HOW ALCOHOL AND BENZODIAZEPINES AFFECT THE ALLOSTATIC LOAD

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HOW ALCOHOL AND BENZODIAZEPINES AFFECT THE ALLOSTATIC LOAD

 

This review will discuss alcohol consumption and benzodiazepine administration with reference to their effects on allostatic load.  The main focus of this discussion will center on excerpts from the following review:

 

Stress and the HPA Axis Role of Glucocorticoids in Alcohol Dependence

Stephens MA, Wand G.

Alcohol Res. 2012;34(4):468-83. Review.

http://pubs.niaaa.nih.gov/publications/arcr344/468-483.pdf

 

Topics that will be covered in this paper will include: Function of the HPA Axis; Tolerance and Dependence; Allostasis and Allostatic Load; Adrenal Insufficiency; and Patterns of Daily Cortisol Secretion.

 

Before we begin I would like to clarify what the term ‘dysregulation’ means with regard to the HPA axis.  Simply put dysregulation means ‘unregulated.’  Normally the body tries to maintain cortisol levels within certain limits.  When the HPA axis becomes dysregulated cortisol levels may fall above or below such limits.  I say this because there seems to be a general misconception that cortisol levels are always high in benzo withdraw.

 

Another word that I would like to elucidate is the term ‘glucocorticoid.’  Glucocorticoids are steroid hormones produced by the adrenal glands.  The main glucocorticoid in humans is cortisol.  The main glucocorticoid in rodents (which are frequently used to research stress responses) is corticosterone.

 

Function of the HPA Axis

The HPA Axis is made up of the Hypothalamus, Pituitary, and Adrenal glands as shown below (22):

 

 

http://data.integrativepro.com/images/hpa-axis-stress-response.png

 

The HPA axis is activated when we experience stress.  Stress can be defined as anything real or perceived that the body views as a threat to its homeostasis.  Homeostasis refers to the normal operating conditions of the body- the body’s equilibrium or internal balance.  Stress can take many forms such as illness, major life changes, loss (e.g. grief), pressure at work, etc.

 

When we experience a stressor the body goes into action to preserve and maintain homeostasis.  One way the body does this is by releasing stress hormones which exert many effects on the body such as: increased awareness, cardiovascular tone, and respiratory rate; and inhibition of other bodily functions such as digestion, growth, reproduction, and immunity. (6)

 

Referring to the figure above- when a stressor activates the HPA Axis, an area of the hypothalamus called the Paraventricular Nucleus (PVN) releases a neuropeptide called Corticotrophin-releasing Factor (CRF).  The release of CRF in turn causes the Pituitary gland to secrete adrenocorticotropic hormone (ACTH).  Next the ACTH enters the blood stream and travels to the adrenal glands- where it activates the synthesis and release of the glucocorticoid cortisol.

 

Studies have shown that drinking Alcohol, even as a social drinker, can activate the HPA Axis and increase cortisol levels:

 

“As with stress, acute alcohol consumption also directly and indirectly activates the HPA axis by resulting in elevated levels of glucocorticoids (Richardson et al.2008]. In fact, alcohol and other drugs of abuse have been described as a physiological stressor because they can activate the HPA axis. In social drinkers, acute doses of alcohol usually increase cortisol levels, particularly if blood alcohol levels exceed 100 mg percent (Waltmanet al. 1993).”

 

Benzo administration has also been associated with changes in HPA axis function.  Chronic Benzo administration has been shown to suppress HPA axis function and there can be a rebound elevation in cortisol upon discontinuation during the acute withdrawal phase. (7)  Additionally, tests of cortisol levels of people recovering from benzos have been shown to be low. [18] This may indicate an ongoing relationship between benzo recovery and HPA axis function.  Inter-dose and progressive increases in baseline AM cortisol levels have also been observed during benzo administration. [8] Such irregularities in HPA axis function may be due to benzo induced homeostatic changes to GABAA receptors (9, 10), which may occur in neurons that contribute to the regulation of the HPA Axis. (11)

 

Tolerance and Dependence

 

“At some point during the transition from social drinking to alcohol dependence and abstinence, however, the HPA axis becomes dysregulated. For example, King and colleagues (2006) found that cortisol reactivity to acute alcohol administration is attenuated in heavy, hazardous drinkers compared with light, social drinkers. This observation may be related to the general process of tolerance that emerges during heavy hazardous drinking. It is important to note that the subjects in this study were binge drinkers—which reflects a pattern of drinking frequently associated with adverse consequences—but were not alcohol dependent, suggesting that alterations in the HPA axis may begin even before dependence develops.

 

Tolerance is defined as the diminished response to alcohol or other drugs over the course of repeated or prolonged exposure. (20)  Although generally tolerance to the effects of alcohol develop over time and over several drinking sessions, it also has been observed to happen within a single drinking session. This phenomenon is called acute tolerance. (1, 20)  In fact, the onset of tolerance may occur within minutes during a single exposure to alcohol.  Chronic tolerance occurs after a longer time, usually following days of continuous or intermittent alcohol exposure.  Rapid tolerance shares many similarities with chronic tolerance but develops faster, typically within 8 to 24 hours. (20)  This attests how quickly molecular changes can happen in the brain after exposure to alcohol.

 

”The onset of alcohol dependence, however, is accompanied by bouts of elevated cortisol levels in the blood (i.e., hypercortisolism) as the drinker cycles though repeated episodes of alcohol intoxication and the stress of withdrawal (Adinoff et al. 1998; Wandand Dobs 1991).”

 

Dependence may occur after prolonged exposure to alcohol.  The chronic presence of alcohol disrupts normal brain chemistry.  As a result the brain makes changes, called neuroadaptations, to restore balance.  After the neuroadaptations have taken place a person may develop physiological signs of withdrawal if they abstain from drinking. (21)  The periods of intoxication result in repeated elevations of cortisol.  The stress of the withdrawal symptoms in between the periods of intoxication can also activate the HPA axis.

 

Allostasis and Allostatic Load

As discussed earlier, when we experience a stressor the body goes into action to preserve and maintain homeostasis.  One way the body does this is by releasing stress hormones which exert many effects on the body.  The term used for the active process by which the body responds and adjusts to daily stress to maintain homeostasis is called allostasis.  The word allostasis literally means “achieving stability through change.” (4)  In other words, allostasis may be defined as the process of restoring the balance when an organism experiences stressors that upset homeostasis. (12)

 

Chronic activation of allostasis over time may lead to dysregulation of the stress mediators- i.e. not being turned off when stress is over or not turned on adequately when they are needed.  This can lead to wear and tear on the body. (2)  The main hormones released in response to stress, cortisol and epinephrine (adrenaline), have both protective and damaging effects on the body. (3, 4)  The wear and tear on the body that results from chronic allostasis, particularly when there is dysregulation, is referred to as the allostatic load. (2)

 

 

Below are a series of pictures illustrating allostasis and the allostatic load from an article written by Billi Gordon, Ph.D. (12):

 

 

http://images.sussexpublishers.netdna-cdn.com/article-inline-half/blogs/137668/2013/12/139629-140113.jpg

This first picture above depicts homeostasis.  This picture is minus stressors and as you can see everything is in balance.

 

 

http://images.sussexpublishers.netdna-cdn.com/article-inline-half/blogs/137668/2013/12/139629-140114.jpg

The next picture shows stressors coming in and disrupting homeostasis- throwing the internal state off balance.

 

 

http://images.sussexpublishers.netdna-cdn.com/article-inline-half/blogs/137668/2013/12/139629-140115.jpg

The picture above shows allostasis taking action and restoring the balance.

 

 

http://images.sussexpublishers.netdna-cdn.com/article-inline-half/blogs/137668/2013/12/139629-140107.jpg

 

This last picture represents the allostatc load, which Dr. Gordon appropriately calls a ‘false sense of balance.’  Allostasis may bring things into balance in the short term, however long term the chronic release of stress hormones can take a toll on the body.  Dr. Gordon explains it like this:

 

”Allostatic Load occurs when your body’s allostatic mechanisms go from keeping you healthy to making you sick. It’s like riding your brakes until the pads are worn down. Suddenly, your brakes, which were a safety feature, now become a hazard because of overuse. For example, a sudden surge in blood pressure is good, when trying to fight or run from something. But when it happens constantly it becomes hypertension. This type of overuse most often occurs because of excessive exposure to stress.”

 

Allostatic load can result from either having too much stress or inefficiencies in the body’s response to stress.  Poor reactions to stress can include things like the body not turning off hormone release (e.g. cortisol) when it is no longer needed or not shutting it off in a timely manner; not releasing an adequate amount of hormone in response to the stressor; or not habituating to the recurrence of the same stressor and thus dampening the allostatic response. (2)  The following graphs represent the different types of allostatic load:

 

 

 

http://physrev.physiology.org/content/physrev/87/3/873/F5.medium.gif

 

 

I am going to refer to the boxes in the diagram above as 1-5 for ease of explanation.

 

Box 1 - The box at the top represents a normal allostatic stress response.  In this scenario a stressor activates the HPA Axis and the blue line represents the subsequent release of stress hormones.  As you can see the release of hormones quickly reaches a peak and then begins to rapidly decline as the stress response is turned off. In this scenario the short duration of stress hormone release has a protective effect on the body. (3, 4)

 

Box 2 - The next box down on the left represents chronic stress resulting in repeated activation of the stress response.  Everyday illustrations of this kind of stress might be pressure at work, home, being in debt, having an illness, etc…  This continual activation of the stress response results in over exposure of the body to its own stress hormones.  Continual release of stress hormones over longer intervals can have damaging effects on the body and result in allostatic load.

 

Box 3 - The next box to the right represents what happens when a person does not habituate or acclimate themselves to a continual stressor they must face.  An example of habituation would be when a person who just learns how to drive might be very nervous driving at first, but as they do it more and more they become more comfortable behind the wheel.  Habituation is represented by the red line on the graph while the blue line represents lack of habituation.  Notice the stress response declines over time for habituation and remains high when there is a lack of habituation.  As you can see a person who does not habituate to the stressor is exposed to higher levels of their own stress hormones than the person who did habituate.

 

Box 4 - The box on the bottom left represents failure of the body to turn the stress response off properly.  An example of this might be where a person’s blood pressure rises in a stressful situation then remains elevated even after the stress has passed.  Another example can be seen in sleep deprivation, which can cause hypersecretion of cortisol in the evening. (4)  This graph reflects a dysregulation in the daily pattern of cortisol release, where the cortisol level remains high when it should be low.

 

In healthy individuals, cortisol rises rapidly after wakening, reaching a peak within 30–45 minutes. It then gradually falls over the day, rising again in late afternoon. Cortisol levels then fall in late evening, reaching a trough during the middle of the night. (5)  In this scenario dysregulation of the stress response causes the cortisol levels to remain high, as represented by the blue line on the graph.

 

Box 5 – The last box on the lower right represents an attenuated response to stress where the body does not release a sufficient amount of stress hormones.  Normally basal levels of cortisol and catecholamines keep inflammatory cytokines in check.  Low levels of stress hormones may result in excess immune activity which may increase vulnerability to inflammatory and autoimmune disturbances, and low levels of cortisol have been also associated with conditions like fibromyalgia and chronic fatigue syndrome. (4)

 

During the development of alcohol dependence the cortisol response may become attenuated:

 

”This transition to alcohol dependence is accompanied by an allostatic shift in HPA axis functioning, resulting in abnormally low cortisol responsivity (Koob and Le Moal2001).

 

As dependence developed the function of the HPA Axis changed.  A healthy stress response is characterized by a quick rise in cortisol levels, followed by a rapid decline with the termination of the stressful event.  However during the shift to alcohol dependence the cortisol response to stress became dampened.  As discussed earlier, changes such as this may lead to allostatic load (wear and tear on the body):

 

"Under conditions of alcohol dependence, the allostatic load—a hypothetical measure of cumulative stress—increases and burdens the organism with excessive exposure to stress hormones and peptides as well as pro-inflammatory cytokines (McEwen2007).”

 

Catecholamines (e.g. adrenaline) and glucocorticoids (e.g. cortisol) are two major hormones released in response to stress.  Catecholamines can increase proinflammatory cytokine production and Glucocorticoids are known to inhibit this production. Therefore inadequate secretion of glucocorticoid may result in increased levels of cytokines. (2)

 

Adrenal Insufficiency

 

”Wand and Dobs (1991) studied HPA axis function in alcohol-dependent subjects during the first week of abstinence following supervised alcohol withdrawal on a clinical research unit. Although the participants had modestly to highly significantly elevated cortisol levels in the urine during the withdrawal period, they also demonstrated blunted HPA axis responses to CRF, a medication that blocks cortisol production (i.e., metyrapone), and the ACTH analog cosyntropin immediately following alcohol detoxification. In fact, many of the alcohol-dependent subjects met diagnostic criteria for adrenal insufficiency.”

 

The increase in cortisol levels after abstinence from alcohol was interesting as a similar increase has been observed during benzo discontinuation. (7, 13)  While there have been no studies monitoring HPA Axis function throughout the benzo recovery process to my knowledge, the fact that the alcohol-dependent subjects showed blunted HPA axis responses is intriguing.  It would be interesting to run the same sort of tests on people in benzo withdrawal to evaluate the entire axis.

 

Adrenal Insufficiency is a term that denotes low levels of cortisol.  Despite its name it does not necessarily mean the cause of the low cortisol is in the adrenal glands.  There are three major types of adrenal insufficiency (16):

 

Primary Adrenal Insufficiency- is due to impairment of the adrenal glands.

Secondary Adrenal Insufficiency- is a decrease in ACTH which may be caused by impairment of the pituitary gland or hypothalamus.

Tertiary Adrenal Insufficiency- is due to a decrease in corticotropin releasing factor (CRF).

 

The end result of all three types is lack of cortisol release from the adrenal glands- which is why they use the term ‘Adrenal insufficiency.’  So as you can see you can have Adrenal Insufficiency even when your adrenal glands are healthy.

 

The most common cause of this Secondary Adrenal Insufficiency in the U.S. are exogenous steroids (e.g. steroid injections).  This is because exogenous steroids elevate the glucocorticoid steroid levels in the blood which in turn can cause the body to shut down cortisol release.  This happens because the PVN and pituitary gland continually monitor the amount of cortisol in the blood.  If there is a sufficient enough increase of cortisol in the blood stream it will cause the PVN and/or the pituitary gland to cease releasing CRF and ACTH respectively.  This is a negative feedback system which prevents plasma cortisol levels from getting too high.

 

One of the drugs the researchers used to check HPA axis function, Metyrapone, works by inhibiting of a mechanism in the adrenal gland called steroid 11β-hydroxylase which shuts down cortisol production. (14)  Below is a chart of the hormone production pathways inside the adrenal glands (15):

 

 

 

 

If you look to the top left you will see that all of the hormones begin with cholesterol.  Cholesterol is converted into pregnenlolone- which is also known as the ‘the Mother of all hormones’ because all of the other hormones are made from it.  Looking over to the top right you will see 11β-hydroxylase in the pink box.  Notice that it lies between 11-deoxycortisol and Cortisol. 

 

When ACTH released from the pituitary gland activates this pathway, 11β-hydroxylase converts 11-deoxycortisol into cortisol.  The cortisol is then released by the adrenal glands into the blood stream which causes plasma cortisol levels to rise.  As discussed earlier, the negative feedback to the pituitary gland will cause the pituitary gland to shut down the release of ACTH so cortisol levels do not get too high.

 

When Metrapone is administered it blocks 11β-hydroxylase and under normal circumstance this should cause levels of 11-deoxycortisol to rise and levels of cortisol to decline.  This is because it inhibits the conversion of 11-deoxycortisol into cortisol.  If 11-deoxycortisol levels do not rise it may be an indication that there is a problem with the function of the adrenal gland.  In addition the pituitary gland should sense the decrease in plasma cortisol, and as a result, start releasing more ACTH in an effort to provoke the adrenals glands to step up their output.  Therefore if ACTH levels don’t rise after administering Metyrapone it may indicate a problem in either the pituitary gland or hypothalamus.

 

 

The other drug they used to check HPA axis function was Cosyntropin.  Cosyntropin is a synthetic form of ACTH.  Therefore administration of Cosyntropin should cause the adrenal glands to release of cortisol in the same manner as ACTH would.  A low adrenal output of cortisol after administration of Cosyntropin may therefore indicate adrenal malfunction.

 

”Other studies have corroborated these findings of elevated cortisol during the first week of withdrawal and also showed that cortisol levels decreased significantly over time, even plunging below the normal range (Esel et al.2001; Keedwell et al. 2001; Majumdaret al. 1989).”

 

After the initial increase in cortisol during the first week of alcohol withdrawal the participants then showed signs of Adrenal Insufficiency as demonstrated by the low cortisol levels.  Here again it would be interesting to see if this pattern occurs in benzo withdrawal as many people going through benzo withdrawal report symptoms consistent with Adrenal Insufficiency such as: weakness, fatigue, anorexia, nausea, vomiting, constipation, diarrhea, abdominal pain, dizziness, muscle and joint pain, and weight loss. (16, 18, 19)

 

Professor C Heather Ashton DM, FRCP, who operated a benzodiazepine withdrawal clinic from 1982 – 1994, mentions in her manual on benzo recovery having found low cortisol levels in the benzo withdrawal patients she tested. [18]  However she did not specify at what time during the recovery timeline the samples were taken.

 

Patterns of Daily Cortisol secretion

 

”Later in abstinence (i.e., at 2 to 6 weeks), alcoholics generally regain normal diurnal patterns of cortisol levels (e.g., Leggio et al. 2008]. However, they may continue to exhibit a deficient cortisol response to psychosocial and pharmacological HPA axis stimulation for several months (Adinoff et al. 1998, 2005a,b; Anthenelli et al. 2001; Bernardyet al. 1996).”

 

Normally there are four major ways cortisol is released: 1) pulsatile secretion (ultradian pulsatility - ultradian rhythms are recurrent periods or cycles repeated throughout a 24-hour circadian day; 2) circadian rhythm (circadian rhythms are changes that follow an endogenous 24-hour cycle; responding primarily to light and darkness); 3) stress-induced secretion; and 4) negative feedback inhibition by plasma levels of glucocorticoids. (17)

 

The ultradian pulsatility rhythm consists of brief episodic bursts of ACTH being released from the pituitary gland every one to two hours throughout the day.  After each burst plasma levels of ACTH rise then fall quickly.  These bursts trigger synthesis and release of cortisol from the adrenals.  Therefore after each burst of ACTH cortisol levels in the blood also rise quickly- however fall at a slower rate.  This is due to a slower rate of clearance of cortisol from the blood. (17)

 

A diurnal rhythm also occurs within the 24 hour circadian cycle that is influenced by daylight and darkness.  In this rhythm the amplitude of the ultradian bursts of ACTH change.  The level of cortisol in each burst begins to increase after three to five hours of sleep, reaching a maximum in the last few hours before and the hour after awakening. (17)  In fact, shortly after awakening the level of cortisol may rise an average of 50%.  This is known as the ‘cortisol awakening response.’  Therefore daily levels of plasma cortisol are at their highest during the first 30 to 45 minutes after awakening.  The amplitude then begins to decline throughout the morning and becomes minimal in the evening. (17)

 

Stress will also illicit a cortisol response by activating the HPA axis.  Cortisol levels are also controlled through negative feedback to the PVN and pituitary gland.

 

The diurnal pattern of the alcoholics normalized 2-6 weeks into withdrawal while the cortisol response to stimulation by drugs or social stress was still abnormal for several months.  Interestingly the diurnal pattern of cortisol release stabilized first before the function of the stress response.

 

”Junghanns and colleagues (2007) compared HPA axis activity in early abstainers (i.e., mean abstinence 22 days) and long-term abstainers (i.e., mean abstinence 117 days). These investigators found that longer-abstaining people showed a stronger cortisol awakening response, another indicator of HPA axis function, implying that diurnal patterns of cortisol may begin to normalize over longer periods of abstinence. Whether regulation of the HPA axis returns completely to normal, and under what conditions, remains unknown.

 

This study showed the cortisol awakening response returning back toward normal levels as time went on.  The longer the person abstained from alcohol the better the response became.  The author leaves the complete recovery of the HPA axis as an unknown.  However, this study only followed the participants for only 117 days- which may not have been long enough to make a determination.  In benzo withdrawal, for example, people appear to have symptom improvement on vastly different time scales- and sometimes recovery may last up to several years.  Professor Ashton stated in her manual “All the evidence shows that a steady decline in symptoms almost invariably continues after withdrawal, though it can take a long time - even several years in some cases.” [18]

 

Ashton went on to say “Most people experience a definite improvement over time so that symptoms gradually decrease to levels nowhere near as intense as in the early days of withdrawal, and eventually almost entirely disappear. All the studies show steady, if slow, improvement in cognitive ability and physical symptoms. Although most studies have not extended beyond a year after withdrawal, the results suggest that improvement continues beyond this time.” [18]

 

This highlights the need for long term studies to investigate HPA axis activity not only during the acute phase of benzo withdrawal but also during any possible phase of protracted symptoms.  Apparently the same need applies to alcohol research.

 

”Coiro and colleagues (2007) examined the effect of exercise as a biobehavioral stressor in control subjects and alcoholics over an 8-week period. Consistent with other studies ACTH and cortisol levels were significantly lower in alcoholics in the first month of withdrawal; by 8 weeks, however, the hormonal response had returned to normal. Interestingly, exercise itself can induce cortisol release (Beavenet al. 2010; Coiro et al. 2007; Usui etal. 2011) and has been investigated as an adjunct for smoking cessation with somewhat promising findings (Williamset al. 2010). This suggests that manipulation of cortisol levels may have therapeutic potential.”

 

Since exercise can cause cortisol levels to rise it may not be advisable during the acute phase of benzo withdrawal when cortisol levels may be elevated already.  However, if cortisol levels in benzo withdrawal follow the same pattern as that seen in alcohol withdrawal, which there is some indication, perhaps there may be therapeutic potential for exercise in benzo recovery as well.

 

People on benzobuddies.org have reported mixed results with exercise, with some members reporting an exacerbation of symptoms while other members report symptom improvement.  Perhaps a dynamic relationship occurs between HPA axis function and benzo recovery- and any benefit from exercise may depend on where the person is on the recovery continuum.

 

”No prospective longitudinal studies have examined HPA axis changes over longer periods of abstinence. One study of alcoholics who had been abstinent for a mean of 3.5 years found similar ACTH and cortisol responses compared with healthy controls in response to both psychological and pharmacological (i.e., opioid challenge) stressors (Munro et al. 2005). However, the study did not determine whether the alcoholics had recovered a normal level of HPA response with prolonged abstinence, whether they had had a normal response all along, or whether their lack of psychological comorbidity indicated that they were less affected by secondary characteristics related to a hyporesponsive HPA axis.  Another study compared alcoholics who had relapsed with abstainers after one year and found that, contrary to findings during short-term abstinence, 1-year abstainers had significantly lower levels of cortisol (Walter et al. 2006). This suggests that the relationship between HPA axis activity and alcohol recovery is dynamic and changes as abstinence persists over time.”

 

Again this highlights the need for long-term controlled studies.  It is unfortunate that the previous condition of the alcoholics in the Munro et al. study was unknown.

 

 

 

 

 

References

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National Institute on Alcohol Abuse and Alcoholism No. 28 PH 356 April 1995

http://pubs.niaaa.nih.gov/publications/aa28.htm

 

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3) Allostatic Load

Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Allostatic_load

 

4) Allostasis and Allostatic Load: Implications for Neuropsychopharmacology

Bruce S McEwen Ph.D

Neuropsychopharmacology (2000) 22, 108–124. doi:10.1016/S0893-133X(99)00129-3

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Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Hypothalamic%e2%80%93pituitary%e2%80%93adrenal_axis

 

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Gafford GM, Guo JD, Flandreau EI, Hazra R, Rainnie DG, Ressler KJ.

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12) The Real Problem with Weight Nazis

How weight bigotry worsens obesity related conditions

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http://www.psychologytoday.com/blog/obesely-speaking/201312/the-real-problem-weight-nazis

 

13) Impaired hypothalamic-pituitary-adrenocortical (HPA) system is related to severity of benzodiazepine withdrawal in patients with depression.

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14) Metyrapone

Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Metyrapone

 

15) Steroid 11-beta-hydroxylase

Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Steroid_11-beta-hydroxylase

 

16) Adrenal Insufficiency

Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Adrenal_insufficiency

 

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Eva N. Kassi, George P. Chrousos

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Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE4 5PL, England, UK

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Andrzej Z. Pietrzykowski, M.D., Ph.D., and Steven N. Treistman Ph.D.

Alcohol Research & Health, Neuroscience: Pathways to Alcohol Dependence Part II — Neuroadaptation, Risk, and Recovery

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21) How Adaptation of the Brain to Alcohol Leads to Dependence

A Pharmacological Perspective

Peter Clapp, Ph.D.; Sanjiv V. Bhave, Ph.D.; and Paula L. Hoffman, Ph.D.

Alcohol Research & Health, Neuroscience: Pathways to Alcohol Dependence Part II — Neuroadaptation, Risk, and Recovery

Volume 31, Number 4, 2008

National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health Publications

http://pubs.niaaa.nih.gov/publications/arh314/310-339.htm

 

22) The HPA Axis

Lise Alschuker, ND, FABNO

Integrative Therapeutics, Integrative Blog February 28, 2014

http://www.integrativepro.com/Resources/Integrative-Blog/2014/The-HPA-Axis

 

[[Na...]]

Interesting presentation Perseverance.

 

Indeed the issue is definitely complex and more study is needed.

 

Thank you very much for putting this together. It is very much appreciated!

[[Bi...]]

Hi P,  Interesting!

 

”Other studies have corroborated these findings of elevated cortisol during the first week of withdrawal and also showed that cortisol levels decreased significantly over time, even plunging below the normal range (Esel et al.2001; Keedwell et al. 2001; Majumdaret al. 1989).”

 

Do you think the addition of artificial hormones would lower cortisol even more?  What about testosterone additions?

 

Keep writing, I soak up your work like a sponge

[[Wi...]]

Eight months after my last benzo, my endo tested and I had elevated cortisol and norepinephrine and received a diagnosis of "pseudo Cushings" along with my Graves disease. So not all become "adrenal insufficient". There is no treatment for me as I don't have tumors.  The only symptom relief she said was available to me were benzos.  So, in other words, there is no treatment.  Hopefully time will resolve this.

[[sn...]]

Hi P,  Interesting!

 

”Other studies have corroborated these findings of elevated cortisol during the first week of withdrawal and also showed that cortisol levels decreased significantly over time, even plunging below the normal range (Esel et al.2001; Keedwell et al. 2001; Majumdaret al. 1989).”

 

Do you think the addition of artificial hormones would lower cortisol even more?  What about testosterone additions?

 

Keep writing, I soak up your work like a sponge

Whoa, I didnt know there was another Birdman on the forum. 

 

I did mean that in a positive way by the way.

[[ca...]]

Thanks, I will read this post.

[[Pe...]]

Hi P,  Interesting!

 

”Other studies have corroborated these findings of elevated cortisol during the first week of withdrawal and also showed that cortisol levels decreased significantly over time, even plunging below the normal range (Esel et al.2001; Keedwell et al. 2001; Majumdaret al. 1989).”

 

Do you think the addition of artificial hormones would lower cortisol even more?  What about testosterone additions?

 

Keep writing, I soak up your work like a sponge

 

Hi Birdman,

 

Looking at the steroid genesis chart you will see there are five separately shaded areas- the yellow area at the top left is progestagens; the purple area to the right is Mineralcorticoids; slightly below that is a green area which is glucocorticoids; the light bluish area at the bottom left is the Androgens; and the pink area at the bottom right is the Estrogens.

 

 

If you locate testosterone on the chart you will see that it is in the light blue area and has a separate biosynthesis pathway than cortisol which is in the green area.  Since these are both end products increasing one would not lower the other.  The green boxes indicate that the enzymes which perform the conversion for testosterone are located in the Endoplasmic Reticulum of the cell.  The Pink boxes indicate that conversion for cortisol takes place inside the mitochondria of the cell.  What they have in common is in the yellow shaded area.

 

 

Since you brought this topic up I would like to say that adding steroids while your body is attempting to reverse the effects of benzos may potentially discourage the normalization of your own natural hormone production IMO.  In addition hormone secretion follows daily rhythms and responds to environment- changes which cannot be duplicated by pills.

 

In lieu of everything I presented plus the anecdotal evidence it appears that if given enough time the HPA axis function will most likely recover on its own.

 

One last thing I would like for people to know is that taking exogenous hormones may also put you at risk for endocrine withdrawal syndromes- as outlined in this article:

 

Endocrine Withdrawal Syndromes

Ze’ev Hochberg, Karel Pacak, And George P. Chrousos

Endocrine Reviews 24(4):523–538 doi: 10.1210/er.2001-0014

http://press.endocrine.org/doi/pdf/10.1210/er.2001-0014

 

 

Exercise has been demonstrated to increase cortisol levels.  You may want to get your cortisol levels checked rather than assuming they are high or low.  Also- you could ask your doctor to run HPA axis function tests which would check HPA axis response as this would not be reflected in a simple blood test.

 

[[Pe...]]

Eight months after my last benzo, my endo tested and I had elevated cortisol and norepinephrine and received a diagnosis of "pseudo Cushings" along with my Graves disease. So not all become "adrenal insufficient". There is no treatment for me as I don't have tumors.  The only symptom relief she said was available to me were benzos.  So, in other words, there is no treatment.  Hopefully time will resolve this.

 

Hi WWWI,

 

I hope that the folks will keep in mind that dysregulation mean unregulated- which means levels may be above or below the norm.

 

I find it interesting that your cortisol levels were high when you were diagnosed with an autoimmune disease.

 

Have you had your levels rechecked since then?

 

[[Wi...]]

Looks like my reply didn't  take so here is the abridged version. Since there is no treatment and there is significant cost for testing im not retesting.  I wanted to confirm my suspicions and i did.  I figure as you have suggested, like my graves has done, things will calm down.

 

I would suggest though being careful making a global statement about not using drug/hormones to treat.  For my situation, Graves causes damage if left untreated as well as risk of thyroid storm, which can be fatal.  So while the endocrine system may right itself in time, no one knows for sure it will, and even if they believe it will, when.

 

I didn't  tolerate the meds well, but for the 2 years my graves was active I'm  guessing  those meds put a limit on how much damage was done to my heart, bones, eyes and muscles.

[[Pe...]]

Hey WWWI,

 

A diagnose of a disease is of course very different than members trying use hormone therapy to find symptom relief in BW.  Obviously if a condition warrants it, as in your case, there may be no other option and the benefit out weighs the risk.  Thanks for the reminder though- I should never assume that people will make that distinction on their own.

 

 

 

[[...]]

Perseverance, I have just gotten cortisol results and my evening is high and my nighttime is off the chart (not figuratively but literally). My daytime cortisol is very low. I also have Hashimoto's, but I am not being treated. Additionally, my DHEA is extremely low.

 

I am waiting in results for my neurotransmitter testing!

 

This is an interesting post, thank you! Hard to imagine that most in benzo wd wouldn't stress their adrenals at least to some degree!

 

I am not treating at all for the cortisol, but would sure love a good nights sleep!!

 

Thanks again!

 

[[Wi...]]

Hey WWWI,

 

A diagnose of a disease is of course very different than members trying use hormone therapy to find symptom relief in BW.  Obviously if a condition warrants it, as in your case, there may be no other option and the benefit out weighs the risk.  Thanks for the reminder though- I should never assume that people will make that distinction on their own.

 

I think for me having had it suggested on past posts when i was originally diagnosed,  to let my body heal itself, as it surely would in time without adding meds probably didnt help make the distinction any easier.

 

Also Im not sure the distinction is all that clear. How does one determine if the source of the symptom is wd or not.  I have graves disease BUT it behaves a lot like w/d and i genuinely believe the stress of w/d was what triggered it. So if someone is boarderline hypothyroid since beginning their taper?  What do they do? Treat or wait?  I agree when it comes to cortisol unless someone actually has a medical diagnosis playing around with hormones could be at the very least unnecessary and expensive all the way to dangerous.

[[Pe...]]

Perseverance, I have just gotten cortisol results and my evening is high and my nighttime is off the chart (not figuratively but literally). My daytime cortisol is very low. I also have Hashimoto's, but I am not being treated. Additionally, my DHEA is extremely low.

 

I am waiting in results for my neurotransmitter testing!

 

This is an interesting post, thank you! Hard to imagine that most in benzo wd wouldn't stress their adrenals at least to some degree!

 

I am not treating at all for the cortisol, but would sure love a good nights sleep!!

 

Thanks again!

 

 

Hi GMIT,

 

Just curious- was it a DHEA or a DHEAS test?  Or both?

 

Your results definitely appear to indicate HPA axis dysregulation.  It would be great if more members did this---I would pass the results along to Dr. Berry.  Maybe he could use the info to persuade the Maine Benzodiazepine Group to do some sort of a study if enough people here had results like that.

[[Pe...]]

 

... How does one determine if the source of the symptom is wd or not.  I have graves disease BUT it behaves a lot like w/d and i genuinely believe the stress of w/d was what triggered it. So if someone is boarderline hypothyroid since beginning their taper?  What do they do? Treat or wait?  I agree when it comes to cortisol unless someone actually has a medical diagnosis playing around with hormones could be at the very least unnecessary and expensive all the way to dangerous.

 

It is too bad that we do not have more information- like what your cortisol levels were when you were on benzos.  I say this because benzos can suppress the HPA axis while you are on them- so could that have opened up a window for the immune system to ramp up?  It is hard to say and without studies all we can do is speculate.

 

I felt bad when you were facing the hard decisions- a very precarious situation to be in for sure.  You have been courageous WWWI...a real fighter.  I will continue to pray for you (even tho I may be an anomaly ).

[[...]]

Perseverance, DHEA is

 

"Dehydroepiandrosterone (DHEA) and its sulfated analog (DHEAS) are steroid hormones principally made in the adrenal cortex. DHEAS is the most abundant steroid in humans with serum concentrations 250-500 times higher than DHEA, 100-500 times higher than testosterone, and 1000-10000 times higher than estradiol.(1,2) DHEAS appears to serve primarily as a precursor molecule that is circulated to peripheral tissues throughout the body. In those locations (and in the adrenal cortex) it is desulfated enzymatically to produce DHEA, which is in turn converted into various estrogenic and androgenic compounds. A portion of the DHEA produced locally may also be converted back to the sulfated form.(2) Because the two forms are easily interconverted, it is hard to discuss one without the other, and it is common to refer to them together as DHEA(S)."

 

http://fpb.case.edu/smartcenter/docs/SpitCamp/DHEA%20and%20DHEAS.pdf

 

"This test is done to check the function of the adrenal glands. The adrenal gland is one of the major sources of androgens in women."

 

http://www.nlm.nih.gov/medlineplus/ency/article/003717.htm

 

I agree with WWWI, it would be nice to know if it was wd or not! But, because i didn't have sleep issues until around month 5 (other than acute where I couldnt sleep at all), I believe that in my case, beginning of wd stressed my adrenals excessively and to the point that in month 5 it became apparent with the sleep issues. Interestingly enough, my thyroid numbers have also been all over the place through this as well (no surprise since the adrenals and thyroid are connected). My numbers were climbing, but since I've begun taking vitamins that I am low on (B12, D) along with vitamin C, K, B Complex, and magnesium, and zinc, my numbers for my thyroid have improved!

 

 

[[Pe...]]

GMIT,

 

I know what DHEA is lol.

 

My question was which DHEA test did they perform - the DHEA test or the DHEAS test.

[[...]]

So sorry! I misunderstood! Lol

 

I thought it was weird you didn't know! Lol

 

DHEAS!

 

 

[[Bi...]]

Hi P,  Interesting!

 

”Other studies have corroborated these findings of elevated cortisol during the first week of withdrawal and also showed that cortisol levels decreased significantly over time, even plunging below the normal range (Esel et al.2001; Keedwell et al. 2001; Majumdaret al. 1989).”

 

Do you think the addition of artificial hormones would lower cortisol even more?  What about testosterone additions?

 

Keep writing, I soak up your work like a sponge

 

Hi Birdman,

 

Looking at the steroid genesis chart you will see there are five separately shaded areas- the yellow area at the top left is progestagens; the purple area to the right is Mineralcorticoids; slightly below that is a green area which is glucocorticoids; the light bluish area at the bottom left is the Androgens; and the pink area at the bottom right is the Estrogens.

 

 

If you locate testosterone on the chart you will see that it is in the light blue area and has a separate biosynthesis pathway than cortisol which is in the green area.  Since these are both end products increasing one would not lower the other.  The green boxes indicate that the enzymes which perform the conversion for testosterone are located in the Endoplasmic Reticulum of the cell.  The Pink boxes indicate that conversion for cortisol takes place inside the mitochondria of the cell.  What they have in common is in the yellow shaded area.

 

 

Since you brought this topic up I would like to say that adding steroids while your body is attempting to reverse the effects of benzos may potentially discourage the normalization of your own natural hormone production IMO.  In addition hormone secretion follows daily rhythms and responds to environment- changes which cannot be duplicated by pills.

 

In lieu of everything I presented plus the anecdotal evidence it appears that if given enough time the HPA axis function will most likely recover on its own.

 

One last thing I would like for people to know is that taking exogenous hormones may also put you at risk for endocrine withdrawal syndromes- as outlined in this article:

 

Endocrine Withdrawal Syndromes

Ze’ev Hochberg, Karel Pacak, And George P. Chrousos

Endocrine Reviews 24(4):523–538 doi: 10.1210/er.2001-0014

http://press.endocrine.org/doi/pdf/10.1210/er.2001-0014

 

 

Exercise has been demonstrated to increase cortisol levels.  You may want to get your cortisol levels checked rather than assuming they are high or low.  Also- you could ask your doctor to run HPA axis function tests which would check HPA axis response as this would not be reflected in a simple blood test.

 

 

 

Thanks for the great answer P.    My doc is nagging me to take testosterone!  He told me it was the most powerful of all hormones and treatments he had found to up regulate GabaA fast.  He did warn me that I could not take it while still on benzo's - He said he has given it to men and women for fast up GabaA regulation of 27 years now.  I refuse since I do not want a beard   

 

Seriously, he wants me on the teste-patch REAL bad!!  What do you think? I am afraid of male hormones in my body, just freaks me out a little.

 

He says within 30 to 40 days I will experience a 40% to 60% drop in benzo w/d symptoms and that it will rev down my tinnitus fast too.

 

Here's some interesting data on it;

 

 

http://www.ncbi.nlm.nih.gov/pubmed/10327197 

 

http://www.pnas.org/content/102/6/2135.full  :thumbsup:

 

http://www.lef.org/magazine/2004/4/report_test/page-01

[[Ba...]]

Eight months after my last benzo, my endo tested and I had elevated cortisol and norepinephrine and received a diagnosis of "pseudo Cushings" along with my Graves disease. So not all become "adrenal insufficient". There is no treatment for me as I don't have tumors.  The only symptom relief she said was available to me were benzos.  So, in other words, there is no treatment.  Hopefully time will resolve this.

 

I have the same physical issues as you (although they haven't checked for tumours because I'm 5f8 and weigh under 100lbs) hello drs - graves!!!! I'd be checking for tumours as when I went into remission my weight went straight where Cushing's weight would go. (90 mins a day at the gym helped somewhat).

 

I'll have to wait for another remission for them to start doing the proper Cushing's tests (they always think its Aitkins and I always test for Cushing's) surely 4 out of 4 deserves further examination. " But you're too skinny, you don't present as etc." bloody hate drs! Don't they realise that even in remission I diet and excersize my way to a size 4! I've always been tall and slim - I'm used to it! (I don't like my Graves size 0-2 though - way too skinny!)

[[Wi...]]

Eight months after my last benzo, my endo tested and I had elevated cortisol and norepinephrine and received a diagnosis of "pseudo Cushings" along with my Graves disease. So not all become "adrenal insufficient". There is no treatment for me as I don't have tumors.  The only symptom relief she said was available to me were benzos.  So, in other words, there is no treatment.  Hopefully time will resolve this.

 

I have the same physical issues as you (although they haven't checked for tumours because I'm 5f8 and weigh under 100lbs) hello drs - graves!!!! I'd be checking for tumours as when I went into remission my weight went straight where Cushing's weight would go. (90 mins a day at the gym helped somewhat).

 

I'll have to wait for another remission for them to start doing the proper Cushing's tests (they always think its Aitkins and I always test for Cushing's) surely 4 out of 4 deserves further examination. " But you're too skinny, you don't present as etc." bloody hate drs! Don't they realise that even in remission I diet and excersize my way to a size 4! I've always been tall and slim - I'm used to it! (I don't like my Graves size 0-2 though - way too skinny!)

 

Thats so interesting what you said about when you were in remission all of your weight went where cushings weught would go.  Im having the exact same problem.  My gut is out of proportion to the rest of me and just last night i was standing in front of a mirror pondering my distended belly.  And while i hate it you are making me aware that this may be how things just are.  I appreciate that.  Sending good joo joo inhopes for you of remission!

[[Wi...]]

 

... How does one determine if the source of the symptom is wd or not.  I have graves disease BUT it behaves a lot like w/d and i genuinely believe the stress of w/d was what triggered it. So if someone is boarderline hypothyroid since beginning their taper?  What do they do? Treat or wait?  I agree when it comes to cortisol unless someone actually has a medical diagnosis playing around with hormones could be at the very least unnecessary and expensive all the way to dangerous.

 

It is too bad that we do not have more information- like what your cortisol levels were when you were on benzos.  I say this because benzos can suppress the HPA axis while you are on them- so could that have opened up a window for the immune system to ramp up?  It is hard to say and without studies all we can do is speculate.

 

I felt bad when you were facing the hard decisions- a very precarious situation to be in for sure.  You have been courageous WWWI...a real fighter.  I will continue to pray for you (even tho I may be an anomaly ).

 

Thanks for those kind words.  And while you may be an anomaly, you are one hell of a smart one

[[Pe...]]

Thanks for the great answer P.    My doc is nagging me to take testosterone!  He told me it was the most powerful of all hormones and treatments he had found to up regulate GabaA fast.  He did warn me that I could not take it while still on benzo's - He said he has given it to men and women for fast up GabaA regulation of 27 years now.  I refuse since I do not want a beard   

 

Seriously, he wants me on the teste-patch REAL bad!!  What do you think? I am afraid of male hormones in my body, just freaks me out a little.

 

He says within 30 to 40 days I will experience a 40% to 60% drop in benzo w/d symptoms and that it will rev down my tinnitus fast too.

 

That may be because in the brain one of the metabolites of testosterone acts like a Positive Allosteric Modulator (PAM) of the GABAA receptor- which would technically classify it as being cross-tolerant to benzos.  Alcohol, barbiturates, and Z-Drugs are also PAMs.  This is most likely why he does not want to prescribe it simultaneously with benzos because they both share a similar mechanism of action by enhancing the GABAA receptor.

 

Here are a few excerpts:

 

"GABA-steroids are positive modulators of GABA responses on the GABAA-receptor (Majewska et al., 1986). Chemically they are 3α-hydroxy-5α/β metabolites of progesterone (pregnanolone and allopregnanolone), testosterone (3α 5α-androstan-diol), and desoxycorticosterone (tetrahydro-desoxycorticosterone, THDOC). GABA-steroids enhance the GABA effect on chloride flux resulting in increased inhibition of neural activity (Majewska et al., 1986; Gee et al., 1987; Birzniece et al., 2006b). GABA-steroids induce sedation and can be used as anesthetic drugs in human (Carl et al., 1990; Timby et al., 2006). GABA-steroids are anti-epileptic (Backstrom et al., 1984; Landgren et al., 1987) and in animal experiments they also possess an anxiolytic effect similar to benzodiazepines (Wieland et al., 1991). An anxiolytic effect of allopregnanolone has, however, never been shown in humans."

 

Neurosteroids and GABA-A receptor function

Mingde Wang

Front. Endocrinol., 04 October 2011 | doi: 10.3389/fendo.2011.00044

http://journal.frontiersin.org/Journal/10.3389/fendo.2011.00044/full

 

As you can see in the citation above they state they classify one of the metabolites of testosterone as a ‘GABA-steroid’ which “enhance the GABA effect on chloride flux resulting in increased inhibition” which is what all GABAAR PAMs do, which is why Benzodiazepines are also classified as a GABAAR PAMs.  So the metabolite of testosterone would therefore work by causing a similar effect as a benzo.  They even suggest that it can induce sedation and therefore be used as an anesthetic.  The fact that they work in a similar fashion on the GABAAR may potentially interfere with reversals to GABAAR gene expression during recovery from benzos.

 

Some Addiction specialist use phenobarbital, another GABAAR PAM to get people off of benzos.  Perhaps your doctor is thinking of the same principle exchanging one GABAAR PAM for another with the testosterone.  Members here have told me that they still experienced WD sxs after the phenobarbital was discontinued…therefore I would ask him what he anticipates will happen once testosterone is discontinued. 

 

"Recently, we showed that testosterone affects seizure activity via its conversion to neurosteroids estradiol and androstanediol in the brain (Reddy, 2004a,b, 2008). Androstanediol (5_-androstan-3_,17_-diol) is synthesized from testosterone by the 5_-reductase pathway (Fig. 1). Androstanediol is a neurosteroid because it is produced locally by glial cells and principal neurons in the hippocampus, which have 5_-reductase and 3_-hydroxysteroid oxidoreductase enzymes (Martini et al., 1993; Mensah-Nyagan et al., 1999; Agís-Balboa et al., 2006). In conclusion, our results demonstrate for the first time that the testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors…"

 

This study also demonstrated that the metabolite of testosterone, Androstanediol, is a GABAAR PAM.

 

Here's some interesting data on it;

 

 

http://www.ncbi.nlm.nih.gov/pubmed/10327197 

 

"We found that both alpha2 mRNA and protein levels are significantly increased by T treatment at embryonic day 20 (E20) and birth (P0). The observed modulation of the expression of GABA(A) receptor alpha2 subunit by T may be translated into changes in the levels or composition of GABA(A) receptor, either of which would be expected to alter neuronal functional response to GABA activation."

 

The excerpt above is from the abstract of the previous link you gave me.  The GABAARs most susceptible to down-regulation from benzos appear to be the alpha 1 containing receptors.  Alpha 2 may also be affected but here again you would be essentially replacing one GABA drug with another.

 

http://www.pnas.org/content/102/6/2135.full  :thumbsup:

 

"The neuronal mechanism underlying TP-induced aggression in female mice very likely is similar to that regulating aggression in untreated SI males. This mechanism involves the GABAergic system, which is positively and allosterically modulated by endogenous Allo (21–25, 46, 47). Thus, protracted exposure of rodents to TP may decrease GABAergic tone by reducing the bioavailability of pregnane steroids (by means of an inhibitory action on 5_-RI expression) that have a prominent endogenous regulatory role in the affinity of GABAA receptors for GABA."

 

What this link is saying is that the negative effects associated with administration of testosterone may be due to testosterone inhibiting another neurosteroid metabolite resulting in reduced attraction for GABA.  This would obviously not be a good thing in BW.

 

http://www.lef.org/magazine/2004/4/report_test/page-01

 

”…evidence that women also become testosterone deficient is largely ignored.”

 

This article is talking about possible benefits of testosterone therapy for testosterone deficiency, which is a different topic than using testosterone to treat WD.

 

[[Bi...]]

Thanks for the great answer P.    My doc is nagging me to take testosterone!  He told me it was the most powerful of all hormones and treatments he had found to up regulate GabaA fast.  He did warn me that I could not take it while still on benzo's - He said he has given it to men and women for fast up GabaA regulation of 27 years now.  I refuse since I do not want a beard   

 

Seriously, he wants me on the teste-patch REAL bad!!  What do you think? I am afraid of male hormones in my body, just freaks me out a little.

 

He says within 30 to 40 days I will experience a 40% to 60% drop in benzo w/d symptoms and that it will rev down my tinnitus fast too.

 

That may be because in the brain one of the metabolites of testosterone acts like a Positive Allostatic Modulator (PAM) of the GABAA receptor- which would technically classify it as being cross-tolerant to benzos.  Alcohol, barbiturates, and Z-Drugs are also PAMs.  This is most likely why he does not want to prescribe it simultaneously with benzos because they both share a similar mechanism of action by enhancing the GABAA receptor.

 

Here are a few excerpts:

 

"GABA-steroids are positive modulators of GABA responses on the GABAA-receptor (Majewska et al., 1986). Chemically they are 3α-hydroxy-5α/β metabolites of progesterone (pregnanolone and allopregnanolone), testosterone (3α 5α-androstan-diol), and desoxycorticosterone (tetrahydro-desoxycorticosterone, THDOC). GABA-steroids enhance the GABA effect on chloride flux resulting in increased inhibition of neural activity (Majewska et al., 1986; Gee et al., 1987; Birzniece et al., 2006b). GABA-steroids induce sedation and can be used as anesthetic drugs in human (Carl et al., 1990; Timby et al., 2006). GABA-steroids are anti-epileptic (Backstrom et al., 1984; Landgren et al., 1987) and in animal experiments they also possess an anxiolytic effect similar to benzodiazepines (Wieland et al., 1991). An anxiolytic effect of allopregnanolone has, however, never been shown in humans."

 

Neurosteroids and GABA-A receptor function

Mingde Wang

Front. Endocrinol., 04 October 2011 | doi: 10.3389/fendo.2011.00044

http://journal.frontiersin.org/Journal/10.3389/fendo.2011.00044/full

 

As you can see in the citation above they state they classify one of the metabolites of testosterone as a ‘GABA-steroid’ which “enhance the GABA effect on chloride flux resulting in increased inhibition” which is what all GABAAR PAMs do, which is why Benzodiazepines are also classified as a GABAAR PAMs.  So the metabolite of testosterone would therefore work by causing a similar effect as a benzo.  They even suggest that it can induce sedation and therefore be used as an anesthetic.  The fact that they work in a similar fashion on the GABAAR may potentially interfere with reversals to GABAAR gene expression during recovery from benzos.

 

Some Addiction specialist use phenobarbital, another GABAAR PAM to get people off of benzos.  Perhaps your doctor is thinking of the same principle exchanging one GABAAR PAM for another with the testosterone.  Members here have told me that they still experienced WD sxs after the phenobarbital was discontinued…therefore I would ask him what he anticipates will happen once testosterone is discontinued. 

 

"Recently, we showed that testosterone affects seizure activity via its conversion to neurosteroids estradiol and androstanediol in the brain (Reddy, 2004a,b, 2008). Androstanediol (5_-androstan-3_,17_-diol) is synthesized from testosterone by the 5_-reductase pathway (Fig. 1). Androstanediol is a neurosteroid because it is produced locally by glial cells and principal neurons in the hippocampus, which have 5_-reductase and 3_-hydroxysteroid oxidoreductase enzymes (Martini et al., 1993; Mensah-Nyagan et al., 1999; Agís-Balboa et al., 2006). In conclusion, our results demonstrate for the first time that the testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors…"

 

This study also demonstrated that the metabolite of testosterone, Androstanediol, is a GABAAR PAM.

 

Here's some interesting data on it;

 

 

http://www.ncbi.nlm.nih.gov/pubmed/10327197 

 

"We found that both alpha2 mRNA and protein levels are significantly increased by T treatment at embryonic day 20 (E20) and birth (P0). The observed modulation of the expression of GABA(A) receptor alpha2 subunit by T may be translated into changes in the levels or composition of GABA(A) receptor, either of which would be expected to alter neuronal functional response to GABA activation."

 

The excerpt above is from the abstract of the previous link you gave me.  The GABAARs most susceptible to down-regulation from benzos appear to be the alpha 1 containing receptors.  Alpha 2 may also be affected but here again you would be essentially replacing one GABA drug with another.

 

http://www.pnas.org/content/102/6/2135.full  :thumbsup:

 

"The neuronal mechanism underlying TP-induced aggression in female mice very likely is similar to that regulating aggression in untreated SI males. This mechanism involves the GABAergic system, which is positively and allosterically modulated by endogenous Allo (21–25, 46, 47). Thus, protracted exposure of rodents to TP may decrease GABAergic tone by reducing the bioavailability of pregnane steroids (by means of an inhibitory action on 5_-RI expression) that have a prominent endogenous regulatory role in the affinity of GABAA receptors for GABA."

 

What this link is saying is that the negative effects associated with administration of testosterone may be due to testosterone inhibiting another neurosteroid metabolite resulting in reduced attraction for GABA.  This would obviously not be a good thing in BW.

 

http://www.lef.org/magazine/2004/4/report_test/page-01

 

”…evidence that women also become testosterone deficient is largely ignored.”

 

This article is talking about possible benefits of testosterone therapy for testosterone deficiency, which is a different topic than using testosterone to treat WD.

 

Thanks P!!!  I guess I will stay away from the treatment for now as I'm doing fairly well anyhow and I do not need a hairy back    I guess I'll just wait it out and heal, this is so slow   Seems like the more I heal the slower any new healing comes around but I guess that's just the nature of this beast we are all burdened with, sigh.

 

Thanks again P