Does trazodone affect cortisol levels? (3+ studies)

In this article, we will discuss whether trazodone affects cortisol levels. We will talk about the mechanism through which trazodone affects cortisol levels, the potential benefits of trazodone’s effects on cortisol, related research findings, and other relevant information. 

Does trazodone affect cortisol levels?

Yes, trazodone affects cortisol levels and is known to decrease cortisol levels in the body. Cortisol, a hormone released by adrenal glands in your body, is widely known as the stress hormone (1). 

The production and release of cortisol from the adrenal glands are under the regulation of the hypothalamus-pituitary-adrenal axis (HPA axis) (1). Trazodone’s interaction with the HPA axis is one of the reasons it influences cortisol levels. 

Trazodone, an antidepressant, is categorized as a serotonin antagonist and reuptake inhibitor (SARI) and is therapeutically used for major depressive disorder (MDD) under FDA approval. Off-label it is widely used as a sedative (2). 

Elevated levels of cortisol have been reported in MDD and insomnia. Trazodone’s effects on cortisol are mainly therapeutic. 

How does trazodone affect cortisol? 

Trazodone has a complex mechanism of action and it influences different neurotransmitters. It inhibits serotonin reuptake that raises serotonin levels and it also blocks some serotonin, histamine (H1), and alpha-1 adrenergic receptors (1). 

Trazodone affects cortisol levels through two mechanisms. The influence of trazodone on neurotransmitters reduces the activation of the HPA axis (3). The HPA axis has several interactions with neurotransmitters like serotonin. 

Secondly, trazodone functions as an antagonist of alpha-1 adrenergic receptors. Alpha-1 adrenergic mechanisms are involved in stimulating cortisol release which is blocked by trazodone (4). 

Thus, trazodone reduces cortisol levels by interacting with the HPA axis and blocking the alpha-1 adrenergic receptors. This explains why reduced plasma cortisol concentration is observed in individuals taking trazodone. 

What are the benefits of trazodone’s effect on cortisol levels? 

The association between elevated levels of cortisol and the development of depression is well established. Research has shown that individuals with MDD present with a dysregulated HPA axis (5). 

The elevated cortisol levels are due to the hyperactivation of the HPA axis. The hyperactivated HPA axis also increases inflammatory cytokines that decrease serotonin concentration and play a role in depression (5). 

Thus, hyperactive HPA axis and increased cortisol levels are involved in the development of depression. Trazodone suppresses HPA activation and reduces cortisol levels which improves MDD. 

Additionally, hyperactivation of the HPA axis and elevated cortisol levels are also linked to sleep disturbances in individuals that can lead to insomnia and obstructive sleep apnea (6). Trazodone’s impact on cortisol levels improves insomnia and sleep apnea

Thus, trazodone’s effect on cortisol is beneficial as it improves depression, and insomnia and reverses the harmful effects of elevated cortisol and a hyperactive HPA axis. 

What does research suggest? 

Several studies have reported the impact of trazodone on cortisol levels. One study compared the efficacy of trazodone and cognitive behavioral therapy (CBT) in resolving insomnia and improving sleep duration (3). 

The results of this study demonstrated that patients taking trazodone showed significant improvements and their salivary cortisol levels were decreased after treatment with trazodone (3). 

Another study assessed trazodone’s impact on cortisol levels in healthy individuals. The results showed a decrease in plasma cortisol concentration. The authors linked this effect with trazodone’s antagonist effect on alpha-1 adrenergic receptors (4).

A systematic review of trazodone’s use for insomnia has discussed that one of the mechanisms through which trazodone improves sleep is by regulating cortisol suppression of the HPA axis (7). 

Some animal studies on trazodone have shown that trazodone reduces serum cortisol levels in dogs, domestic goats, and blue wildebeest (8,9). 

What factors influence trazodone’s effect on cortisol levels?

Different factors may influence the impact of trazodone on serum cortisol levels. They include: 


The activity of trazodone is dose-dependent and it is possible that at higher doses trazodone’s impact on cortisol levels is enhanced. Trazodone saturates the serotonin receptors at high doses which can potentiate its impact on the HPA axis. 

Individual variations:

Several factors like age, genetic makeup, and physiology impact how a medication is metabolized and absorbed in the body. This individual variation may influence how trazodone interacts with cortisol regulation in the body. 

Health conditions: 

Different health conditions are associated with abnormal cortisol levels in the body and may interact with trazodone’s influence on cortisol levels. Conditions like Addison’s disease and Cushing’s syndrome occur due to abnormal cortisol levels. 

Other medications:

Concomitant use of medications that also affect cortisol levels can influence trazodone’s impact on cortisol. Several antidepressants like sertraline are known to interact with cortisol regulation. 

How to manage trazodone’s impact on cortisol levels?

The trazodone’s impact on cortisol levels is therapeutic and does not cause any health concerns. Some symptoms of low cortisol levels in the body include:

  • weight loss
  • fatigue
  • hypotension
  • hyperpigmentation of skin
  • craving salt 
  • irregular periods
  • reduced appetite

It is important to remember that the occurrence of one or more symptoms does not necessarily indicate low cortisol levels. Some of the symptoms may occur as a side effect of trazodone. Common side effects of trazodone include (2):

Therefore, you must contact your healthcare provider if you are concerned about any of the side effects you experience while taking trazodone.

Your healthcare provider will educate you on the common side effects of trazodone or consider dose reduction if the side effects are intense. 

In my perspective, trazodone affects cortisol levels as it reduces plasma cortisol concentration. This effect is produced by trazodone’s interaction with the HPA axis and blocking of the alpha-1 adrenergic receptors. 

Cortisol reduction by trazodone is beneficial because HPA axis hyperactivation and elevated cortisol levels are involved in the development of depression, insomnia, and sleep apnea. Trazodone improves these conditions by regulating the HPA axis. 

Different factors like the dosage, individual variations, health conditions, and other medications can influence trazodone’s impact on cortisol. If you experience unusual side effects while taking trazodone, contact your healthcare provider. 

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