fluctuates around a mean value. This fluctuation is influenced by the autonomic nervous system, which regulates HR through the sympathetic and parasympathetic nervous systems (Cohen et al. 1999).

Patients diagnosed with PTSD, Gulf War Illness, and TBI have all demonstrated HRV measurements consistent with autonomic nervous system dysfunction (Mellman et al. 2004) (Hayley et al. 2004) (King, Lichterman 1996).

Elevated psychophysiology of PTSD, Gulf War Illness, and TBI is suggestive of autonomic nervous system dysfunction. Autonomic nervous system dysfunction among these patients is often characterized by excess sympathetic nervous system activity or ineffectual parasympathetic activity (i.e., hyperarousal, difficulty with responsiveness to stressors, as well as an impaired relaxation response). These psychophysiological processes suggest that autonomic dysfunction may be a potential pathogenic mechanism in the etiology and maintenance of PTSD, Gulf War Illness and TBI. Additionally these findings also suggest that correcting HRV disruptions may have a positive impact on the duration and symptoms of these conditions.

Acute severe brain damage reduces all normal cyclic changes in heart rate (Lowensohn et al. 1977). HRV, as assessed using time domain analysis, is decreased following acute injury and may parallel subsequent return of neurological function (Van Ravenswaaij, et al. 1993). Abnormalities in HRV from acute brain injury may not be related to increased intracranial pressure alone, but also to dysfunction of the parasympathetic nervous system ( Leipzig, et al. 1986). The hypothalamus and brainstem are important regulators of this system, and cortical mechanisms have recently been defined. These may involve the loss of supratentorial excitatory influence on brainstem vagal cardioinhibitory neurons (parasympathetic activity), possibly related to disruption of the connections between these regions (Frank et al. 1992) or the disruption in autonomic nervous system function. Abnormalities in HRV follow TBI, and show that this abnormality extends into the post-acute recovery phase.

Parasympathetic Nervous System

Controls Rest and Digestive Functions

Governs Restorative and Growth Functions

Slows Heart Rate

Increases Intestinal and Gland Activity

Relaxes Sphincter Muscles

Constricts Pupils

Increases Smooth Muscle Activity Along GI Tract

Sympathetic Nervous System

Controls Fight or Flight System

Decreases Motility of the Large Intestine

Constrict Blood Vessels

Controls Perspiration

Increases Blood Pressure

Release Glucose Stores from Liver

Mobilizes Amino Acids fromBlood into Tissue


Medical Foods: Improving Parasympathetic TonePTSD, Gulf War Illness and Traumatic Brain Injury

Figure 1: Gulf War Veteran, HRV measurement indicates autonomic nervous system dysfunction. Parasympathetic nervous system is suppressed as indicated by reduced HF band.

Figure 2: Following a 35 day administration of Sentra AM (2 capsules in the morning) and Sentra PM (2 capsules at night) patient began to activate parasympathetic activity. Parasympathetic activation corresponded with a reduction in reported symptoms associated with Gulf War Illness.

Circadian HF Band Parasympathetic Response

Pe

rce

nta

ge

Ch

an

ge

Fro

m

Mid

nig

ht

Hours Since Midnight

400

300

200

100

0

-100

-2001.00.0

Normal

Patient

2.0 3.0 4.0 5.0 6.0

Circadian HF Band Parasympathetic Response

Mid

nig

ht

Hours Since Midnight

1200

1000

800

600

400

200

0

-2001.00.0

Normal

Patient

2.0 3.0 4.0 5.0 6.0

Open Access: Full open access to this and thousands of other papers at http://www.la-press.com.

Journal of Central

Nervous System Disease

IntroductionCombat-related illnesses include posttraumatic stress disorder

(PTSD), Gulf War Illness (GWI), and other symptoms that fall

under the rubric of “postdeployment multisymptom disorder

and related syndromes.”1,2 While similar syndromes have been

reported since the Civil War, the etiology and pathophysiology

of these conditions remain poorly understood.1,3 Thus far,

treatments for these syndromes have been insufficient, due to

limited efficacy, high cost, and low sustainability.4–7

Recently, attention has been directed to abnormalities

of the autonomic nervous system, particularly the parasym-

pathetic autonomic nervous system.8–12 In both PTSD and

GWI, there is a blunting of total autonomic activity, marked

in particular by a reduction of parasympathetic activity. This

imbalance leads to an increase of sympathetic nervous system

symptoms including anxiety, rapid heartbeat, panic spells,

and amplified sweating. Parasympathetic suppression also

manifests as a failure to sleep, abnormal dream patterns, and

memory disturbances.13 There is an emerging consensus that

sleep disturbance may be a core feature of PTSD.14

Alternatives to therapy and psychiatric medication are

essential for treating combat personnel. Active service and mil-

itary veterans are often reluctant to seek treatment for PTSD

symptoms because of the perceived stigma associated with a

psychiatric diagnosis. Sentra AM® (acetyl l-carnitine HCl,

choline bitartrate, l-glutamic acid) and Sentra PM® (acetyl

l-carnitine HCl, choline bitartrate, 5-Hydroxytryptophan,

l-glutamic acid) are specially formulated medical foods that

Administration of an Amino Acid–Based Regimen for the Management of Autonomic Nervous System Dysfunction Related to Combat-Induced Illness

William E. Shell1, Marcus Charuvastra1, Mira Breitstein1, Stephanie L. Pavlik1, Anthony Charuvastra2, Lawrence May1 and David S. Silver1

1Targeted Medical Pharma, Los Angeles, CA, USA. 2New York University Medical Center, Department of Child and Adolescent Psychiatry,

New York, NY, USA.

ABSTRACT: The etiology and pathophysiology of posttraumatic stress disorder (PTSD) remains poorly understood. The nutritional deficiencies associated

with the altered metabolic processes of PTSD have not previously been studied in detail. This pilot study measured the reduction in symptoms in 21 military

veterans reporting moderate to severe symptoms associated with PTSD. Two amino acid–based medical foods specifically formulated with biogenic amines

and other nutrients were administered to study subjects targeting specific neurotransmitter deficiencies resulting from altered metabolic activity associated

with PTSD. This study included the Physician Checklist – Military (PCL-M), Short Form General Health Survey (SF-36), and Epworth Sleepiness Scale

to measure the change in each subject’s score after 30 days of administration. An average decrease of 17 points was seen in the PCL-M, indicating a reduc-

tion in PTSD symptoms (P 0.001). The mental health component of the SF-36 showed an average 57% increase in the subjects’ mental health rating

(P 0.001). The results of this initial study demonstrate that addressing the increased dietary requirements of PTSD can improve symptoms of the disease

while eliminating significant side effects. A larger, double-blind, randomized, placebo-controlled trial is warranted.

KEYWORDS: amino acids, acetylcholine, glutamine, serotonin, Gulf War Illness, PTSD, autonomic nervous system

RECEIVED: December 3, 2013. RESUBMITTED: February 25, 2014. ACCEPTED FOR PUBLICATION: February 27, 2014.

ACADEMIC EDITOR: Alexander Rotenberg, Editor in Chief

TYPE: Original Research

FUNDING: Authors disclose no funding sources.

COMPETING INTERESTS: All authors except AC are or were employees of Targeted Medical Pharma. WS is also a shareholder of Targeted Medical Pharma.

COPYRIGHT: © the authors, publisher and licensee Libertas Academica Limited. This is an open-access article distributed under the terms of the Creative Commons CC-BY-NC 3.0 License.

CORRESPONDENCE: [email protected]

This paper was subject to independent, expert peer review by a minimum of two blind peer reviewers. All editorial decisions were made by the independent academic editor. All authors have provided signed confirmation of their compliance with ethical and legal obligations including (but not limited to) use of any copyrighted material, compliance with ICMJE authorship and competing interests disclosure guidelines and, where applicable, compliance with legal and ethical guidelines on human and animal research participants.

CITATION: Shell et al. Administration of an Amino Acid–Based Regimen for the Management of Autonomic Nervous System Dysfunction Related to Combat-Induced Illness. Journal of Central Nervous System Disease 2014:6 93–98 doi: 10.4137/JCNSD.S13793.

JOURNAL OF CENTRAL NERVOUS SYSTEM DISEASE 2014:6 93

Shell et al

influence the production and absorption of neurotransmitters

essential to autonomic nervous system function.15,16 They may

be particularly effective at targeting symptoms of PTSD and

GWI. We report the results of a pilot study exploring the use

of these medical foods to ameliorate symptoms of PTSD that

are strongly influenced by autonomic nervous system function.

We will refer to these amino acid formulations by brand name

as there is no generic name or version available.

Materials and MethodsThis was a single-arm, open-label study, whose aim was to col-

lect pilot data concerning the efficacy and side effect profile

of Sentra AM® and Sentra PM®. Subjects were veterans and

active duty military personnel, who were recruited via clini-

cian referral and social networking sites between August and

December of 2011. Prospective subjects were directed to a

secure, Health Insurance Portability and Accountability Act

(HIPAA)–compliant Web portal (http://tmedpharma.com/

app/survey/ptsd_GWF001) where they completed an initial

screening questionnaire that verified military status, deploy-

ment locations, current PTSD symptoms, and presence of

suicidal ideation. Screening results were reviewed by study

doctors, including a psychiatrist with experience in assessing

PTSD and suicidal ideation. If significant suicidal ideation was

present, as measured by the Columbia-Suicide Severity Rating

Scale (C-SSRS), subjects were contacted and directed to seek

immediate help from their current clinician or caregiver.

Eligible subjects were men and nonpregnant, nonlactating

women, between the ages of 18–75, with a history of military

deployment in a combat theatre, and symptoms of PTSD as

rated on the Primary Care PTSD Screen (PC-PTSD). The

PC-PTSD is a four-item screen that was designed for use in

primary care settings and is currently used to screen for PTSD

within the United States Department of Veterans Affairs.

Subjects were included if they endorsed three or more items.

Subjects were excluded if they were pregnant, breastfeeding, or

had significant suicidal ideation as measured by the C-SSRS.

Once subjects were accepted into the study, informed consent

was obtained via ground mail or electronically through the

HIPAA-compliant Web Portal. The study protocol was pub-

lished on www.clinicaltrials.gov in compliance with Federal

registration regulations. All elements of the study protocol

were approved by Aspire IRB, an independent institutional

review board. The research was conducted in accordance with

the principles of the Declaration of Helsinki.

After reviewing and completing the informed consent

document, subjects completed baseline questionnaires

including the Physician Checklist-Military (PCL-M),17–19

Short Form General Health Survey (SF-36),20–23 Epworth

Sleepiness Scale (ESS),24,25 and Cognitive Emotion Regula-

tion Questionnaire Short (CERQ-short).26 The PCL is used

for diagnosing PTSD, screening individuals for PTSD, and

monitoring symptom change during and after treatment.

The PCL-M asks about symptoms in response to “stressful

military experiences.” It is often used with active service mem-

bers and Veterans. The SF-36, a widely used general health

profile questionnaire with established reliability and validity,

assesses health-related quality of life.27 The SF-36 has demon-

strated sensitivity to health differences in the general popula-

tion within various scales. These scales include (1) limitations

in physical functioning activities because of health, (2) limi-

tations in social functioning activities because of physical or

emotional problems, (3) limitations in role activities because

of physical health problems, (4) limitations in role activities

because of emotional problems, (5) bodily pain, (6) general

mental health, (7) vitality, and (8) general health perceptions.

The SF-36 is frequently used to assess the status of military

patients with PTSD. The ESS is a seven-question patient-de-

rived sleep questionnaire that looks at the quality and quantity

of sleep. It is utilized to determine the level of daytime sleepi-

ness. A score of 10 or more is considered sleepy. This ESS

score is frequently used to assess sleep disorders in patients

with PTSD. The CERQ was developed to fulfill an omni-

present need for a questionnaire in order to identify cognitive

coping strategies someone uses after experiencing negative

incidents or situations.

Subjects then received the medical foods consisting

of one bottle (60 capsules) of Sentra AM® and one bottle

(60 capsules) of Sentra PM® with all relevant instructions per-

taining to use and warnings via overnight mail. The medical

foods used in the study were prescribed under the supervi-

sion of the study physicians, who reviewed the medical history

forms of all the subjects and were on call to answer any ques-

tions or address any concerns either before beginning treat-

ment or during treatment. Subjects were instructed to take

two capsules (950 mg) of Sentra AM® in the morning and two

capsules (961 mg) of Sentra PM® at bedtime for 30 days. At

the completion of the 30-day period, subjects were asked to

complete posttreatment measures, including the PCL-M, the

SF-36, CERQ-short, and ESS. Data were collected using a

HIPAA-complaint Web-based portal linked to an SQL data-

base. The screening, pretreatment, and posttreatment self-

report measures were automatically entered into the database

as subjects completed them.

The primary endpoint was the PCL-M, as a measure of

PTSD symptoms. Secondary outcomes were daytime groggi-

ness as measured on the ESS, cognitive and emotive function

using CERQ-short, and the mental health score on the SF 36.

All comparison of before and after deltas were examined using

paired Student’s t-tests. The comparisons were made assuming

unequal variance.

A total of 87 individuals were screened, of whom

74 screened positive and were sent informed consent docu-

ments. Of these, 33 individuals completed and returned the

informed consent document and the baseline questionnaires.

Three subjects did not begin the study medical food due to

new and unrelated occurrence of a more serious health issue.

Of the 30 subjects who initiated taking the medical food, 21

94 JOURNAL OF CENTRAL NERVOUS SYSTEM DISEASE 2014:6

Amino acid based regimen to treat combat related illnesses

completed the treatment and posttreatment questionnaires

through the HIPAA-compliant Web-based portal.

ResultsPTSD and GWI symptoms include fatigue, cognitive dys-

function predominately affecting immediate and short-term

memory, sleep disturbance, alteration of dreams, depression,

anxiety, and panic attacks. There was improvement in these

symptoms overall, as measured by the PCL-M, SF-36 mental

component, and ESS questionnaires. All tests were scored

based on normal distributions. Normal distribution was veri-

fied with an f-test comparing the variances at baseline and

day 30. The PCL-M pretreatment mean score was 64.91 with

a standard deviation of 9.55, while the posttreatment mean

score was 47.19 with a standard deviation of 12.51. The paired

t-test gave a value of 6.39 indicating a substantial correlation

with a P-value of less than 0.001 (Fig. 1). A post hoc analysis

looking at the questions on the PCL-M showed a statisti-

cally significant improvement in sleep parameters. The SF-36

pretreatment mental component mean score was 24.41 with a

standard deviation of 10.42, while the posttreatment mental

component mean score was 38.51 with a standard deviation

of 10.88. The paired t-test gave a value of 5.12 indicating

a significant correlation with a P-value of less than 0.001

(Fig. 2). The ESS pretreatment mean score was 10.71 with

a standard deviation of 6.26, while the posttreatment mean

score was 8.10 with a standard deviation of 5.74. The paired

t-test gave a value of 3.32 indicating a significant correlation

with a P-value of less than 0.001 (Fig. 3). The SF-36 physical

pretreatment mean score was 38.24 with a standard deviation

of 7.51, while the posttreatment mean score was 39.65 with

a standard deviation of 9.24. The paired t-test gave a value

of 1.13, which did not meet the level of significance accord-

ing to the P-value set at 0.05 (Fig. 4). The CERQ-short

pretreatment mean score was 47.28 with a standard deviation

of 9.40, while the posttreatment mean score was 46.19 with

a standard deviation of 5.85. The paired t-test gave a value of

0.56, which did not meet the level of significance according

to the P-value set at 0.05 (Fig. 5). There have been no prior

SF-36, PCL-M sleep items, or ESS reports with improve-

ment of this magnitude in patients with deployment-related

PTSD. The precise components of the products used in this

study are listed in Table 1.

DiscussionWe found that a nutritional intervention using a proprietary

medical food formulation significantly reduced PTSD symptoms

among combat veterans with self-reported PTSD symptoms

and distress. The observed reduction in the primary endpoint

was clinically relevant, with an average decrease of 17 points.

In particular, we observed clinically relevant improvements in

measures of sleep quality, an outcome of particular relevance for

treating PTSD. Other pharmacological treatments show only

partial improvement in PCL-M scores, and sleep disturbance in

PTSD is a prominent source of distress and impairment.28

We hypothesize that the mechanism of action for this

nutritional intervention is via its effect on the autonomic

Baseline

Mean PCL-M PTSD

Co

mp

on

en

t sco

re

30

35

40

45

50

55

60

6564.90

47.19

P < 0.001

70

75

Day 30

Figure 1. Baseline and Day 30 mean PCL-M scores.

Baseline0

5

10

15

20

25 24.41

Mean mental health using SF-36

Co

mp

on

en

t s

co

re

38.51

P < 0.00130

35

40

45

Day 30

Figure 2. Baseline and Day 30 mean SF-36 mental component scores.

Baseline

Day time drowsiness

ES

S s

leep

sco

re

0

2

4

6

8

10

12

10.71

8.10

P < 0.001

Day 30

Figure 3. Baseline and Day 30 mean ESS scores.


Shell et al

management of the signs and symptoms of postdeployment

autonomic irregularities.

Nutritional management of disease has been fundamen-

tal since the advent of therapeutic medicine. Tepaske et al.35

administered an arginine-based preparation to patients

prior to cardiac surgery. Postoperative creatinine clearance

and immune function were improved. Tepaske et al.35 and

Kalantar-Zadeh et al.36 demonstrated that administration

of amino acid neurotransmitter precursors in patients with

congestive heart failure improved clinical outcomes. These

two examples demonstrate the potential of the nutrient

management of diseaes.

Serotonin and acetylcholine initiate sleep, elicit REM

sleep, and promote delta sleep. Sentra PM® provides amino

acid precursors 5-hydroxytryptophan and choline that should

Baseline45

45.5

46.5

47

47.28

Mean CERQ-shortP

erc

en

t c

ha

ng

e

46.19

47.5

48

46

Day 30

Figure 4. The percent change from baseline to day 30 based on mean CERQ-short scores. The P-value did not meet the level of significance.

Baseline36.5

37

37.5

38

38.5

39

38.24

Mean physical health using SF-36

Perc

en

t ch

an

ge

39.6539.5

40

40.5

Day 30

Figure 5. The percent change from baseline to day 30 based on mean SF-36 physical component scores. The P-value did not meet the level of significance.

Table 1. Table describing the precise components of Sentra AM and Sentra PM.

PRODUCT INGREDIENTS MG/CAPSULE

Sentra AM Choline bitartrate 250

Sentra AM Cocoa extract theobroma cacao (fruit) (6% Theobromine)

70

Sentra AM L-Glutamic acid 40

Sentra AM Acetyl L-carnitine HCL 40

Sentra AM Dextrose 35

Sentra AM Ginkgo ginkgo biloba (leaf) 25

Sentra AM Hawthorne crataegus spp. (fruit) 15

Sentra AM Gelatin excipient

Sentra AM Tricalcium phosphate 159.3

Sentra AM Silicon dioxide 12.0

Sentra AM Magnesium stearate 5.0

Sentra AM Cellulose 1.0

Sentra AM Shellac excipient

Sentra AM Carmine excipient

Sentra PM Choline bitartrate 250

Sentra PM Cocoa extract theobroma cacao (fruit) (6% Theobromine)

70

Sentra PM L-glutamic acid 40

Sentra PM Acetyl L-carnitine HCL 40

Sentra PM Dextrose 35

Sentra PM Ginkgo ginkgo biloba (leaf) 25

Sentra PM Hawthorne crataegus spp. (fruit) 15

Sentra PM Griffonia extract griffonia simplicifolia (seed) (95% 5-HTP)

5.5

Sentra PM Gelatin excipient

Sentra PM Tricalcium phosphate 159.3

Sentra PM Silicon dioxide 12.0

Sentra PM Magnesium stearate 4.9

Sentra PM Cellulose 1.0

Sentra PM Shellac excipient

Sentra PM Carmine excipient

nervous system. There is significant evidence supporting the

role of a dysfunction in autonomic nervous system activity

in patients diagnosed with PTSD, with the parasympathetic

autonomic nervous system showing suppression resulting in

disturbed and augmented sympathetic reactivity. The sup-

pression of the parasympathetic system, particularly during

sleeping hours, is also closely associated with sleep disor-

ders.29 Failure to activate parasympathetic activity leads to an

inability to initiate sleep, maintain sleep, activate REM sleep,

and reach delta sleep. This constellation of events is associ-

ated with residual daytime grogginess and exacerbation of

mood disorders. Consistent with our hypothesis, we observed

improvement in daytime grogginess and improvement in sleep

quality.

The predominant neurotransmitter involved in regulating

parasympathetic autonomic nervous system activity is

acetylcholine.27,28,30–33 Acetylcholine is intimately involved

in REM sleep, deep delta sleep, and sleep maintenance.29,34

Serotonin, another neurotransmitter, initiates sleep and

maintains sleep. Previous work has shown that providing the

neurotransmitter precursors for acetylcholine and serotonin

can improve sleep architecture.28 While we recognize that

each of these neurotransmitters could be impacted on a higher

central nervous system level, the nutrient management of sleep

and other autonomic functions is a promising approach to the


Amino acid based regimen to treat combat related illnesses

augment the production of neurotransmitters implicated in

sleep disorders.37–39 The precursor 5-hydroxytryptophan is

converted to serotonin; choline is converted to acetylcholine,

bursts of which are essential for REM sleep. Sentra AM® pro-

vides amino acid precursors glutamate and acetylcholine that

should augment the production of neurotransmitters impli-

cated in initiating and propagating normal cognitive processes

and general muscle function.

Medical foods are a class of Food and Drug Administra-

tion (FDA)–regulated products indicated for the dietary man-

agement of specific disease states. Medical foods are required

to be provided under the supervision of a prescribing physician

and are composed of ingredients that are generally recognized

as safe. The FDA has published extensive reviews of the safety

of amino acids in both nutrient and pharmacologic doses and

did not find any pharmacokinetic interaction between amino

acids and pharmaceuticals.

In this study, Sentra AM® and Sentra PM® were asso-

ciated with the improvement of PCL-M, SF-36, and ESS.

The data were highly statistically significant, and there

was a nearly uniform positive response. The uniformity of

response allowed for demonstration of statistical signifi-

cance with a relatively small cohort of patients. There were

no side effects reported during the course of this study.

This could reflect that the active ingredients are amino acid

based or could reflect that we did not systematically assess

for side effects.

This was a pilot study to explore the response to specific

nutritional deficiencies associated with autonomic dysfunction

among combat veterans with PTSD symptoms Limitations to

this study include the small sample size, and the possibility

of a placebo effect as this was a single-arm, open-label study.

This will be explored through a multicenter, double-blind,

placebo-controlled trial to follow.

Author ContributionsConceived and designed the experiment: WES, MC, DSS.

Analyzed the data: WES, DSS. Wrote first draft: WES, MC,

SP, AC, DSS. Contributed to the writing of the manuscript:

WES, MC, MB, SP, AC, LM, DSS. Agree with manuscript

results and conclusion: WES, MC, MB, SP, AC, LM, DSS.

Jointly developed the structure and arguments for the paper:

WES, MC, AC, DSS. Made critical revisions and approved

final version: WES, MB, AC, DSS. All authors reviewed and

approved of the final manuscript.

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Surviv. 2004;20(3):209–17.

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