Frequent and vivid recall of dreams occurs in approximately 80% of cases where individuals are awakened from rapid eye movement (REM) sleep [1]. Dreams can also occur during non-REM (NREM) sleep. However, dreams occurring during REM sleep are often more complex, vivid, bizarre, last longer, and are associated with content that revolves around visually perceptual and emotional memories [2]. Some dreams become nightmares, defined as vivid dreams with strong and negative emotional content. They often lead to such high levels of activation that the dreamer awakens [3]. Nightmares occur during REM sleep, but posttraumatic nightmares can also occur during NREM sleep. After waking from nightmares, the dreamer rapidly becomes alert and oriented and can easily remember and reproduce the content, which in most cases involves threats to life, security, or self-esteem [4].

The most common emotions associated with nightmares are fear-related, but other less common emotions such as anger and disgust have also been reported [5]. Several scholars distinguish between idiopathic and posttraumatic stress disorder (PTSD)-related nightmares, and physiological differences between those suffering from the two forms of nightmares have been described [6]. Idiopathic nightmares are often illogical and bizarre [6]. PTSD-related nightmares are often considered a more severe form [5]. PTSD is a psychiatric disorder that may develop after a traumatic experience, and flashbacks of the event alongside, or in the form of, nightmares, are two core symptoms.

In the general adult population, the prevalence of nightmares is relatively high, where 2–6% of adults report having weekly nightmares, while 35–45% report having nightmares at least once a month [7,8,9,10,11,12]. According to most studies, nightmares also appear to be age-related, with the highest prevalence among children and adolescents [13,14]. The prevalence of nightmares is elevated in populations with mental disorders, especially in anxiety, mood, and psychotic disorders [15,16,17,18]. Furthermore, nightmares are more common in populations with a high probability of being exposed to traumatic events, such as war veterans [11]. The healthcare and societal costs of nightmares seem largely unknown, but the costs of PTSD, where nightmare is a common symptom, amounted to USD 232.2 billion for 2018 in the USA alone [19]. Nightmares are reported more frequently after being exposed to traumatic life events (e.g., physical and sexual abuse, witnessing or victimization of accidents, domestic violence, war experience, and terrorism), and during periods of high levels of stress in general [10,20,21,22,23,24]. The association between nightmares and stress-related symptoms and conditions is in line with the notion that nightmares can be linked to dream functions involving regulation of fear and other emotions [4,5,25]. Women report more nightmares than men, although this difference is largest among young adults [5,11,26]. Several drugs such as amphetamines, anticholinergics, benzodiazepines, dopamine agonists, ethanol, hallucinogenics, and tricyclic antidepressants may induce nightmare, either following intake or due to withdrawal effects [27].

Some regard nightmares as non-functional, whereas other scholars view nightmares as a mechanism for emotion regulation. The functional theories vary when it comes to the specific mechanism involved, including among others, stress mastery, desomatization of affect, fear memory extinction, and emotional contextualization [28]. Regardless of its functionality, frequent nightmares significantly deteriorate quality of life and are also associated with suicidal thoughts, suicide attempts, and suicide [28]. Nightmares may also lead to avoidance of going to sleep in fear of further nightmares, which may lead to sleep deprivation, which in turn exacerbates nightmares [29]. Nightmares may also predispose for insomnia [30]. This emphasizes the importance of efficacious treatments.

Currently, several psychological treatments have been developed, of which Imagery Rehearsal Therapy (IRT) is recommended for both PTSD-related and idiopathic nightmares [31]. IRT involves a positive rewriting of the negative content in nightmares. The rewriting should be visualized in the awake state for 10–20 min every day [32,33], and it is assumed that the positive images gradually become more dominant and accessible when dreaming. Other psychological treatments that are empirically supported for idiopathic nightmares are systematic desensitization, self-exposure therapy, lucid dreaming, and multicomponent therapies [31]. The multicomponent approach has received increased attention during the last years, with exposure, relaxation, and rescripting therapy (ERRT) as a prominent example, where IRT is supplemented with an exposure component [34].

Regarding pharmacological treatment, studies have largely focused on their effect on PTSD-related nightmares. Several pharmaceuticals have been studied, in particular prazosin, which is an α₁-adrenergic antagonist assumed to inhibit fear responses by, among others, blocking α₁-adrenergic receptors in the brain [35]. Prazosin was marketed as an antihypertensive drug but was by chance found to reduce PTSD-related nightmares [36]. That finding led to several placebo-controlled, randomized clinical trials comparing the efficacy of prazosin against placebo [37,38,39,40,41,42,43,44,45,46]. Several recent meta-analyses show that prazosin is associated with statistically significant improvement in PTSD-related nightmares [47,48,49,50], and Morgenthaler et al. [31] highlight prazosin as one of the preferred drugs to prescribe for PTSD-related nightmares.

One of the studies examining prazosin [37] also examined the effect of hydroxyzine, a histamine-H₁-antagonist that has been shown to influence sleep and stress in patients with PTSD [51,52]. Exactly how hydroxyzine influences sleep is unknown, but it is known that hydroxyzine, in addition to acting as an H₁-antagonist, also has some affinity for the serotonin 5H_2A-, the dopamine D₂-, and the α1-adrenergic receptors [53,54,55]. Regarding other pharmacological agents studied regarding the effect on nightmares, one finds cyproheptadine, a 5-HT₂ antagonist, which has been used to increase the amount of NREM sleep [56] and improve sleep in general [57].

Clonazepam, a high-potency drug that binds to benzodiazepine α-receptors and potentiates GABA-ergic inhibition has also been investigated. The drug is used to treat epileptic seizures [58], but an open study [59] showed that clonazepam had a good effect on PTSD-related nightmares. Treatment studies have further examined the effects of nabilone [60] and doxazosin [61]. Nabilone is a synthetic cannabinoid that activates cannabinoid-₁ receptors (CB₁) and has long been approved for the treatment of chemotherapy-induced nausea and vomiting [62]. However, it has also reduced PTSD-related nightmares [63]. Doxazosin, which is also prescribed against nightmares, is, like prazosin, an α_1-antagonist [64].

When it comes to pharmacological interventions, there is currently no firm basis for making clear recommendations, as studies based on placebo-controlled designs are relatively few. Under these circumstances, it is essential to produce summaries of effects across the existing studies. As far as we know, it has been almost 10 years since the last time this was done [65]. Against this backdrop, we conducted a systematic literature review and meta-analysis to investigate how different pharmacological interventions affect nightmare symptomatology in studies where placebo comprised the control condition. Specifically, we aimed to estimate an overall effect size based on a random effects model, as well as effect sizes (Hedges’ g) for the different drugs separately, as well as estimating heterogeneity and trim-and-fill results as adjustment for potential publication bias. In order to evaluate the robustness of the findings, we used the Knapp–Hartung adjustment [65], and also ran a separate meta-analysis only including studies with low risk of bias.

Such a literature review should guide clinicians by pointing out the best documented and most effective pharmacological approaches, and pointing out future research needs in the field.

In this systematic literature review and meta-analysis, the main findings showed a significant overall and positive effect size of pharmacological interventions for nightmares. Our findings thus differ from the meta-analysis of Augedal and colleagues [65], where the authors concluded that pharmacological interventions for nightmares did not have a significant effect. The discrepancy in results probably reflects that several studies have emerged since then. Recent studies have also examined effects of new types of pharmaceuticals, such as nabilone [60]. Despite the fact that we found an overall significant effect of pharmacological treatments of nightmares, it can be considered small to moderate (g = 0.42) following adjustment for publication bias.

The heterogeneity of the analysis was significant and indicated differences in treatment effects between the various drug interventions. A possible explanation may be that the included studies examined drugs with different mechanisms of action. Still, the heterogeneity may also reflect several differences between the studies in terms of sex, age, comorbidity, dosage, treatment duration, and outcome measures. The overall effect size can thus be somewhat misleading regarding the effect of the individual drugs. Therefore, a sub-group analysis, broken down by specific groups of drugs, was conducted. Nabilone was the drug with the largest effect (g = 1.86) and is included in current treatment recommendations [31]. It is still worth mentioning that the finding is based on a single RCT-study [60] and that the sample size was small. In addition, the study had some risk of bias. Still, the findings of Jetly and colleagues [60] are nevertheless promising, and it is essential to note that nabilone appears to be well tolerated [81]. Thus, further research on nabilone in the treatment of nightmares is encouraged.

The second most effective pharmaceutical was hydroxyzine (g = 1.17). As for nabilone, only one RCT examined this pharmaceutical [37]. That study, with a sample size of 34 participants in the hydroxyzine condition, showed that hydroxyzine was well tolerated and associated with few side-effects. On the other hand, the study had some limitations and was regarded to have a high risk of bias related to missing outcome data.

Prazosin is the drug that has been most studied and was, in the present meta-analysis, investigated across 10 trials, with an overall effect size of g = 0.54. This finding is in line with previous meta-analyses of prazosin’s effect on nightmares [47,48] and in line with “Best practice” guidelines based on an initiative from the American Academy of Sleep Medicine [29]. Notably, the effect of the individual prazosin studies in the analysis diverged. In this regard, the finding by McCall et al. [39] stood out, where prazosin had a negative effect on nightmare symptomatology (g = −1.81). McCall et al. [39] point out that this divergent finding may result from the sample they included, which was small and comprised highly suicidal patients taking a complex composition of psychotropic drugs. Raskind et al. [40] reported no effect of prazosin (g = 0.00). That study was the largest of the ones included. Following the finding by Raskind et al. [41], the treatment recommendation regarding prazosin was downgraded; still, Morgenthaler et al. [31] argue that prazosin is a drug that seems well tolerated, without special side-effects, and thus is relevant in treating PTSD-related nightmares. Taken together, the divergence in the findings regarding prazosin emphasizes the need for more studies with larger samples before conclusions can be drawn.

Cyproheptadine did not show a significant therapeutic effect. Still, Morgenthaler et al. [31] highlight cyproheptadine as one of the pharmaceuticals that can be prescribed for PTSD-related nightmares. Their recommendations are, in addition, based on findings from case studies and non-placebo-controlled studies; still, Morgenthaler et al. [31] acknowledge that the literature is contradictory. Neither clonazepam nor doxazosin were associated with a significant treatment effect. It should be noted that doxazosin is very similar to prazosin in terms of mechanisms of action [64], and should therefore not yet be written off as a relevant pharmacological intervention for nightmares.

All the drug interventions in the included studies address PTSD-related nightmares. It is questionable whether the findings can be generalized beyond this study group. Comparing the effects of pharmaceutical treatment of nightmares for idiopathic and PTSD-related nightmares could be of interest. Women were strongly underrepresented in the included studies, even though women report more nightmares than men [11,26,28], are overrepresented in populations with PTSD, and report higher symptom levels in terms of anxiety and depression, both being associated with an increased incidence of nightmares [82,83]. Therefore, future studies should aim for a more even distribution of gender so that the findings can also be generalized to women with greater certainty.

Furthermore, there were only four studies [37,39,45,46] out of a total of fourteen in which the samples consisted of populations with PTSD where the PTSD-related nightmares were unrelated to war. Based on this, it is questionable whether the findings of the present meta-analysis can be generalized to populations suffering from PTSD-related nightmares in general.

As far as we know, none of the included studies were based on diagnostic criteria for nightmare disorder. It is conceivable that many of the participants in the included studies would meet these criteria, but this still makes our findings difficult to generalize to populations with nightmare disorder in general. The studies included in this meta-analysis also had other limitations. Very few of them had long-term follow-up after treatment, only two studies [41,75] were anchored in a priori power calculations, and few studies were considered to have a low risk of bias. Overall, this indicates that most of the studies had noticeable methodological limitations. The dropout rate was also relatively high in the included studies, with an average of 20% dropping out before the end of treatment.

Some limitations of the current meta-analysis should also be noted. The language restrictions may have led us to miss out on some relevant studies. Databases for gray literature were not used in the literature search and may have led to overestimating the effect [83]. On the other hand, it has been argued that unpublished data are unlikely to impact meta-analyses significantly [84,85]. It has also been argued that identifiable unpublished data are not representative of unpublished data in general [70]. The findings regarding nightmare symptomatology in the present meta-analysis were significant, and Orwin’s Fail-safe N [71] showed that 19 studies with no effect were necessary to bring the overall effect size down to a trivial level (g = 0.20). When using the Knapp–Hartung adjustment, the overall effect size still remained significant, but when limiting the analysis to studies with a low risk of bias, the overall effect size became non-significant. This may suggest that the findings are not very robust. Still, we argue that the overall effect size is of less importance, and recommend putting more emphasis on the effect sizes calculated for the drugs separately when interpreting the results. Despite a high degree of agreement (75.7%) between the raters in terms of risk of bias, it is also worth noting that the updated version of the Cochrane Risk of Bias 2 tool (RoB 2). [86] has been criticized for producing a low degree of inter-rater reliability, in addition to being complex and challenging to apply [87]. Most of the included studies in our meta-analysis are based on small samples. A strength of our meta-analysis is that we used a “random-effects model”. Noble [88] states that this method is preferable to a “fixed-effects model” in testing null hypotheses. Meta-analyses, in general, are further highlighted as a good tool for investigating the extent to which experimental findings can support or disprove connections and effects [87].

It should be noted that many studies with other designs than RCTs have been used to investigate treatment effects of pharmacological interventions for nightmares [89]. Still, we limited the current review to RCTs, as this design is regarded as the standard to provide unbiased estimates of treatment effect [90].

Even though we are starting to gain some knowledge about the treatment of nightmares, the field still lacks knowledge. When it comes to the various pharmacological therapies, prazosin is the one we have the best reasons to recommend, even though only a moderate effect of prazosin was found in the present meta-analysis. Nabilone and hydroxyzine both show promising effects, but there are too few controlled studies to conclude about their applicability. Still, these pharmaceuticals should be of interest for further research. The present meta-analysis does not provide a basis for recommending treatment with clonazepam or cyproheptadine.

For future research, trials of pharmacological interventions should be based on proper power analysis, include adverse drug effects in the analysis, aim for more even gender distributions, and include longer follow-ups. Inclusion of multiple outcomes, comprising nightmare frequency, distress, and intensity, is encouraged. Comparing the effects of pharmacological interventions on PTSD-related versus idiopathic nightmares will also be of interest. Future RCTs should also compare the effect of pharmacological and psychological interventions, separately and in combination.