Therapeutic Effect of BR+NAD on Opioid and Alcohol Withdrawal

Therapeutic Effect of 𝑩𝑹+𝑵𝑨𝑫® on Opioid and Alcohol Withdrawal: Implications for Clinical Populations

Susan Broom Gibson, PhD
Associate professor of psychology
School of natural and behavioral sciences
William Carey University October 1, 2019.

Presentation Summary

Recognition of Substance Use Disorders as public health crises underscores the need for evidence based strategies in treating these chronic conditions.

These conditions cause brain dysfunction, therefore it is imperative to develop treatment protocols that alleviate symptoms associated with acute withdrawal as well as enable successful outcomes in long-term recovery. 

A clinic in Springfield, LA developed an alternative protocol using IV administration of Nicotinamide Adenine Dinucleotide (NAD) for acute withdrawal symptoms associated with chronic opioid and alcohol exposure (known as 〖BR+NAD〗^TM).  Data show that〖BR+NAD〗^TM significantly reduces symptoms associated with acute withdrawal.  Studies are underway to validate these data in order to standardize a protocol for use in similar clinical settings.

Objectives

1. Participants will gain an understanding of how long term exposure to opioids and alcohol compromises brain functioning and the limitations that exist with more traditionally viewed “standard of care” treatment protocols.

2. Participants will be shown statistically significant results from studies utilizing IV 〖BR+NAD〗^”®” administration protocols in treating symptoms associated with acute withdrawal.

3. Participants will be presented data from ongoing studies evaluating the safety and efficacy of IV BR+NAD”®” in these and other clinical populations

Defining Substance Use Disorders

Traditional
(DSM-IV-TR; APA 2000)

Separated between abuse/dependence.  Abuse is beyond what is deemed “normal” therapeutic treatment in terms of dose/time

Dependence was defined by long-term consequence of abuse behavior; Use is beyond control of social and legal consequences Often accompanied with development of tolerance/withdrawal symptoms

 

Current
DSM 5; APA 2013

Substance-use disorders are patterns of symptoms resulting from the use of a substance that you continue to take, despite experiencing problems as a result.

Substance-induced disorders, including intoxication, withdrawal, and other substance/medication-induced mental disorders, are detailed alongside substance use disorders (ex, methamphetamine psychosis, opioid withdrawal syndrome).

Dopamine Reward Pathway

Acute Exposure to substances such as Alcohol, Opioids, Psychostimulants and Benzodiazepines cause increased release of DA in the NA; Amount of dopamine released determines level of reward (i.e., positively reinforcing effects). Also, small increases in stress-induced DA in NACC are a sign of coping with stressors (i.e., negatively reinforcing effects).
Although acute effects appear primarily focused on extracellular DA in Nacc, it is important to note that chronic exposure affects this area which has a long term effect on all structures in the mesolimbic pathway. LC, AMG and BNST are major players in opioid withdrawal and stress-induced drug relapse

Chronic Use Disrupts The Mesolimbic Dopamine Pathway

Chronic substance use can cause functional changes in the mesolimbic Dopamine pathway resulting in functional changes in behavior (i.e, operant conditioning) that are resistant to extinction.

Chronic Use Disrupts The Mesolimbic Dopamine Pathway; Interactions with Stress

Previous studies using a chronic meth rat model indicate reduction of basal extracellular DA in Nacc; also noted that chronic use blocks stress induced DA release.  This is evidence of chronic effects on behaviors such as mood, cravings, coping response to stress, stress induced drug relapse and drug seeking behaviors

It is important to point out that several brain structures and NT systems (GABA, GLU) interact to influence the mesolimbic DA reward pathway.  In the chronic meth rat study, we observed changes in Transporter protein (NET) in regulating extracellular DA.

Broom, S. L., & Yamamoto, B. K. (2005). Effects of subchronic methamphetamine exposure on basal dopamine and stress-induced dopamine release in the nucleus accumbens shell of rats. Psychopharmacology, 181(3), 467–476. https://doi.org/10.1007/s00213-005-0007-6

Long Term Consequences

Tolerance- reduced effects due to repeated administration of the same dose.  (Can happen at the cellular level)

Withdrawal- symptoms are both psychological (i.e., cravings) and physiological (i.e., opioid withdrawal syndrome).

These symptoms can further contribute to the sustainment of substance use disorders due to negatively reinforcing properties

On a cellular level, overall function is compromised (example, inflammatory markers increase, energy and metabolism decrease).

Behaviors associated with high levels of oxidative stress and decreased cellular energy production include:

Depression, Anxiety, Sleep Problems and Fatigue

TRADITIONAL TREATMENT FOR SUBSTANCE USE DISORDERS (SUD’S)

Naltrexone and Naloxone are opioid antagonists and produce immediate reversal of opioid effects.  Most commonly administered in opioid overdose.

Methadone is a synthetic opioid that blocks the effects of heroin and other opioids, eliminates withdrawal symptoms, and relieves drug craving. Methadone reduces severity of opiate withdrawal and allows patients to “taper off”.

Buprenorphine is a partial mu-opioid receptor agonist and kappa-opioid receptor antagonist.  Approved in 2002, it has a longer half-life and less severe withdrawal syndrome.  Results mixed regarding effectiveness compared to Methadone.

Suboxone combines naloxone and buprenorphine

Limitations

These clinical conditions are perceived as complex brain disorders that are chronic and relapsing in nature; current approaches are lacking in evidence-based approaches that address these issues.

Despite their success at acute detox, these traditional approaches (combined with the associated stigma and treatment as a criminal justice issue) lack support in addressing safety concerns and measurable success in long term positive outcomes (i.e, participation in follow-up, reduced relapse rates, etc).

(Volkow, N. D., Poznyak, V., Saxena, S., Gerra, G., UNODC-WHO Informal International Scientific Network (2017). Drug use disorders: impact of a public health rather than a criminal justice approach. World psychiatry : official journal of the World Psychiatric Association (WPA), 16(2), 213-214.)

Traditional methods of detox are undesirable due to issues related to tolerance and abuse liability.

The stigma associated with these clinical diagnoses (in both hospital and civilian settings) further impedes progress toward the development of successful long-term approaches.

Proposed Solution

Optimal therapies will maximize therapeutic effects while minimizing abuse liability;

In other words, these approaches will safely help the brain restore healthy cell function and maintain sobriety over the long term by alleviating cravings and reducing relapse episodes.

It is also of importance that combinations of approaches particularly focused on after care support will lead to higher success in the long term

You can’t provide a quick fix for the acute problems and not prepare patients for what will happen after they leave treatment.

Brief History on the Development of BR+NAD®

Following earlier discoveries on the effects of DPN (NAD) on cravings and symptoms associated with acute and chronic alcohol exposure (see O’Hollaren), Dr. William Hitt developed  IV drug treatment protocols in Mexico using a proprietary blend of nutrients. Later analysis revealed that the primary active ingredient was NAD+.

By the early 2000’s, Dr. Hitt collaborated with Paula Norris-Mestayer and other select practitioners in the US on his IV treatment protocol. This was the protocol used in the first retrospective project I presented at SFN 2008 investigating the effects of IV NAD+ on self-reported cravings and additional symptoms associated with acute withdrawal.

The focus of the 2008 retrospective study was to identify quantifiable measures of therapeutic benefit in pre-existing records of patients who sought treatment for withdrawal symptoms associated with SUDs.

We concluded from this study that self reported ratings of overall affect improved significantly over the 10 day treatment protocol.

Significant reductions in cravings, stress, depression and anxiety suggested effectiveness in treating symptoms associated with acute withdrawal and negative affect.

No change in measures of reward indicated minimal abuse potential.

In 2010, a new formulation was derived (BR+NAD®) at Springfield Wellness Center (in collaboration with Archway Apothecary) again identifying NAD+ as the primary ingredient and creating both a proprietary product and IV protocol for use in similar clinical populations and settings.

Stimulant, Opioid, Alcohol and Poly groups; N = 60

BR+NAD®

Benefits:

Outpatient setting; 8-10 day (short duration)

Safe; uses natural products as opposed to synthetically derived medications that possess abuse potential; descriptive notes from pre-existing patient charts indicate no serious adverse events.

Efficacy measures collected on both Short and Long Term Outcomes.

Incorporates behavioral therapy and counseling in preparation for success in long term recovery

For a complete review of the history, development and  research from patients treated with the IV BR+NAD® at Springfield Wellness Center

Society For Neuroscience Conference Washington, D.C., November 2014

Intravenous Administration of Nicotinamide Adenine Dinucleotide Significantly Reduces Self Report Craving Ratings Associated with Opiate and Alcohol Withdrawal

*S. L. BROOM1, R. MESTAYER2, E. STULLER3, D. COOK4, J. CARSON2, K. SIMONE2, P. NORRIS2, P. HOTARD2
1Dept Psychol, William Carey Univ., Hattiesburg, MS; 2Springfield Wellness Center, Springfield, LA; 3Stullerresettings, LLC; 4 ABAM.SoberMD,LLC

Objective

This pilot study retrospectively examined the anti-craving properties of NAD+ in a group of 60 patients. Additionally, patients were assessed on severity of cravings  and relapse episodes at 12-20 months post treatment.

Method

The patients were adult males and females who sought treatment at SWC for opioid or alcohol use disorders (N=60).

The treatment,  Brain Restoration Plus (BR+NAD)® comprised of IV infusions of NAD+ as well as vitamins, oral amino acids, NAC and variable PRN medications for an average of 10 consecutive days ranging from 5 to 10 hours daily at a dose range of 500mg-1500mg each day.

Self-reported craving ratings (0-10 Scale) were collected on Day 1 (before starting treatment), Day 5, and on Day 10 (last day  of treatment).

Follow up phone surveys were conducted from 12-20 months post treatment (N= 27).

Patients reported severity of cravings (1-5) and number of relapse episodes at the present time.

Conclusions  From Society For Neuroscience (2014)

BR+NAD® is an effective detox treatment for alcohol and opioid substance use disorders as evidenced by a significant  reduction in craving ratings.

Chart records indicate that 45% of the original sample (27/60) participated in and completed long term follow-up phone surveys.

BR+NAD® effectively reduces the number of relapse episodes, as well as severity of drug cravings over a 12-20 month follow up period. 

BR+NAD® shows potential as a long-term therapy in maintaining sobriety through minimizing drug cravings and preventing relapse.

13/27 opioid = 48%

14/27 alcohol = 52%

The Retrospective Study (2008-2014)

Expanded population numbers for both groups; still using pre-existing chart information from self report and nurses’ notes as well as standardized assessments.

Includes additional Short Term Outcome measures (STO’s) in response to IV BR+NAD®.  Additional data obtained from SWC population where available included:

Demographic information (age and sex) and completion rates (completed minimum of 8 days IV BR+NAD®).

Patient Reported Cravings, Anxiety, Depression, Pain, Sleep (also reported on nurses’ notes).

First 5 days of COWS/ CIWA scores.

Measures of plasma NAD+, NAD/NADH ratios, Inflammatory markers

and Correlations with COWS/CIWA, affective measures assessed during the 10 day protocol

Current Research in Alcohol and Opioid Clinical Populations

Continue to identify, quantify and standardize STO’s and LTO’s on measures of efficacy

Designing an IRB approved prospective outcome study to compare across treatment types on both STO’s and LTO’s measures of efficacy and safety (modeling after the National Association of Addiction Treatment Providers Outcomes Measurement Toolkit (2019)

Plasma study conducted in 2018 showed Improved Withdrawal Symptoms and Reduced Oxidative Stress and Inflammation Following Intravenous Nicotinamide Adenine Dinucleotide Therapy in Opiate and Alcohol Abuse Patients (Funded by NAD+Research, Inc.; investigation in additional efficacy measures)

Prospective Alcohol study

Standardized Safety Measures (to address NIH and FDA concerns; also to place in clinical outcome study in alcohol patients)

Animal Studies (Winsaur, P., Lefer, D., Sharp, T., LSUHSC)

Demographics and Descriptive Data for the Alcohol Group

The average age for alcohol patients was 52 (+/- 2.03).  Population comprised 59.46% males and 37.84% females of the total sample (1 unspecified). 

These data represent patients who completed 7-10 days of 𝑩𝑹+𝑵𝑨𝑫® and had at least 4 of 5 days of recorded CIWA scores.

Typical alcohol withdrawal symptoms reported in patients included changes in sleep (mostly insomnia and vivid dreams) and appetite (poor).  Patients also reported signs of G. I. distress (i.e., diarrhea), headaches and muscle cramps.

CIWA-AR Assessment Form

Changes in Circulating Oxidative Stress & Pro-inflammatory Markers and Correlations with Affective Measures in Alcohol Patients Following IV NAD+

Improved Withdrawal Symptoms and Reduced Oxidative Stress and Inflammation Following Intravenous Nicotinamide Adenine Dinucleotide Therapy in Opiate and Alcohol Abuse Patients; Research Funded by NAD Research, Inc.

Demographics and Descriptive Data for the Opioid Group

The Opioid Group averaged 36 (+/-1.95) years of age comprised of 81.08% Males and 13.51% Females (2 unspecified).

The pattern of withdrawal symptoms noted on the COWS assessment form in comparison to the patient reported cravings rating support that patients are experiencing withdrawal defined as LOW severity according to COWS and MODERATE-SEVERE on cravings ratings. 

Three/eighteen patients had a COWS score reported for DAY 6 (scores 2, 5, 9) and one patient had scores reported for days 6 through 10 (scores 9, 7, 9, 3, 4). 

COWS ASSESSMENT FORM

Changes in Circulating Oxidative Stress & Pro-Inflammatory Markers and Correlations with Affective Measures in Opioid Patients Following IV NAD+

Improved Withdrawal Symptoms and Reduced Oxidative Stress and Inflammation Following Intravenous Nicotinamide Adenine Dinucleotide Therapy in Opiate and Alcohol Abuse Patients; Research Funded by NAD Research, Inc.

Evaluating Safety

The following dependent measures were documented as adverse events (AE) if they were noted in patient record (Alcohol Group) during the initial treatment protocol: histamine response causing congestion, heaviness sensation in chest/core area sometimes dissipating to extremities, tightness in the chest, or general discomfort.    These events tended to be more common on days 1-2 and became significantly less frequent throughout the remainder of treatments days. 

No serious adverse events were reported from IV BR+ NAD® over the first 3 days in the Alcohol Group.

In the Opioid Group- The nurses’ notes page for patient rated symptoms (scaled 0-10) of cravings, anxiety, depression, irritability and pain are limited; however anxiety, depression, irritability and pain are indicating on average less than 3 (anxiety DAY 1 was 3.4) across the 10 day treatment period, consistent with the COWS scores indicating a less severe withdrawal.

Typical withdrawal symptoms reported in the Opioid group include changes in sleep (insomnia) and appetite (nausea, poor), stomach and muscle cramps, and G.I. distress (diarrhea).  It should be noted that these symptoms appear to be dropping off by DAY 7.

This is intended for use in all patients receiving IV BR+NAD®

Proposed Short Term Outcome Assessment Form

Proposed outcome study will measure these and additional measures outlined in the NAATP Addiction Treatment Outcomes Measurement Toolkit (2019)

Assessment of Long Term Outcomes

Original form used in SFN 2014

Other Clinical Applications and Projects

  • Grant, R, Berg, J, Mestayer, R, Braidy, N, Bennett, J, Broom, S, Watson, J. Changes in plasma and urine NAD+ metabolome in humans during a 6 hour Intravenous infusion of NAD+ (Frontiers in Aging Neuroscience, in press).
  • Broom, S., Mestayer, R. Grant, R., Berg, J., Braidy, N., Bennett, J., Watson, J. (part of the IRB Protocol #2017-12).  The effects of IV NAD+ on Cognitive Performance: A Controlled Randomized Pilot Study in Adult Males (manuscript in preparation; see next slide).
  • Gadol, E., Mestayer, R., Grant R., Grigoryev, Y., Broom-Gibson, S., Happel, M. (2019). A case of Parkinson’s Disease symptom reduction with Intravenous NAD+. Case Reports and Literature Review, Volume 3, Issue 1, Article ID: 100021.
  • Rutherford, L., Broom, S., Olds, T, Mestayer, R., Norris-Mestayer P. Intravenous administration of nicotinamide adenine dinucleotide alleviates tremors associated with parkinson’s disease:  A case report. Poster Presentation at the upcoming Society For Neuroscience Conference, October 2019.
  • Anxiety and Related Symptoms Associated with PTSD in Military Veterans (in development Walker-Dixon, B., Mestayer, R.).

Effects of IV NAD+ on Global Cognitive Function and Global Cognitive Processing In Adult Males

This was a 5 day IV NAD (750mg) protocol. Scores represent Level 3 GCF and GCP on the Microcog® computerized version assessment. Pilot data suggest that IV NAD improves cognitive performance over and above practice effects; however more research is needed.

 

Broom, S., Mestayer, R. Grant, R., Berg, J., Braidy, N., Bennett, J., Watson, J. (part of the IRB Protocol #2017-12).  The effects of IV NAD+ on Cognitive Performance: A Controlled Randomized Pilot Study in Adult Males

Acknowledgments

Springfield Wellness Center-Paula Norris-Mestayer, MEd, LPC,

NAD Research, Inc. – Dr. Richard Mestayer and Science Advisory Board Members

SWC Staff- James Bennett, Karen Simone, Sherry Summers, Dr. Tyson Olds.

Australasian Research Institute- Dr. Ross Grant, Dr. Jade Berg, Dr. Naidy Brady

LSU Health Sciences Center, New Orleans, LA- Dr. Lefer, Dr. Sharp, Dr. Polhemus

William Carey University Professional Development Committee

William Carey University Institutional Review Board