The Calming Effect of Tamoxifen

Tamoxifen, the active ingredient in the antioestrogenic drug Nolvadex, makes you calmer. So calm in fact that psychiatrists would like to use tamoxifen to treat manias. According to an animal study done by pharmacologists at the Universidade Federal do Parana in Brazil, tamoxifen can even negate the mental effects of amphetamines.

Question: how are medicines such as lithium and valproate capable of treating mania, the hyperactive condition that can arise from a psychiatric disorder or drugs use?

Answer: because they inhibit the enzyme protein kinase C in brain cells. As does tamoxifen, a substance that is marketed for its ability to deactivate the sex hormone estradiol and is therefore popular among chemical athletes who notice that the steroids they are using are having oestrogenic side effects.

In the late 1990s the American psychiatrist Joseph Bebchuk discovered that tamoxifen was also capable of fighting manias in people with bipolar disorder. [Arch Gen Psychiatry. 2008 Mar; 65(3): 255-63.] Bebchuk’s study was small, but since then bigger studies have confirmed his results. One of these was done at Dokuz Eylul University in Turkey. The figure reproduced below comes from this study.

It shows the effect of a hefty course of tamoxifen [the researchers built up the dose over a week to 80 mg per day] on mania, measured using two different methods. The effect is comparable with that of lithium and valproate, the Turks claim in their publication.


Researchers have studied the anti-manic effects of medicines on animals by putting rats in a large cage, where they have no place to hide away. This is called an open field study: rats get nervous when placed in this kind of environment. The researchers enhance the rats’ nervousness by giving them amphetamines and then look at the number of times the animals change their behaviour [Number of interruptions].

In 2008 Brazilian pharmacologists at the Universidade Federal do Parana published the results of an open field study in which they studied the anti-manic effect of tamoxifen. [Prog Neuropsychopharmacol Biol Psychiatry. 2008 Dec 12; 32(8): 1927-31.] The table below comes from that study.


A dose of 0.5 mg tamoxifen per kg bodyweight doesn’t counteract the mental effects of amphetamines, but a dose of 1 mg per kg bodyweight does. If you convert that dose to an adult human weighing 80 kg, you arrive at about 15 mg tamoxifen.

The researchers administered the tamoxifen via an intraperitoneal injection. An oral dose would be about twice as high, so about 30 mg tamoxifen per day.

The antimanic-like effect of tamoxifen: Behavioural comparison with other PKC-inhibiting and antiestrogenic drugs.

Sabioni P, Baretta IP, Ninomiya EM, Gustafson L, Rodrigues AL, Andreatini R.


Department of Pharmacology, Universidade Federal do Paraná, Setor de Ciências Biológicas, Centro Politécnico C.P. 19031, 81540-990 Curitiba, PR, Brazil.


Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and valproate, and tamoxifen, an antiestrogenic drug with PKC inhibition activity, also demonstrates an antimanic effect. Thus, the aim of the present study was to evaluate whether the antimanic effect of tamoxifen is mediated through the PKC inhibitory and/or the antiestrogenic action(s) of the drug. In the present study, the effects of tamoxifen, chelerythrine (a PKC inhibitor) and medroxyprogesterone (an antiestrogenic drug) were investigated in amphetamine-induced hyperlocomotion of mice, an animal model of a manic state. Lithium carbonate (100 and 150 mg/kg, i.p.), tamoxifen (1.0 mg/kg, i.p.) and chelerythrine (1 microg/site, i.c.v.) completely blocked the amphetamine-induced hyperlocomotion. However, while the intermediate medroxyprogesterone dose (3.0 mg/kg, i.p.) partially reduced the amphetamine-induced hyperlocomotion, lower (1.0 mg/g) and higher (6.0 mg/kg) doses produced no effect. Our results indicate a major role for PKC inhibition in the antimanic-like effect of tamoxifen, although its antiestrogenic action may also contribute to this effect.

PMID: 18930105 [PubMed – indexed for MEDLINE]