New Article on Science of Endorphinate

This is an abstract of an article that will be published in the Journal of Behavioral and Brain Science, which summarizes the decades of scientific studies that validate the discoveries upon which Endorphinate is based:

Endorphinergic Attenuation of Distress Dysfunctions by Concomitantly Enhancing Endogenous Opioid Release and Switching Opioid Receptor Signaling from an Excessively Excitatory to a Normal Inhibitory Mode1

Steven Crain, PhDa and Stanley M. Crain, PhDb

aTherapeutic Alliance, State College, PA  16801, USA                                

bDept. of Neuroscience, Albert Einstein College of Medicine,

Yeshiva University, Bronx, NY  10461, USA


There is increasing evidence that the endogenous opioid system has a significant role in the etiology of a wide variety of previously considered distinct clinical distress dysfunction disorders, including chronic anxiety, depression, addiction, anger, autism, and pain, though the mediating processes have been elusive.  Many types of clinical distress dysfunction disorders show interesting similarities to the excitatory autonomic withdrawal effects in chronic opioid-dependent animals and humans, as well as to the “quasi-morphine withdrawal syndrome” that is evoked in naïve rodents shortly after acute systematic injection of a cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitor (e.g., theophylline or caffeine).  These symptoms appear to be caused by excessive excitatory opioid receptor signaling as well as reduced endorphin production.

Well-documented pharmacologic analyses of the remarkably plastic bimodal (excitatory/inhibitory) properties of opioid receptor functions, have been carried out, at first, by analyses of intracellular microelectrode recordings from opioid-sensitive neurons in tissue cultures of mouse dorsal root ganglia attached to spinal cord cross-sections and subsequently in vivo, utilizing hot-water tail-flick assays in mice.  These coordinated in vitro and in vivo studies have led to discovery of specific chemical formulations that switch opioid receptor signaling from an excessively excitatory to a normal inhibitory mode. This groundbreaking discovery has been validated in large clinical pain trials, which demonstrate the remarkable ability of opioid receptor “switchers” to reduce serious emotional and physical distress symptoms typically produced by exogenous opioid use.

Critically formulated combinations of cAMP-PDE inhibitors (e.g., rolipram or caffeine) that release endorphins, together with specific agents (e.g, ultra-low-dose naltrexone) that switch opioid receptors from excitatory Gs-coupled to inhibitory Gi/Go-coupled molecular pathways have been shown to elicit endorphinergic attenuation of hyperalgesia and distress evoked by diverse chemical stressors (e.g., very low-dose opioids, cAMP-PDE inhibitors, elevated GM1 ganglioside), thereby enhancing thermal pain tolerance and reducing distress in mouse tail-flick assays. Both the “quasi-morphine withdrawal syndrome” in naïve rodents as well as the excitatory withdrawal effects in chronic, opioid-dependent animals and humans may, indeed, be extreme manifestations of common clinical distress dysfunction disorders, including chronic anxiety, addiction, and pain.  We suggest that endorphinergic attenuation of a wide variety of distress dysfunction disorders can be significantly enhanced by concomitantly increasing endogenous opioid release and switching excessively excitatory (Gs-coupled) opioid receptor signaling to normal inhibitory (Gi/Go-coupled) signaling throughout the entire central and peripheral nervous system.

This combination of endorphin enhancers with opioid receptor “switchers” provides a completely novel method to attenuate emotional and physical distress using naturally occurring endogenous rather than exogenous opioids or other non-specific pharmaceuticals with numerous noxious side effects.  These discoveries are consistent with recent neural imaging studies, which reveal the critical role of excessive activation of the limbic system, especially the amygdala, in a variety of neuropsychiatric disorders, and the high prevalence of endorphins in these stress/emotion-related brain centers.  There is also increasing evidence that endorphinergic imbalances are produced by a wide variety of factors, including prolonged stress, illness, certain drugs and chemicals, processed food, unhealthy lifestyles, and genetic vulnerabilities.  Recent sophisticated analyses that reflect the critical role of endorphins in the complex inter-relationships among stress/emotion-related neurotransmitter systems, including dopamine, serotonin, GABA, and norepineprhine, also support the potential therapeutic benefits of restoring healthy endorphinergic balance to the brain and gut.

Pilot trials of critically formulated oral nutraceutical preparations, containing both endorphin enhancers (e.g., caffeine, ginkgo biloba) and opioid receptor “switchers” (e.g., N-acetyl cysteine, magnesium sulfate) have resulted in marked long-term anxiolytic efficacy and enhanced calming and mood-elevating effects while simultaneously promoting mental clarity and a remarkably adaptive response to stress in large numbers of individuals with distress dysfunction symptoms. These new insights into specific dysfunctional processes underlying clinical distress disorders will stimulate a new generation of endorphinergic formulations which safely restore normal homeostatic balance to the complex endogenous opioid system, thereby resolving the neurophysiologic dysfunction underlying a variety of previously considered distinct neuropsychiatric disorders including chronic anxiety, depression, addiction, anger, autism, and pain.

1Full article to be published, by invitation, in the Journal of Behavioral and Brain Science (JBBS, ISSN:2160-5874)

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