The good and the bad
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Let’s take a good look at ketamine
Ketamine is an old anesthetic – it is relatively safe as anesthetics go.
(It’s still a risky substance to mess around with, you can overdose and it is addictive.)
At some point it became a type of party drug and these days that’s what it’s most well known as.
Researchers became interested in it as a potential antidepressant after more and more reports came out claiming depression was cured after recreational use of ketamine.
Later research showed that ketamine could indeed reverse depression – and quite rapidly too.
Now, ketamine formulations are approved for depression by the FDA in the United States.
But the fact that ketamine works so rapidly poses a problem for the low serotonin hypothesis of depression, the complexities of this hypothesis mean that any cure would take days or weeks.
More recent research shows that ketamine probably works by blocking biological stress – it’s another nail in the coffin for the serotonin hypothesis.
The animal experiments were performed at Huainan First Peoples’ Hospital in Anhui, China. The paper was published in Behavioural Brain Research.
You might not know it because of all of the direct to consumer advertising for antidepressant medications but it is widely understood by animal researchers that stress, not low serotonin, is the cause of depression.
“Chronic stress is an important factor for depression.”
Some people (and animals) are more resilient to stress than others.
There are many reasons for this.
The authors of this study were experimenting with different substances in order to try and understand stress resilience and individual susceptibility to depression.
“Most individuals recover from stress, while some develop into depression. The pathogenesis of resilience or susceptibility remains unclear.”
At a basic level, stress activates the HPA axis – stress leads to a rapid increase in stress hormones. These include cortisol, adrenaline, serotonin, histamine and estrogen.
“Stress activates the HPA axis and releases stress hormones to regulate individual response to stress.”
The researchers carried out animal experiments using previously validated techniques to increase stress and the likelihood of depressive behaviors in rodents.
They looked at the levels of corticosterone – the animal equivalent of the human stress hormone cortisol.
The researchers also looked at what was going on with the glucocorticoid receptor.
This is a cell receptor which is activated by corticosterone/cortisol and maybe one of the activators of depression under stress.
“We assessed the effects of chronic stress on susceptible behaviors, plasma corticosterone concentration, glucocorticoid receptor expressions in the brain.”
Greater increases in corticosterone were strongly associated with depressive behaviors in animals.
For humans this probably means that elevated cortisol is a trigger for depression.
“Mice that plasma corticosterone concentration is increased 2 h after single social defeat stress developed into susceptible mice after 10 d social defeat stress.”
Stress hormones remained elevated for some time after the stressful events in depression-susceptible animals.
“The plasma corticosterone concentration was still higher than that of resilient mice 48 h after the last defeat stress.”
Another experiment showed that simply increasing stress hormones – even without the stressful event – increases the risk of depression.
“Mice administered corticosterone via drinking water showed susceptibility.”
A treatment which blocks the glucocorticoid (cortisol) receptor decreased the likelihood of depression – further narrowing down the possibilities.
“A glucocorticoid receptor antagonist improved susceptibility to chronic stress.”
And finally, the research showed that the novel antidepressant ketamine produces at least some of its antidepressant effects by reducing the effects of stress.
Ketamine lowered corticosterone and reversed increases in glucocorticoid receptor activity.
“Ketamine improved depressive-like behaviors, decreased plasma corticosterone and rescued glucocorticoid receptor expression in susceptible mice.”
Ketamine’s antidepressant effects in humans are likely due to the fact that it lowers the primary stress hormone cortisol and the sensitivity of the receptors are activated by cortisol.
“These results suggest that abnormal corticosterone concentration after stress may predict susceptibility to depression in the clinic.”
The results again put the absurdity of the low serotonin hypothesis of depression in the spotlight.
Ketamine is an excellent option for the treatment of severe depression in a clinical setting.
It’s not really something you can mess around with at home and hope for good results.
But, as I often write about my articles and newsletters, there are many, many safe ways to limit your exposure to stress hormones like cortisol – techniques which may be as effective as ketamine in the medium to long term.
“Ketamine may exert the antidepressant effect via normalizing HPA axis response and have significance in the clinic.”
You should always consult your healthcare practitioner for guidance on medical diagnosis and treatment.
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