NOTE: This is a continuation and expansion of the podcast of September 19, 2008.
Stress and Substance Dependence: The link and Treatment Implications for CP-154,526
The parallel neurochemistry and neural functioning of the brain in emotional disorders like stress and depression to that which occurs during the substance use disorder symptoms of drug-withdrawal and drug-cravings has been observed since the mid 1980s. 1
Each of these four negative emotional states (stress, depression, withdraw, craving) initiates and maintains a stress hormone cycle in the body. The stress hormone cycle begins when either the perception of stress occurs in a normie or when stress, drug withdrawal and/or drug cravings occur in addicts. Major depression persists during the stress hormone cycle since cortisol levels remain consistently elevated in people with depressive disorders. All of these conditions result in the stress hormone cycle that starts with the release corticotrophin releasing factor (CRF) from the hypothalamus located in the mesolimbic cortex of the brain. CRF then causes the brains pituitary gland to secrete another hormone, adrenocorticotropic hormone (ACTH). Current research indicates that both CRF and ACTH are neurotransmitters as well as hormones. As neurotransmitters, CRF and ACTH may trigger unpleasant emotions of aggression, anxiety and dysphoria prompting the person to embark on a fright, fight or flight reaction. ACTH then travels through the bloodstream to the adrenal glands that sit on top of the kidneys where it triggers the release of cortisol, the third hormone/neurotransmitter of the stress hormone cycle. Cortisol travels the bloodstream throughout the body to help it cope with stress and when it reaches the brain, it inhibits the further release of CRF and ACTH to complete the cycle. However, if the stressor is very intense, during withdrawal and craving for example, the brain just keeps on releasing CRF and ACTH unabated by the inhibitory effects of cortisol and the unpleasant emotions of the stress hormone cycle persists. 2
Alcohol, barbiturates, benzodiazepines, heroin, opioid substances and endorphin/enkephalin neurotansmitters inhibit the release of CRF and ACTH of the stress hormone cycle maybe even more powerfully than cortisol. Addicts to these substances who also suffer from mental health disorders may have begun their dependence when they discovered that depressant drugs of abuse were effective in helping them cope with an underlying stress, depression, anxiety or panic disorder. Withdrawal from depressant drugs of abuse triggers the stress hormone cycle and results in feelings of anxiety and panic in those who have a co-occurring psychiatric problem of stress disorder. Those who do not have an underlying anxiety disorder experience the drug withdraw or drug craving induced stress hormone cycle as unpleasant emotions. Persistent intermittent withdrawal states of active addiction with its unpleasant stress emotions results in a hypersensitivity to the stress cycle and drives the addict to continue using.
Abuse of cocaine, methamphetamine and other stimulant drugs actually trigger the activation of the stress hormone cycle. But, stimulants also directly activate the nucleus accumbens septi, the brains reward center, and most stimulant drug abusers perceive the stress reaction as part of the stimulants rush or high. When stimulant addicts go into withdrawal, their stress hormone cycle is triggered similar to withdrawal from depressant drugs. Since withdrawal results from the absence of stimulant drugs, the addict only experiences the stress cycle with its negative feelings without any activation of their reward center. Thus, only very unpleasant emotions are experienced. A persistent withdrawal state of stimulant addiction also creates a hypersensitivity to the stress cycle. This results in a substance-dependent individuals inability to cope with even the slightest stressors and leads to strong cravings to return to drug use when their stress cycle is triggered by seemingly minimal environmental cues or negative experiences.
At a 2008, Haight-Ashbury Free Clinics Conference in San Francisco, Dr. George F. Koob of Scripps Research Institute mentioned that drugs that suppress the CRF/ACTH stress response demonstrate an ability to prevent relapse in alcohol treatment. This observation was made during his presentation on medications in development to treat substance use disorders. In the past few months, Dr. Koob has been exploring the potential of a medication that blocks the actions of CRF and therefore suppresses activation of the stress hormone cycle in the brain.3 The medication is known as CP-154,526 and is patented by Pfizer.4
Dr. Tamara Phillip is also doing research with this medication on laboratory mice at Oregon Health and Science University in Portland. Contrary to Dr. Koobs findings, Dr. Phillips research demonstrates an ability of CP-154,526 to block alcohols reinforcing pleasurable effects even in mice who were already accustomed to alcohol positive feelings before receiving the medication.5 Dr. Phillip and her research team suggest CRF is actually a neurotransmitter that provides euphoria and pleasure instead of unpleasant emotional feelings. This is a bit confusing since other scientists suggest alcohol, opioids and other depressant drugs inhibit the release of CRF from the hypothalamus. If CRF produces positive emotional effects why would its suppression by depressants drugs result in a need to continue taking those drugs? Moreover, why would CRF inhibition by CP-154,526 result in decreased drug cravings in abstinent depressant and stimulant drug addicts? Whatever the precise mechanism of action may be, there is a growing excitement that medications that block the stress hormone cycle in the brain will be a vital new weapon in the treatment of substance dependence disorders.
Darryl S. Inaba, PharmD., CADC III
September 2008
1. Kreek MJ, et al. (1984), ACTH, cortisol, and b-endorphin response to metyrapone testing during chronic methadone maintenance treatment in humans. Neuropeptides, 5:277-278; Kreek MJ and Koob GF (1998), Drug dependence: Stress and dysregulation of brain reward pathways. Drug and Alcohol Dependence, 51:23-47; Stocker, S (1999), Studies link stress and drug addiction. NIDA Notes, 14(1):12-14
2. Stocker, S (1999), Studies link stress and drug addiction. NIDA Notes, 14(1):12-14).
3. Heilig M and Koob GF (2007), A key role for corticotrophin-releasing factor in alcohol dependence. Trends Neurosci. 30(8):399-406
4. Lowery EG, Sparrow AM, Breese GR, Knapp DJ and Thiele TE (2008), The CRF-1 receptor antagonist, CP-154,526, attenuates stress-induced increases in ethanol consumption by BALB/cJ mice. Alchol Clin Cep Res, 32(2):240-248.
5. Pastor R, McKinnon CS, Scibelli AC, Burkhart-Kasch S, Reed C, Ryabinin AE, Coste SC, Stenzel-Poore MP, Phillips TJ (2008), Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: a urocortin 1-independent mechanism. Proc Natl Acad Sci USA, 105(26):8809-10; Korn, P (2008), OHSU on trail of alcoholism cure. Portland Tribune 7/29/08.