Add-on Pregnenolone with L-Theanine to Antipsychotic Therapy Relieves Negative and Anxiety Symptoms of Schizophrenia: An 8-week, randomized, double-blind, placebo-controlled trial (2015)

I haven’t yet seen the full text but here are the initial results from a trial I was keeping an eye on:

Add-on Pregnenolone with L-Theanine to Antipsychotic Therapy Relieves Negative and Anxiety Symptoms of Schizophrenia: An 8-week, randomized, double-blind, placebo-controlled trial (2015)


Pregnenolone (PREG) and L-Theanine (LT) have shown ameliorative effects on various schizophrenia symptoms. This is the first study to evaluate the efficacy and safety of augmentation of antipsychotic treatment among patients with chronic schizophrenia or schizoaffective disorder with PREG – LT.


Double-blind, placebo-controlled trial of PREG – LT or placebo augmentation was conducted for 8 weeks with 40 chronic DSM-IV schizophrenia and schizoaffective disorder patients with suboptimal response to antipsychotics. Oral PREG (50 mg/day) with LT (400 mg/day) or placebo were added to a stable regimen of antipsychotic medication from March 2011 to October 2013. The participants were rated using the Scale for the Assessment of Negative Symptoms (SANS), Hamilton Scale for Anxiety (HAM-A), and Positive and Negative Syndrome Scale (PANSS) scales bi-weekly. The decrease of SANS and HAM-A scores were the co-primary outcomes. Secondary outcomes included assessments of general functioning and side effects.


Negative symptoms such as blunted affect, alogia, and anhedonia (SANS) were found to be significantly improved, with moderate effect sizes among patients who received PREG-LT, in comparison with the placebo group. Add-on PREG-LT also significantly associated with a reduction of anxiety scores such as anxious mood, tension, and cardiovascular symptoms (HAM-A), and elevation of general functioning (GAF). Positive symptoms, antipsychotic agents, concomitant drugs, and illness duration did not associate significantly with effect of PREG-LT augmentation. PREG-LT was well-tolerated.


Pregnenolone with L-Theanine augmentation may offer a new therapeutic strategy for treatment of negative and anxiety symptoms in schizophrenia and schizoaffective disorder. Further studies are warranted.

TRIAL REGISTRATION: Identifier: NCT01831986.

See also:

Effect of l-theanine on glutamatergic function in patients with schizophrenia (2015)

Neurosteroids as therapeutics

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review (2015)

Dietary and nutritional therapies for schizophrenia

Clinical Management of Negative Symptoms of Schizophrenia: An update (2015)

My trials with supplements for schizophrenia

Effect of l-theanine on glutamatergic function in patients with schizophrenia (2015)

Effect of l-theanine on glutamatergic function in patients with schizophrenia


Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. Previous studies suggested that l-theanine affects the glutamatergic neurotransmission and ameliorates symptoms in patients with schizophrenia. The aims of the present study were twofold: to examine the possible effects of l-theanine on symptoms in chronic schizophrenia patients and to evaluate the changes in chemical mediators, including glutamate + glutamine (Glx), in the brain by using 1H magnetic resonance spectroscopy (MRS).


The subjects were 17 patients with schizophrenia and 22 age- and sex-matched healthy subjects. l-Theanine (250 mg/day) was added to the patients‘ ongoing antipsychotic treatment for 8 weeks. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), Pittsburgh Sleep Quality Index scores and MRS results.


There were significant improvements in the PANSS positive scale and sleep quality after the l-theanine treatment. As for MRS, we found no significant differences in Glx levels before and after the 8 week l-theanine treatment. However, significant correlations were observed between baseline density of Glx and change in Glx density by l-theanine.


Our results suggest that l-theanine is effective in ameliorating positive symptoms and sleep quality in schizophrenia. The MRS findings suggest that l-theanine stabilises the glutamatergic concentration in the brain, which is a possible mechanism underlying the therapeutic effect.

  • l-theanine attenuates MK-801-induced deficits in prepulse inhibition (PPI) in rats and displays antipsychotic and antidepressant-like activity [1]
  • l-theanine improves PPI in healthy humans: “The administration of 200 mg of l-theanine and that of 400 mg, but not 600 mg, significantly increased the % PPI compared to the baseline”  [2]
  • Several studies show that l-theanine has an influence on mood
  • l-theanine increases sleep quality and satisfaction without increasing sleep duration or causing wake-up grogginess [3]
  • an 8-week, randomized, double-blind, placebo-controlled, 2-center study showed that l-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder [4]
  • Circulating BDNF levels and cortisol-to-DHEAS*100 molar ratio may be involved in the beneficial clinical effects of l-theanine as an augmentation strategy with antipsychotic therapy in schizophrenia and schizoaffective disorder patients [5]

“8-week add-on l-theanine treatment significantly reduced the PANSS scores in schizophrenia patients who were under treatment with antipsychotic medication. MRS revealed that l-theanine affected the concentration of Glx in the frontal and inferior parietal regions. Interestingly, there were significant negative correlations between Glx at baseline and the % ratio in Glx at the frontal and inferior parietal regions. To our knowledge, this is the first study that obtained evidence of the effect of l-theanine on Glx, which is related to glutamatergic neurotransmission in humans.

The therapeutic effects of l-theanine against the schizophrenic symptoms observed in the present study are consistent with those of previous studies. In addition, our finding of a positive effect of l-theanine on sleep supports the results of preceding studies.

l-Theanine, which has a chemical structure that is similar to that of glutamate, affects glutamatergic neurotransmission. The effects of l-theanine on schizophrenia symptoms and Glx concentrations in the brain observed in the present study might be attributable to its chemical structure. It is known that l-theanine has weak affinities for kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and NMDA receptors. On the other hand, l-theanine was reported to be able to suppress the excitotoxic release of glutamate derived from the Gln/glutamate cycle through the inhibition of Gln incorporation in glutamatergic neurons in a particular situation.

In a previous study, we focused on the effect of l-theanine on PPI, a measure of sensorimotor gating that is known to be impaired in schizophrenia , and we observed the enhancement of PPI at particular doses of l-theanine. It is possible that l-theanine exerts its effects, at least in part, through a partial agonistic-like action on the glutamatergic system. …l-theanine may have a stabilising effect on the glutamatergic neurotransmission.

Several studies examined glutamatergic changes in first-episode schizophrenia, chronic schizophrenia, and individuals at high risk for schizophrenia. The results obtained at each clinical stage and the clinical severity indicate that the glutamatergic metabolites of schizophrenia change in a course-dependent manner. l-Theanine was shown to be a safe and well-tolerated medication, and the stabilising effect of l-theanine on glutamatergic neurotransmission could be of significant benefit in clinical practice.”