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

My trials with supplements for schizophrenia

I’m abandoning my trials with most supplements – they simply have not demonstrated any substantial improvements to my health. I did everything I could to research and try and treat my schizophrenia, believing current antipsychotics were not going to be that effective… Time for a new phase in my life. Wish me luck!

My subjective experiences were:

Longer trials:

L-lysine 6g/day added to clozapine for several months: No decline in auditory hallucinations. No benefits over clozapine alone on total symptomatology. See more
Pregnenolone 100mg/day added to clozapine and aripiprazole for many months: Perhaps a slight improvement in anxiety and negative symptoms. No effect on positive symptoms See here and here [review]
DHEA 100mg/day added to clozapine and aripiprazole for many months: Improvement in negative symptoms. Increase in energy and improvement in depressive symptoms. Some subjective prosocial improvements. Worth further investigation. See here and here [review]
DHEA + Pregnenolone 100mg each added to clozapine and aripiprazole for several months. Perhaps slightly synergistic. Improvement in negative and depressive symptoms.
D-serine 2g bd added to clozapine + aripiprazole for a couple of months: no significant improvement in positive symptoms nor any notable cognitive improvement. Potentially a slight improvement in negative symptoms? There was perhaps a slight decline in cognition, particularly with regard to attention span, on ceasing.
Sodium benzoate + D-serine see here

[A] patient noted rapid improvements in cognition and mood when 1g sodium benzoate tds was added to 2g/day D-serine but this was not trialed for a long period. 500mg sodium benzoate b.d. and D-serine 1g b.d. was as effective as 2g D-serine b.d. but the subjective beneficial effects were minimal in both cases, even on prolonged administration. No subjective improvement in positive symptoms or cognition was noted but there was a slight (?) improvement in negative symptoms.

Sodium benzoate – Slightly activating/mild antidepressant effects at all doses used. see here

One patient with sub-therapeutic levels of clozapine, also taking therapeutic doses of aripiprazole failed to find benefit from 1g sodium benzoate added once daily. Replicating the 2013 study by using 500mg b.d. may be more effective.

L-theanine 400mg added to various antipsychotics: improvement in agitation and attention span. Slight anxiolytic effect. Worth further investigation. See more here and here
Sarcosine 2g/day added to various antipsychotics: Dose dependent improvement in concentration (worsening of concentration at higher doses). Acute effects included an improvement in mood. See more here and here
N-acetylcysteine ~3g/day addded to clozapine and aripiprazole: No improvement in positive or negative symptoms. Abnormal LFTs potentially attributed to its use? Really bad flatulence. See more
Acetyl-l-carnitine 5g/day added to clozapine: No notable antidepressant effects despite the claims. Abandoned due to ending up smelling like trimethylamine. See more
Oral lavender oil (80mg +): effective for mild anxiety. See more here
Raw cacao powder 15-30g/day: no notable benefits
Fish oil – 2.7g omega-3 daily ~1 year: No notable benefits?
Combination: Fish oil (2.7g omega-3), aspirin (600mg), curcumin (600mg), coenzyme Q10 (150mg), vitamin E (1000IU), ascorbic acid (2500mg), vitamin D (1000IU), vitamin B12 (1mg), folic acid (5mg), full spectrum multivitamin/B complex and dietary nitrate (8mmol, twice daily) added to aripiprazole 30mg/day resulted in an almost complete attenuation of my auditory hallucinations

Shorter trials:

Sunifiram (20mg acute) added to various antipsychotics: no notable improvements in memory. Slight improvement in attention span and positive symptoms. Improvement in agitation associated with aripiprazole. See more here
Galantamine: 6-20mg nocte: improvement in sustained concentration and memory recall at higher doses. Worth further investigation. See more here
Pregabalin see here
Phenibut 750mg – 1g: Dramatic improvement in the intensity of auditory hallucinations. Acute anxiolytic and antidepressant effects. Worth further investigation. See more here
Agmatine 3g/day added to clozapine and aripiprazole for several weeks: No substantial antidepressant effects. No reduction in total symptomatology. See here
Oxytocin added to clozapine and aripiprazole:

I’ve tried buccal (200IU) and intranasal oxytocin at various doses (exceeding 24IU) and for periods of up to a couple of weeks in the past without noticing anything subjectively. I was more focused on improving negative affect, most particularly relating to loneliness and didn’t specifically try to evaluate improvements in social cognition. My social skills are pretty crappy and I have an autism spectrum condition which adds to my social impairments.

See more [review]

Please note: Most of these trials were done while on a high dose of a SNRI (venlafaxine 375mg/day – I have comorbid TRD). Also note that some trials overlapped.

To conclude, I’d say the most promising leads are galantamine for attention/cognitive symptoms, GABA-B agonism (via phenibut in my case, which also binds to the α2-δ subunit of voltage-dependent calcium channels [1]) for auditory hallucinations, L-theanine for anxiety and activation symptoms, GlyT1 inhibition via sarcosine for attention and depressive symptoms (dose dependent), DHEA for negative and depressive symptoms and pregabalin or oral lavender oil for anxiety. Sunifiram and ampakines deserve further research. I did not notice much improvement from NMDAR glycine site modulation with D-serine or DAAO inhibition with sodium benzoate but recommend further research in the area. D-serine shows encouraging potential, particularly for individuals at high risk for FEP, see here.