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A proof-of-principle study of the short-term effects of MDMA (3,4-methylenedioxymethamphetamine) on tinnitus and neural connectivity

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Background: This study was conducted to investigate the short-term behavioral and neurophysiological effects of MDMA (3,4-methylenedioxymethamphetamine) on tinnitus perception. Methods: A double-blind randomized controlled cross-over design. Part 1. Behavioural measures of tinnitus following 30 mg MDMA or placebo administration (N = 5 participants) and Part 2. Behavioral measures of tinnitus and correlations between pairs of apriori regions of interest (ROI) using resting-state functional magnetic resonance imaging (rs-fMRI) before and after 70 mg of MDMA or placebo (N = 8 participants). Results: The results to MDMA were similar to placebo. For the 70 mg dose there was a significant reduction after 4 hours in annoyance and ignore ratings. RsMRI showed decreased connectivity compared to placebo administration between the left hippocampal, right hippocampal, left amygdala and right amygdala regions, and between the right posterior parahippocampal cortex and the left amygdala after two hours of 70 mg MDMA administration. Increased connectivity compared to placebo administration was found post MDMA between the right post-central gyrus and right posterior and superior temporal gyrus, and between the thalamus and frontoparietal network. Conclusions: Following 70 mg of MDMA two tinnitus rating scales significantly improved. There was, however, a placebo effect. Compared to placebo the rsMRI following the MDMA showed reductions in connectivity between the amygdala, hippocampus and parahippocampal gyrus. There is sufficient proof of concept to support future investigation of MDMA as a treatment for tinnitus.
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... In total, 10 publications described MDMA-assisted treatment of PTSD (total N = 214 patients): seven RCTs (Mitchell et al., 2021;Mithoefer et al., 2011;2013b, 2018, 2019Oehen et al., 2013;Ot'alora et al., 2018), one openlabel trial (Jardim et al., 2020), one case series (Monson et al., 2020;Wagner et al., 2019), and one qualitative study (Barone et al., 2019). Other RCTs reported on the treatment of end-of-life anxiety (EOLA) (Wolfson et al., 2020), social anxiety in adults with autism (Danforth et al., 2018), and tinnitus (Searchfield et al., 2020); one open-label study focused on alcohol use disorder (AUD) (Sessa et al., 2019;2021b). Active doses ranged from 50 to 125 mg (sometimes followed by an optional supplemental half-dose). ...
... Of all MDMA studies, 11 reported AEs only when spontaneously reported by participants; one study did not report on AEs (Searchfield et al., 2020). Two RCTs systematically assessed AEs (Mitchell et al., 2021;Mithoefer et al., 2019), another study employed the UKU scale of secondary effects; this was the only study reporting AE severity (Oehen et al., 2013). ...
... Two RCTs systematically assessed AEs (Mitchell et al., 2021;Mithoefer et al., 2019), another study employed the UKU scale of secondary effects; this was the only study reporting AE severity (Oehen et al., 2013). Six studies did not report whether participants had ever used MDMA or "ecstasy" prior to study participation (Bouso et al., 2008;Jardim et al., 2020;Monson et al., 2020;Ot'alora et al., 2018;Searchfield et al., 2020;Sessa et al., 2021b); prior exposure to MDMA in the other nine quantitative studies varied from none (Danforth et al., 2018) to 56% (Wolfson et al., 2020). The qualitative study was of medium/high quality (Barone et al., 2019) but did not report on AEs. ...
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... However, after a higher dose, it showed reduced annoyance and altered brain connectivity. Further research is warranted to explore the potential of MDMA as a tinnitus treatment [50]. ...
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... This reduction in connectivity was not specific to locations with a frequency preference corresponding to the tinnitus pitch, as shown by a recent ultra-high field fMRI study (Berlot et al., 2020). Additionally, tinnitus attenuation by sound or pharmacological therapies was accompanied by normalization of thalamic functional connectivity (Han et al., 2019;Lv et al., 2020;Searchfield et al., 2020). While reduced functional connectivity with tinnitus thus seems to be a consistent result from the functional imaging literature, it does not allow discriminating between the two MGB tinnitus theories. ...
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... Other drugs aim to affect central processes, for example oxytocin increases the salience of sound through inhibition (Marlin et al. 2015) with preliminary benefits for tinnitus (Azevedo et al. 2017). Similarly methylenedioxymethamphetamine (MDMA) has been shown to create an indifference to negative sounds, by mediating serotonergic signaling (Kuypers et al. 2018) and preliminary investigations of MDMA as a potential tinnitus therapy have begun (Searchfield et al. 2020a). There is no conclusive evidence yet that these drugs will be effective clinically, but the mechanisms putatively modified by these drugs are worth exploring further. ...
Chapter
This volume has highlighted the many recent advances in tinnitus theory, models, diagnostics, therapies, and therapeutics. But tinnitus knowledge is far from complete. In this chapter, contributors to the Behavioral Neuroscience of Tinnitus consider emerging topics and areas of research needed in light of recent findings. New research avenues and methods to explore are discussed. Issues pertaining to current assessment, treatment, and research methods are outlined, along with recommendations on new avenues to explore with research.
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4-phosphorloxy-N,N-dimethyltryptamine (psilocybin) and methylenedioxymethamfetamine (MDMA), best known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research during the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and in patients with advanced cancer with anxiety. MDMA is showing encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, rather than as stand-alone drug treatments. This model of drug-assisted psychotherapy is a possible alternative to existing pharmacological and psychological treatments in psychiatry. Further research is needed to fully assess the potential of these compounds in the management of these common disorders that are difficult to treat with existing methods.