Mental Side Effects of Testosterone Injections

Which mental side effects does the label list?

Depo-Testosterone is the brand-name testosterone cypionate injection, given deep into the gluteal muscle every 2 to 4 weeks at 50 to 400 mg [1]. Its adverse reactions section lists increased or decreased libido, headache, anxiety, depression and generalized paresthesia under nervous system effects, without rates [1].

The most detailed psychiatric language in the cypionate label sits in its abuse section, which covers doses above those recommended and use alongside other anabolic steroids: major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression, plus hypomania and irritability [1].

Does testosterone cypionate help depression?

On average, a little. A 2019 meta-analysis in JAMA Psychiatry pooled 27 randomized placebo-controlled trials with 1,890 men and found a significant reduction in depressive symptom scores with testosterone (Hedges g 0.21, 95% CI 0.10 to 0.32). Response, defined as a score drop of 50% or more, favored testosterone (odds ratio 2.30, 95% CI 1.30 to 4.06), and dropout did not differ significantly from placebo (odds ratio 0.79, 95% CI 0.61 to 1.01) [2].

The Testosterone Trials studied older men. Investigators assigned 790 men aged 65 and older with serum testosterone below 275 ng/dL to testosterone gel or placebo gel for one year. Testosterone produced no significant benefit on vitality (FACIT-Fatigue), but men who received it reported slightly better mood and lower severity of depressive symptoms than placebo. Sexual activity increased significantly (P<0.001), and walking distance improved in an analysis that included men from all three trials [4]. That trial used a gel, not cypionate injections.

Neither result makes testosterone a depression treatment. The approved indication for these products is replacement in men with hypogonadism, confirmed by morning serum testosterone measured on at least two separate days and below the normal range [1].

What about mania, irritability and aggression?

A randomized, placebo-controlled crossover trial gave testosterone cypionate to 56 men aged 20 to 50 for 6 weeks in doses rising to 600 mg per week, with a 6-week washout between periods. Manic scores rose on the Young Mania Rating Scale (P=.002) and on daily diaries (P=.003), and provoked aggressive responses rose on the Point Subtraction Aggression Paradigm (P=.03). The response was uneven: of 50 men who received 600 mg weekly, 42 (84%) had minimal psychiatric effects, 6 (12%) became mildly hypomanic and 2 (4%) became markedly hypomanic [3].

A separate trial found no mood change at a similar weekly dose. In 43 normal men given 600 mg of testosterone enanthate weekly for 10 weeks, neither mood nor behavior was altered in any group [7].

In the cypionate trial, the 8 men who reacted did not differ from the 42 who did not on baseline demographic, psychological, laboratory or physiological measures, and the mechanism of the variable reactions remains unclear [3].

Can mood swing between injections?

The hormone kinetics are well described. In 11 hypogonadal men given 200 mg of testosterone cypionate intramuscularly, serum testosterone rose about threefold, peaked on days 2 to 5, and fell back to baseline by days 13 to 14; estradiol rose about threefold over days 2 to 7 [5]. The Depo-Testosterone label gives a half-life of about 8 days and a dosing interval of 2 to 4 weeks [1]. That study measured hormone levels, not mood, so it does not show whether a peak or a trough affects mood in a particular man [5].

Does it help or worsen anxiety?

Anxiety is on the Depo-Testosterone adverse reaction list [1]. The controlled evidence on anxiety itself is thin and indirect. In a double-blind crossover study, 20 healthy women given a single sublingual dose of testosterone showed reduced fear-potentiated startle four hours later, with no change in baseline startle [8]. That is one dose in women, not repeated replacement in hypogonadal men.

Does it affect sleep, and does that change mood?

In a crossover trial of 17 healthy men over 60, men received three injections of testosterone esters at weekly intervals (500 mg, then 250 mg, then 250 mg) or matching oil placebo, with an 8-week washout between periods. Testosterone shortened total sleep by about an hour, lengthened nightly hypoxemia by about 5 minutes and raised the respiratory disturbance index by about seven events per hour (P<0.05). Mood on the Profile of Mood States did not change [9].

What happens to mood after high doses stop?

The Depo-Testosterone label states that people taking supratherapeutic doses may have withdrawal symptoms lasting weeks or months after abrupt discontinuation: depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism. Drug dependence at approved doses has not been documented [1].

Is testosterone cypionate a controlled substance?

Yes. Testosterone is a Schedule III controlled substance under the Controlled Substances Act [6], and the Depo-Testosterone label states this [1].