Open AccessReview


The profound economic burden of schizophrenia is due, in part, to the negative symptoms of the disease, which can severely limit daily functioning. There is much debate in the field regarding their measurement and classification and there are no FDA-approved treatments for negative symptoms despite an abundance of research. 3,4-Methylenedioxy methamphetamine (MDMA) is a schedule I substance that has emerged as a novel therapeutic given its ability to enhance social interactions, generate empathy, and induce a state of metaplasticity in the brain. This review provides a rationale for the use of MDMA in the treatment of negative symptoms by reviewing the literature on negative symptoms, their treatment, MDMA, and MDMA-assisted therapy. It reviews recent evidence that supports the safe and potentially effective use of MDMA to treat negative symptoms and concludes with considerations regarding safety and possible mechanisms of action.

1. Introduction

Schizophrenia is a complex psychiatric syndrome characterized by psychosis, or loss of touch with reality. Individuals with schizophrenia can suffer from positive symptoms, including hallucinations, delusions, and disorganized speech or behavior, as well as negative symptoms, including deficits in affect, speech, motivation, and sociality [1]. Schizophrenia can be difficult to treat, and the mean proportion of patients who achieve recovery is estimated to be as low as 13.5% [2]. Those living with schizophrenia have an increased risk of premature mortality, with an estimated near 29 years of life lost on average and suicide rates approaching 5% [3,4,5]. They are at a higher risk for developing various chronic medical conditions, with suboptimal recognition and treatment. Examples include coronary artery disease and metabolic abnormalities such as diabetes, cancer, respiratory illnesses, and stroke [2,5]. The health, social, and economic burden of schizophrenia vastly overshadows its prevalence of 2–6 per 1000 [6]. The total economic burden of schizophrenia is estimated to be over USD 60 billion per year in the United States [7].

Clinically significant negative symptoms are estimated to be present in approximately 60% of patients with schizophrenia in community and research samples [8,9]. For many it is the first symptom to manifest in the prodromal phase, well before the first psychotic episode. Negative symptoms continue to persist despite antipsychotic treatment [9] and correlate with increased disease severity and poorer functioning [8]. Negative symptom burden is associated with poor response to treatment and related functional outcomes [10]. It is abundantly clear that negative symptoms confer a significant financial burden on society and increased utilization of primary care [11,12]. To date, there are no approved treatments for negative symptoms anywhere in the world.

3,4-Methylenedioxy methamphetamine (MDMA) is a schedule I substance with a controversial history and resulting stigmatization. In recent years, it has emerged as a novel therapeutic given its ability to enhance social interactions, generate empathy, and induce a state of metaplasticity in the brain [13,14]. MDMA has been shown to be an effective treatment for PTSD and is currently in phase III clinical trials [15]. As such, it is being explored as a treatment for other indications. The present review will detail how MDMA may also be uniquely qualified to target negative symptoms in schizophrenia.

2. Negative Symptoms

The terms “positive” and “negative” symptoms can be traced back to the mid-1800s, when British neurologists distinguished between distortions and deficits of motor and cognitive functions [16]. Over time, this became increasingly applied to mental disorders, eventually being described by Kraepelin as irreversible and progressive deficits in individuals with dementia praecox [17]. Shortly after coining the term “schizophrenia,” Bleuler emphasized negative symptoms as the core process of the illness, speculating that symptoms were rooted in the weakening of mental functions [18]. In the early 1980s, the first negative symptom scale was developed, paving the way for its conceptualization as a distinct domain [19]. Over the next few decades, additional tools were developed, leading to various constructs. It became increasingly clear that negative symptoms research was limited by a lack of consensus [17]. As such, an NIMH-sponsored meeting was convened in 2005, leading to the construct that predominates to this day [20,21].

Blunted affect refers to the reduction in observed emotional expression that is independent of an individual’s subjective experience of emotion. It is widely accepted that individuals with schizophrenia show reduced emotional expressivity regardless of medication status, for both positive and negative emotions [22]. This has been supported by research examining alterations in responsible muscle groups [23]. Relatedly, analyses of verbal and nonverbal expression among those with schizophrenia have demonstrated consistent results, independent of medication and internal states [24,25].

Alogia refers to the decrease in quantity and spontaneity of speech as rated by the clinician. Alogia has often been associated with various aspects of cognition, particularly verbal fluency [21]. Deficits in verbal fluency are highly correlated with and specific to alogia, suggesting a possible shared mechanism [26]. Although several aspects of speech have been shown to be impaired in individuals with schizophrenia, the most significant seem to be in production, particularly pauses [27]. Given the significance of speech in role and social functioning, alogia remains an important consideration in schizophrenia research.

Anhedonia refers to the diminished capacity to feel pleasure. It has long been considered central to both schizophrenia and depression. Given this overlap, efforts have been made to characterize different aspects of anhedonia that may contribute to each spectrum of illness. It was traditionally thought that depression reduces an individual’s ability to experience pleasure from ongoing activities (consummatory anhedonia), whereas schizophrenia limits an individual’s ability to anticipate future pleasure (anticipatory anhedonia). However, this characterization has been challenged in recent literature, as depressed patients are also known to experience anticipatory anhedonia [28]. Adding to the complexity of the construct are various confounders, including source of information, comorbid depression, motivation, and cognition [22,29,30,31]. As a result, recent studies have failed to demonstrate differences between individuals with schizophrenia and healthy controls, emphasizing the need to further narrow the construct and related measures [32].

Avolition refers to reduced initiation and persistence of goal-directed activity, as reported and observed. Substantial efforts have been made to understand it, as it is the domain most intricately linked to functional impairment [33]. Relatedly, such deficits have been shown to be a predictor of functional outcome in individuals with schizophrenia [34]. Despite their preserved ability to experience pleasure relative to healthy controls, there is a known deficit in behaviors to obtain pleasure [35,36]. As such, there has been greater emphasis on reward prediction mechanisms, particularly as they relate to learning and executive function [35,37,38].

Asociality refers to the reduction in social initiative resulting from decreased interest and motivation to form relationships. Research has shown that this deficit is remarkably similar to that seen in autism spectrum disorders, particularly in those with predominantly negative symptoms [39]. As a construct, asociality has been the most challenging to study, given the contribution of related factors, including positive symptoms, comorbid depression, cognition, functional impairment, and lack of opportunities [21]. Research has even implicated avoidance as an important mechanism despite not being part of the construct [40]. Although the true etiology of asociality has yet to be elucidated, associations have been made with social cognition, dysfunctional beliefs, and the oxytocin system [41,42,43].

2.1. Secondary Negative Symptoms

Secondary negative symptoms refer to negative symptoms that are not intrinsic to schizophrenia. Secondary negative symptoms can be multifactorial and also respond to treatment [44]. They can arise from positive symptoms, depression, PTSD, dementia, substance use, or anxiety [44,45]. For instance, an individual with paranoid or persecutory delusions may be asocial and withdraw further from society due to fear, or an individual with concurrent PTSD may feel overwhelmed in crowds and similarly withdraw from social interactions. This is etiologically distinct from the negative symptom construct described above. Secondary negative symptoms can also arise from medical factors, such as insomnia, comorbid illnesses, and even medications (Figure 1). Patients with schizophrenia are commonly on antipsychotic medications, which are frequently associated with sedation, attenuation of motivation, extra-pyramidal motor disturbances, and other unpleasant side effects [44,45]. For these reasons, antipsychotic medications themselves may create a secondary cause of negative symptoms. The related changes in weight, libido, and appearance may also exacerbate pre-existing difficulties with relationships. Causes of secondary negative symptoms are difficult to disentangle from their primary negative counterparts in clinical trials, making measurement of treatment response even more complicated [44,45]. It is important for assessments to distinguish negative symptoms from external factors and those inherent to an individual’s schizophrenia. Thoughtful and appropriate data collection and measurement are thus of utmost importance in study design.

Figure 1. Actionable factors that cause or contribute to secondary negative symptoms.