Journal of Psychiatric Research 110 (2019) 31–37 Contents lists available at ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/jpsychires L-theanine in the adjunctive treatment of generalized anxiety disorder: A T double-blind, randomised, placebo-controlled trial ∗ Jerome Sarrisa,b, , Gerard J. Byrnec, Lachlan Cribbb, Georgina Oliverb, Jenifer Murphyb, Patricia Macdonaldc, Sonia Nazarethc, Diana Karamacoskaa, Samantha Galeab, Anika Shortc, Carolyn Eea, Yoann Birlinga, Ranjit Menonb, Chee H. Ngb a NICM Health Research Institute, Western Sydney University, Westmead, NSW, Australia b The Professorial Unit, The Melbourne Clinic, Department of Psychiatry, The University of Melbourne, Richmond, VIC, Australia c The University of Queensland, Faculty of Medicine, Discipline of Psychiatry, Herston, QLD, Australia ARTICLE INFO ABSTRACT Keywords: Partial or non-response to antidepressants in Generalized Anxiety Disorder (GAD) is common in clinical settings, L-theanine and adjunctive biological interventions may be required. Adjunctive herbal and nutraceutical treatments are a Anxiety novel and promising treatment option. L-theanine is a non-protein amino acid derived most-commonly from tea Sleep (Camellia sinensis) leaves, which may be beneficial in the treatment of anxiety and sleep disturbance assug- GAD gested by preliminary evidence. We conducted a 10-week study (consisting of an 8-week double-blind placebo- Randomised controlled trial controlled period, and 1-week pre-study and 2-week post-study single-blinded observational periods) involving 46 participants with a DSM-5 diagnosis of GAD. Participants received adjunctive L-theanine (450–900 mg) or matching placebo with their current stable antidepressant treatment, and were assessed on anxiety, sleep quality, and cognition outcomes. Results revealed that adjunctive L-theanine did not outperform placebo for anxiety reduction on the HAMA (p = 0.73) nor insomnia severity on the Insomnia Severity Index (ISI; p = 0.35). However, LT treated participants reported greater self-reported sleep satisfaction than placebo (ISI item 4; p = 0.015). Further, a separation in favour of L-theanine was noted on the ISI in those with non-clinical levels of insomnia symptoms (ISI ≤ 14; p = 0.007). No significant cognitive effects (trail making time and the modified emotional Stroop) were revealed. While this preliminary study did not support the efficacy of L-theanine in the treatment of anxiety symptoms in GAD, further studies to explore the application of L-theanine in sleep dis- turbance are warranted. 1. Introduction increasingly being considered as novel adjunctive options in psychiatric disorders, due to their potential efficacy and acceptable tolerability Effective first-line treatments for Generalized Anxiety Disorder (Sarris et al., 2016, 2010). (GAD) include psychotherapy such as Cognitive Behavioural Therapy L-theanine (n-ethylglutamic acid; LT) is a non-proteinogenic amino (Carpenter et al., 2018) and pharmacotherapies such as antidepressants acid derived almost exclusively from tea leaves (Camellia sinensis), with and anxiolytic agents (Reinhold and Rickels, 2015). With anti- the highest concentrations found in green, oolong, and Pu-erh tea (Syu depressant treatments, the remission rates are typically in the realm of et al., 2008). A natural ethylamide analogue of glutamate, preclinical 30–50% (Reinhold et al., 2011). As such, adjunctive agents (such as studies have found LT to pass freely through the blood-brain barrier, benzodiazepines, pregabalin and/or antipsychotics) are often used to reduce presynaptic glutamate release (Kakuda et al., 2008), increase enhance the effectiveness of antidepressants in those who are non-re- inhibitory neurotransmitter GABA, and enhance glycine and dopamine sponsive (Latas et al., 2018). A common co-occurrence with GAD is release (Kakuda et al., 2008; Kimura and Murata, 1971; Shen et al., insomnia (Ferre Navarrete et al., 2017), and subjectively reported sleep 2011; Yamada et al., 2007, 2005). Although the direct effects of LT on disturbance is an important part of GAD symptomology (Cox and GABA pathways is not well understood, a recent study has shown dif- Olatunji, 2016). Nutraceuticals and ‘phytoceuticals’, pharmaceutical ferential decreases of cortical and hippocampal GABA in mouse models grade nutrients or plant-based compounds with bioactive effects, are (Schallier et al., 2013). A comprehensive review of LT's ∗ Corresponding author. NICM Health Research Institute, Western Sydney University, Westmead, 2145, Australia. E-mail address: [email protected] (J. Sarris). https://doi.org/10.1016/j.jpsychires.2018.12.014 Received 26 August 2018; Received in revised form 6 December 2018; Accepted 7 December 2018 0022-3956/ © 2018 Elsevier Ltd. All rights reserved. J. Sarris et al. Journal of Psychiatric Research 110 (2019) 31–37 neuropharmacology has also highlighted its neuroprotective effects, as 2.3. Measures well as the ability to increase alpha wave brain activity (Lardner, 2014). Alpha brain-activity is a measure of wakeful relaxation and has been Due to the two major hypothesis-driven clinical areas of inquiry associated with creativity, improved concentration, and decreased an- (anxiety and insomnia), we used dual primary outcome measures: the xiety (Lardner, 2014). Owing to its influence on inhibitory neuro- Hamilton Anxiety Rating Scale (HAMA) was administered according to transmission, as well as promotion of alpha brain wave activity, LT has the Structured Interview Guide for the Hamilton Anxiety Scale (SIGHA) been investigated in animal models of anxiety, demonstrating anxio- for the anxiety outcome (Hamilton, 1959), and the Insomnia Severity lytic as well as antidepressant activity (Ogawa et al., 2018; Unno et al., Index (ISI) for the insomnia outcome (Morin et al., 2011). Secondary 2013a; Wakabayashi et al., 2012). outcome measures included the MADRS (Montgomery and Asberg, While preclinical and clinical evidence (covered in the Discussion) 1979), a clinician reported measure of depression severity, the Beck suggests that LT has anxiolytic and hypnotic properties, clinical trials Anxiety Inventory (BAI) (Beck et al., 1988), Penn State Worry Ques- investigating its therapeutic effects in anxiety disorders are lacking. tionnaire (PSWQ) (Meyer et al., 1990) and World Health Organisation Further, there is a deficit of augmentation studies in GAD, and nostu- Quality of Life-BREF (WHOQOL-BREF) (The WHOQOL GROUP, 1998). dies have investigated the potential usefulness of different doses of LT. A trail making task (measuring time in seconds to complete task) was Thus our current study aimed to elucidate the efficacy and safety of used to determine the effect of LT on cognition. A modified emotional adjunctive LT in the treatment of GAD, with an a priori hypothesis that Stroop task was also undertaken in which participant's response times the compound would reduce participant's anxiety and insomnia se- to name colours of positive, neutral and anxiety-related words (such as verity. An additional aim was to assess whether a titrated high dose of stroke, debts, crazy) was measured. The self-reported Systematic As- LT (900 mg/day) is needed in cases of non-response to the initial sessment for Treatment Emergent Effects (SAFTEE) was used to assess 450 mg/day dose. for the presence and severity of adverse events (Levine and Schooler, 1986). The WHOQOL-BREF, trail making time and the modified emo- tional Stroop were completed at baseline and Week-8. All other mea- 2. Methods sures were completed at each time point. 2.1. Overview 2.4. Treatment intervention This was a phase II, randomised, double-blind, placebo controlled, Eligible participants were initially randomised, via independent multi-centre pilot study comparing adjunctive LT to adjunctive placebo computer-generated block randomisation to receive, in addition to their in individuals with GAD who were non-responsive to their current an- current antidepressant, LT at 450 mg per day (given as one 225 mg tidepressant. The study was conducted between 2016 and 2018 and capsule twice per day, or placebo matched for appearance, taste, and study sites were located in Australia at The Melbourne Clinic scent) for the first four weeks of the study. Participants who didnot (Richmond, Melbourne), The Royal Brisbane and Womens Hospital achieve a ≥35% reduction in their baseline HAMA score at Week-4 (Herston, Brisbane) and NICM Health Research Institute were titrated to two capsules, twice per day (900 mg LT per day, or (Campbelltown, New South Wales). The trial was registered on the matching placebo) for the remaining four weeks of the treatment in- Australian New Zealand Clinical Trials Registry (ANZCTR # tervention phase. Titration at Week-4 is in line with flexible dosing seen 12616000759493) on 9th June 2016, and Human Research Ethics in clinical practice where some patients, due to individual pharmaco- Committee approvals obtained from each trial site to conduct the study kinetic and pharmacodynamic differences, require a higher dose to (TMCREC 273; UQ MREC 2016000774; WSU HREC H12268). achieve response. Participants ceased taking capsules for the last two weeks of the study (from Week-8 to Week-10) which was used to 2.2. Eligibility criteria monitor for any potential ongoing therapeutic activity or withdrawal effect from the LT. Eligible participants met the following criteria: aged between 18 and 75 years; primary diagnosis of GAD at study entry (DSM-5;