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AddEeze Science

The Science of AddEeze®

 Addictions to substances and behaviors have been rapidly escalating and are generally considered a very serious global epidemic and burden to individuals, families, and society.  According to a five-year study by the National Center on Addiction and Substance Abuse at Columbia University, 40 million Americans, has the disease of addiction involving nicotine, alcohol, or other drugs, of which 90% receive no form of treatment at all.  Meanwhile another 80 million Americans fall into the category of risky substance users, and tens of millions suffer from addictive/compulsive behaviors unrelated to substance abuse.!

 A major reason for this tragic epidemic is that current treatments are generally ineffective with frequent relapses. Moreover, clinical practice often involves simply providing the patient with a similar drug perhaps with less toxic side effects, such as methadone or buprenorphine for opioid addiction.  Addictions are not resolved, but simply transferred to other substances and behaviors. The underlying neurophysiological imbalances remain or are often exacerbated depending on the treatment approach.2 

 Fortunately, three decades of scientific and clinical research on the endogenous opioid system has provided the potential of a safe and effective treatment for many addictions.  Ground breaking preclinical studies by Drs. Stanley M. Crain and Ke-Fei Shen at Albert Einstein College of Medicine led to the discovery of the bimodal nature of the endogenous opioid system. In a normal balanced state, the endogenous opioid receptors are in an inhibitory mode thereby producing reduced pain and stress sensitivity when triggered by endogenous opioids (i.e., endorphins) or exogenous opioids (e.g., morphine).  On the other hand, opioid receptors can be also be switched to an excitatory mode, which stimulates the opposite effect, that is, increased pain and stress sensitivity.3 

 Crain and Shen determined that while acute use of opioid drugs typically triggers opioid receptor inhibitory signaling, thereby producing pain and stress relief, prolonged use tends to switch the receptors to an excitatory mode, leading to increased pain and stress sensitivity.  Therefore, opioid dependence and tolerance appears to be caused by excessive opioid receptor excitatory signaling.4 Moreover, Crain and Shen discovered that specific agents, such as ultra-low-dose opioid antagonists (e.g. naltrexone) and sulfate-enhancing substances (e.g., sodium sulfate), act as Opioid Receptor Switchers, returning opioid receptors from an excessively excitatory mode back to a normal inhibitory mode.5,6 

 Therefore, Crain and Shen developed a simple method to reduce the development of opioid tolerance and dependence as well as facilitate withdrawal from opioid drugs without noxious side effects.  This method was validated in several clinical studies, at the cost of over $50 million, including a large-scale clinical trial of 700+ low-back pain patients in which the addition of ultra-low-dose naltrexone (ULDN) to oxycodone reduced withdrawal symptoms and other opioid side effects by more than 60%.7 Furthermore, Dr. Paolo Mannelli and his team at Duke University Medical Center conducted a series of clinical opioid detox studies, which revealed that ULDN significantly reduced withdrawal symptoms in chronic opioid dependent patients as well as increased abstinence even after ULDN was discontinued.8

 Crain and Shen also demonstrated in preclinical studies that the combination of an Endorphin Enhancer, such as cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors (e.g., caffeine, forskolin) with an Opioid Receptor Switcher (e.g., ULDN, sodium sulfate) increased pain tolerance similar to levels produced by exogenous opioids (e.g., oxycodone).9  This finding was remarkable since it suggested a path toward not only reducing opioid tolerance and dependence, but also the development of safer yet potent non-opioid pain and stress formulations.

 Dr. Steven Crain translated his father’s preclinical discoveries into clinical applications, using agents Generally Recognized as Safe (GRAS) by the FDA, for safe and effective pain and stress relief as well as treatment of drug, alcohol, and behavioral addictions.10 His team at Pondera Pharmaceuticals found that N-acetylcysteine (NAC), an amino acid that metabolizes into sodium sulfate, functions extremely well as an Opioid Receptor Switcher.  NAC has clear advantages over other Opioid Receptor Switchers since it is more tolerable than sodium sulfate, not as dose-sensitive as ULDN and has numerous health benefits.  When combined with caffeine, an Endorphin Enhancer, this formulation provides remarkable pain and stress relief benefits in both cold-pressor and clinical studies with hundreds of patients.11

 These clinical studies have shown that this natural formulation reduces the emotional and physical distress, including cravings, associated with substance abuse, more generally, as well as minimizing withdrawal symptoms and enhancing abstinence. Furthermore, this novel formulation is effective in reducing behavioral addictions and compulsions as well.11 Therefore, imbalances in the endogenous opioid system, characterized by excessive excitatory receptor signaling and depleted endorphin levels appear to be involved in a variety of substance and behavioral addictions.  By restoring healthy levels of endorphins and balance to the endogenous opioid receptors, this endorphinergic formulation reduces the emotional and physical distress associated with addictions and compulsions, providing the person with greater ability to make healthy choices regarding their behaviors, including abstinence from drugs and alcohol.

 In fact, dozens of independent clinical studies have demonstrated that NAC may be the “miracle” nutraceutical in neuropsychiatry.12 NAC alone has been shown to provide safe and effective treatment for various drug addictions and behavioral compulsions as well as anxieties more generally, though these studies have had inconsistent results.12,13 Pondera’s research suggests that the addition of caffeine to NAC leads to more consistent and effective treatment outcomes.  This finding supports the theory that many people with addictions, compulsions, pain, and stress sensitivity have depleted endorphin levels in addition to excessive opioid receptor excitatory signaling.  Therefore, the combination of NAC and caffeine should be considered as an effective method to:

  • safely wean patients from drugs and alcohol; and
  • maintain abstinence from addictive and compulsive behaviors by reducing the emotional and physical distress associated with addictions and compulsions.

 By restoring healthy balance to stress-related neurotransmitter systems, the combination of NAC and caffeine, the key ingredients of AddEeze®, is a safe and effective method to reduce the emotional and physical distress associated with a variety of addictions and compulsions.  The AddEeze® formulation also continues several synergizing ingredients, which have been shown to significantly increase its efficacy.  L-theanine, the predominant amino acid in tea, naturally produces calming benefits in the brain by increasing levels of dopamine and serotonin, and has synergizing benefits with caffeine in tea to create calming energy.  In addition to L-theanine, AddEeze® contains BCM-95®, a patented highly bio-available extract of curcumin, the psychoactive component of turmeric. Curcumin potentiates NAC’s ability to restore healthy functioning in the endorphin, dopamine, and serotonin neurotransmitter systems, critically involved in addictions, compulsions, and anxieties.  Finally, B-12 and other B-vitamins are included in the formulation since they are critically needed for production of endorphins, dopamine, and other stress-related neurotransmitters.

 The scientifically developed patented AddEeze® formulation14 is in a class by itself regarding its remarkable ability to reduce the emotional and physical distress associated with addictions and compulsions, thereby providing the freedom to finally let go of dysfunctional habits including abstinence from abusive consumption of drugs, alcohol, and food as well as other unhealthy behaviors.  Thousands of people worldwide have already benefited from this formulation, as illustrated in the graph below.15


 Furthermore, the scientifically selected ingredients of the AddEeze® formulation have remarkable health-promoting benefits well beyond their restoration of balanced brain functions. NAC and L-theanine restore intracellular levels of the body’s most powerful antioxidant, glutathione, thereby dramatically boosting the immune system. Curcumin also enhances the immune system and is well known as a powerful natural anti-inflammatory. These natural ingredients, together with B-vitamins, powerfully promote healthy brain and bodily functioning and restore normal balance to systems dysregulated by stress, illness, and exercise.

The AddEeze® formulation has been endorsed by leading neuropsychiatric experts including Dr. Keith Ablow, Assistant Clinical Professor of Psychiatry, Tufts University School of Medicine, Network TV News Commentator, and New York Times bestselling author.  Available online and in retail stores, AddEeze®’s state-of-the-art patented formulation is the only safe and effective method to reduce the emotional and physical distress associated with addictions and compulsions by restoring healthy balance to underlying dysfunctional neurotransmitter systems.  For more serious addictions and compulsions, AddEeze® can be combined with cognitive-behavioral treatment for maximal effectiveness. At a fraction of the cost of conventional addiction treatment, AddEeze® will become the gold standard for the more than 120 million adults and adolescents who abuse alcohol and drugs as well as countless others with behavioral addictions including compulsive eating, sex, and gambling.


1The National Center on Addiction and Substance Abuse at Columbia University. Addiction medicine: closing the gap between science and practice, New York, NY, June 2012.

 2Sederer, L. A blind eye to addiction: drug and alcohol addicts in the U.S. aren’t getting the comprehensive treatment they need.  U.S. News and World Report, June 1, 2015.

 3Shen, K.-F. & Crain, S. M. (1989).  Dual opioid modulation of the action potential duration of mouse dorsal root ganglion in culture.  Brain Research, 491(1), 227-242.

 4Crain, S., M. & Shen, K.-F. (1998).  Modulation of opioid analgesia, tolerance, and dependence by Gs-coupled, GM1 ganglioside-regulated opioid receptor functions. Trends in Pharmacologic Science, 19(9), 358-365.

 5Crain, S. M., & Shen, K.-F. (2000).  Antagonists of excitatory receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability.  Pain, 84(2-3), 121-131.

 6Crain, S. M., & Shen, K.-F. (2004).  Neurominidase inhibitor, oseltamivir blocks GM1 ganglioside-regulated excitatory receptor-mediated hyperalgesia, enhances opioid analgesia and attenuates tolerance in mice.  Brain Research, 995(2), 260-266.

 7Webster, L., et al. (2006).  Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain, The Journal of Pain, 7(12), 37-946.

 8Mannelli, P., et al. (2009).  Early outcomes following low dose naltrexone enhancement of opioid detoxification.  The American Journal on Addictions, 18(2), 109-116.

 9Crain, S. M., & Shen, K.-F. (2008).  Low doses of cyclic AMP-phosphodiesterase inhibitors rapidly evoke opioid-mediated theram hyperalgesia in naïve mice which converted to prominent analgesia by cotreatment with ultra-low-dose naltrexone.  Brain Research, 1231, 16-24.

 10Crain, S., & Crain, S. M. (2013).  Endorphinergic attenuation of distress by concomitantly enhancing endogenous opioid release and switching opioid receptor signaling from an excessively excitatory to a normal inhibitory mode.  Journal of Behavioral and Brain Science, 3(7), 497-508.

 11Crain, S., et al. (2013).  Emotional and physical distress relief using a novel endorphinergic formulation.  Journal of Behavioral and Brain Science, 3(6), 441-453.

 12Berk, M., et al. (2013).  The promise of N-acetylcysteine in neuropsychiatry.  Trends in Pharmacological Sciences, 34(3), 167-177.

 13Asevedo, E., et al. (2014).  Systematic review of N-acetylcysteine in the treatment of addictions.  Revista Brasileira de Psiquiatria, 36, 168-175.

 14US Patent No. 8,372,414; February 12, 2013