Search criteria

The authors followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines to complete this scoping review (S1 PRISMA Checklist) [9]. The research question did not utilize PICO guidelines to avoid limiting the clinical question, and in order to capture the breadth of the literature and identify key concepts. The search was conducted on November 8, 2024, through PubMed, Embase, PsycINFO, and Cochrane Central Register of Controlled Trials (CENTRAL) databases to identify articles in major health/mental health databases and to identify ongoing clinical trials. The primary keyword search used in retrieval of articles was: Doxazosin AND (Substance Use Disorder OR Substance Related Disorder OR Drug Use Disorder OR Drug Use OR Substance Abuse OR Drug Abuse OR Substance Dependence OR Drug Dependence OR Chemical Dependence OR Addiction OR relapse OR alcohol OR cocaine OR opioids OR nicotine OR hallucinogen OR sedative OR steroid OR cannabis OR cannabinoid OR posttraumatic OR post-traumatic OR PTSD OR depression OR anxiety OR mood OR mental health OR mental disorder OR psych). Chosen keywords were based on an initial literature review of mental health conditions treated by doxazosin and keywords used in the search for relevant article references.

Eligibility criteria and data collection

During the first literature review, the lead author (CR) performed automated searches of the keywords in the included databases and removed duplicate articles, managed and automated in EndNoteTM21 software. CR manually reviewed the removed duplicate articles and screened the titles and abstracts for relevance to doxazosin used for mental health disorders (included in DSM-5). During the second literature review, all study members (CR, DA, AK, AB, PS) reviewed full texts for inclusion and exclusion criteria.

Inclusion criteria included doxazosin used for the treatment of any DSM-5 mental health disorder or related symptom(s), including depression, anxiety, and nightmares. Only articles in the English language were included. There was no cutoff for article dates published due to doxazosin for mental health disorders being a relatively new practice, and to be more inclusive. Exclusion criteria included articles not in the English language or not related to doxazosin treatment of a mental health disorder. Other excluded articles included animal trials, systematic reviews and/or meta-analyses, abstracts only, or full results not being available, or commentaries. If there were any discrepancies about inclusion or exclusion criteria, the articles were reviewed with the lead author (CR) for consensus. The authors reviewed the articles and pulled data for review, including study design, participant demographics, primary outcome measures, doxazosin dose and adverse effects, and major findings. Final screening of the articles included in the final review process was completed by the lead author (CR).

PTSD and/or nightmares

Nine articles evaluated doxazosin for PTSD and/or nightmares (Table 1) [10–18]. Doxazosin doses ranged from 1-16 mg per day. Only one RCT was identified, which found a significant reduction in some PTSD symptoms with doxazosin treatment compared to placebo [10]. Two open-label trials found a reduction in PTSD symptoms and sleep disturbance with doxazosin [11,12]. A retrospective chart review found a significant reduction in trauma-associated nightmares with doxazosin in patients with a primary diagnosis of either PTSD or borderline personality disorder [13]. Four case reports illustrated either complete remission (no further reported nightmares during the study period) or significant reduction of nightmares in patients with a PTSD diagnosis [14–17]. In one case report, non-trauma-related nightmares resolved with doxazosin in a patient with a primary diagnosis of major depressive disorder [18].

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Table 1. Summary of included studies of doxazosin used for PTSD and/or nightmares.

https://doi.org/10.1371/journal.pmen.0000494.t001

Substance use disorders

Twelve articles evaluated doxazosin for the treatment of substance use disorders (Table 2) [19–30]. Doxazosin doses ranged from 4-16 mg per day. All articles were RCTs (two clinical trials without associated publications). Seven of the articles studied doxazosin for cocaine use disorder (CUD), with all except for two studies (one being clinical trial data without an associated publication) showing a reduction in cocaine use with doxazosin [19–25]. One article evaluated doxazosin for both cocaine and methamphetamine, which showed increased positive urine toxicology screens with doxazosin use [23]. Two articles found that doxazosin reduces cravings for cigarette smoking [26,27]. The remaining three articles evaluated doxazosin for the treatment of alcohol use disorder (AUD) [28–30].

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Table 2. Summary of included studies of doxazosin used for substance use disorders.

https://doi.org/10.1371/journal.pmen.0000494.t002

Dual diagnoses

Two articles evaluated doxazosin for the treatment of dual diagnosis conditions (Table 3) [30,32]. Doxazosin doses ranged from 1-16 mg per day. An RCT evaluated doxazosin for veterans with co-occurring PTSD and AUD and found no improvement in PTSD scores with doxazosin but an increased likelihood to abstain from alcohol compared to placebo [30]. A case report for a female with PTSD and AUD described continued successful treatment of PTSD symptoms when switched from prazosin to doxazosin [32].

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Table 3. Summary of included studies of doxazosin used for dual diagnosis.

https://doi.org/10.1371/journal.pmen.0000494.t003

PTSD and/or nightmares

A recent systematic review and meta-regression analysis of prazosin found significant improvement in insomnia and nightmares but not overall PTSD symptoms [35]. The RCT by Rodgman et al. studying doxazosin for PTSD did show significant improvement in the PTSD Checklist for DSM-5 (PCL-M) but not in the Clinician-Administered PTSD Scale (CAPS) or depression scales [10]. The authors did note that CAPS is clinician-administered and more intensive, which could trigger more memories and symptoms compared to PCL, which is self-administered [10]. In addition, the study was very short (16-day treatment period) compared to prior prazosin studies (typically 8–15 weeks), the sample size was small (n = 8), and participants were limited to male veterans compared to other PTSD open-label studies and a retrospective review with prazosin in which most of the participants were female [10,36,37]. The two open-label studies studying doxazosin for PTSD found a significant reduction in CAPS, and one saw reductions in PCL and Pittsburgh Sleep Quality Index (PSQI); however, both studies had a small number of participants complete the full trial, with many dropping out due to side effects, especially drowsiness [11,12]. The retrospective chart review also found a reduction in CAPS (B2) and PSQI-A scores in patients with either PTSD or borderline personality disorder [13]. Complicating the picture further, an RCT of doxazosin for comorbid PTSD and AUD diagnoses found a reduction in both CAPS and PCL scores, but not significantly compared to placebo [30]. Notably, though, this study only looked at male veterans as well, indicating participant demographics may influence response and limited generalizability. The five case reports on doxazosin for PTSD and/or nightmares only reported improvement of nightmares (one report with a non-PTSD diagnosis), indicated by clinical interview, PCL-5, and diary-based self-report. The current trials and case reports on doxazosin for PTSD and/or nightmares suggested that doxazosin reduces the intensity and frequency of nightmares and can improve sleep quality in patients with PTSD, similar to findings for prazosin; however, the current evidence is limited to small participant trials and case reports [10–18].

Prazosin has been suggested to reduce daytime PTSD symptoms in addition to nightmares, including re-experiencing (flashbacks) and hypervigilance to trauma reminders when dosed multiple times a day [38–40]. Two of the three clinical trials for treating PTSD symptoms with doxazosin did not specifically document a reduction in daytime symptoms. While the two open-label studies in this review reported a statistically significant reduction in CAPS with doxazosin, the only sub-score changes noted to be significant were related to nightmare reduction [11,12]. The retrospective review combined PTSD and borderline personality disorder diagnoses and only obtained the CAPS B2 score, which just evaluates for nightmare intensity and frequency [13]. The one RCT reported on daytime symptoms for CAPS, including reexperiencing, avoidance, and hyperarousal, which did improve with doxazosin but were not statistically significant [10]. One case report illustrated the reduction of daytime symptoms (disturbing memories, thoughts, or images of a stressful military experience) from 4 (quite a bit) to 2 (a little bit) at four and eight weeks with 4 mg/day of doxazosin [16]. Another case report also described complete resolution of daytime flashbacks with doxazosin 4 mg/day [17]. More studies should be done to evaluate for changes in PTSD daytime symptoms with a single dose of doxazosin.

In addition to IR, doxazosin is available as XL, also known as GITS. An RCT by Andersen et al. in 2000 evaluated the efficacy and tolerability of doxazosin IR and XL for BPH and found that both formulations were effective with similar incidence and types of adverse effects [41]. Doxazosin IR in this study had a slightly increased number of adverse events compared to XL, which likely drove future RCTs for other indications to consider XL as the formulation of choice [41]. The limitation of a study using doxazosin for BPH is that typically the dose must be closer to 8 mg to improve maximum urinary flow rates, while significantly lower doses have been effective for PTSD and nightmares. According to the FDA, there is theoretically less variation in plasma levels with doxazosin XL and thus fewer side effects, although the half-lives of doxazosin IR and XL are relatively the same, and both are well-tolerated with similar rates of adverse effects [1]. The RCT and two open-label studies in this review only utilized doxazosin XL, while the retrospective review and three of the case reports indicated improvement in nightmares with doxazosin IR. The participant dropout rate due to adverse effects was significant in the open-label trials, especially given the low number of participants, which may have been due to needing to start at a higher doxazosin dose (XL starts at 4 mg versus IR starts at 1 mg) and lack of tolerance to this dose [11,12]. Richards et al. noted in their open-label study with doxazosin XL that they only perceived the XL formulation to be advantageous due to its ease of initiation at a higher and more therapeutic dose, but also recognized that the limitation in dose ranges may have limited tolerability [12]. The retrospective review did not specify doxazosin IR or XL use, but IR was more likely primarily used due to reported doses under 4 mg [13]. Only one case report specified doxazosin IR use, and two others reported doses under 4 mg [15,17,18]. Reports describing only 4 mg or 8 mg could indicate the XL version being utilized, as these are the only formulation doses available. Given concern for participant dropout rate due to adverse effects in the studies using doxazosin XL, there should be more studies utilizing doxazosin IR to assess if it is better tolerated due to having a lower needed dose and being able to titrate in smaller increments.

Substance use disorders

Seven articles were identified that addressed doxazosin for CUD, all of which were RCTs. There has been increasing evidence in animal trials that peripheral noradrenergic mechanisms have a role in the mediation of stimulant effects, thus leading to studies of alpha-1 adrenergic antagonists to reduce the physiological effects of stimulants and cravings [42]. Animal trials suggest that prazosin may reduce cocaine cravings [43]. Doxazosin was likely chosen for the human trials in this review primarily for its once-daily dosing and longer half-life. A study by Newton et al. suggested that doxazosin IR 4 mg/day can reduce subjective cravings for cocaine, but it was a small trial [23]. Two RCTs suggested a correlation between adrenoceptor and dopamine-β hydroxylase polymorphisms and doxazosin’s effect on cocaine use [19,20,31–]. Specifically, the RCT by Shorter et al. found that doxazosin reduced cocaine use in the AT/TT (adrenoceptor) and CT/TT (DβH) genotypes compared to the typical genotype and placebo, suggesting a genetic connection to doxazosin’s effectiveness. A trial by Shorter et al. found that more quickly titrated doxazosin (over four weeks) was more effective at reducing cocaine use compared to a slower titration (over eight weeks), but the subject size was low, and the results have not been replicated [21]. An RCT by Mancino et al. found that doxazosin did not reduce use of both cocaine and methamphetamine, but the participant number was very low, and there was no differentiation by genotype or titration schedule [22]. One clinical trial data set did not indicate any reduction in cocaine use with doxazosin [24]. Of note, most participants in these CUD trials were African American males, which inherently limits generalizability.

Two RCTs with presumed same study participants addressed doxazosin for nicotine use disorder [25,26]. The study by Roberts et al. evaluated doxazosin’s effect on cognitive functioning and found improvement on continuous performance tasks (CPT) during nicotine withdrawal, longer resistance to smoking, and less overall smoking with doxazosin compared to placebo [25]. Interestingly, only doxazosin 4 mg/day improved withdrawal symptoms, and participants who received 8 mg/day reported an increase in withdrawal symptoms, thought to be due to paradoxical sympathomimetic effects at higher doses or altered noradrenergic tone with increased susceptibility to stressors, namely nicotine withdrawal [25]. The study by Verplaetse et al. suggested that doxazosin can attenuate stress (delivered via personalized guided imagery) on tobacco cravings, reducing cigarette use, possibly by normalizing cortisol’s response to stress in nicotine-deprived smokers [26]. These two articles did indicate that doxazosin may be used in smoking cessation, but were completed by the same institution on what appears to be the same study participants. More studies are needed to verify these results.

Three RCTs evaluated doxazosin for AUD (including one clinical trial without publication). Two of the RCTs utilized the same participant population and focused on patient characteristics affecting doxazosin’s effects on alcohol use [27,28]. The parent study by Kenna et al. found preliminary data that doxazosin may be effective in reducing alcohol craving and consumption in those with high FHDA [28]. The following study by Haass-Koffler et al. suggested that standing blood pressure may be an independent biomarker of doxazosin’s response in AUD, as higher diastolic blood pressure predicted a more robust response to doxazosin in reducing alcohol use [27]. A clinical trial without publication evaluated startle potentiation during a stress reactivity task (shock) for participants given doxazosin versus placebo, but did not appear to find any major differences and trended towards the doxazosin group having increased unpredictable startle potentiation [29]. In addition, reported heavy drinking scores between groups did not appear to be statistically significant, but other RCTs did indicate that participant features (genetics and blood pressure) may indicate doxazosin’s effectiveness, which this trial did not stratify [29]. Current studies on doxazosin for AUD, especially for specific patient populations, are promising, but more RCTs should be completed to more confidently recommend doxazosin as part of AUD treatment.

Similar to doxazosin studies for PTSD and/or nightmares, it appears that most of the studies for substance use disorders likely utilized the doxazosin XL formulation. However, only two articles specified formulation (Mancino et al. used XL and Newton et al. used IR [22,23]), so it is assumed that, because the other study methods only indicated starting doses of 4 mg, and maximum doses of 8 or 16 mg, the XL formulation was used. Adverse effects did not appear to lead to large dropout rates, possibly indicating higher tolerability in substance use disorder participants.

In comparison to studies about doxazosin for PTSD and nightmares, all the studies on substance use disorders had a significantly skewed population towards males, which is not surprising, as males are 2–3 times more likely to have a substance use disorder compared to females [44]. Another noted limitation that prevents generalizability is that most participants in the CUD studies were African American males, and most of the participants in the alcohol use disorder studies were white males. Although males are statistically more likely to have a substance use disorder, the use of substances in females has also been rising, leading to increasing rates of substance use disorders due to the telescoping effect, or the faster progression to substance dependence in females compared to males [45]. These points should be considered in future studies, as race and gender differences can change dosing and tolerability of medications.

Dual diagnoses

Two articles addressed doxazosin for co-occurring PTSD and AUD. An RCT by Back et al. found a reduction in the number of drinking days with doxazosin IR, but with greater consumption on drinking days and no significant difference in PTSD scores [30]. This study only included veterans and may not be generalizable, and outcome measures were only self-reported. Results were consistent with similar studies with prazosin, which also showed a reduction in alcohol use but with no significant changes in PTSD scales [46]. Another study evaluating prazosin for PTSD and AUD in veterans found no benefit for alcohol reduction or PTSD symptoms [47]. A case report by Hessel et al. found that switching from prazosin to doxazosin in a patient with PTSD and AUD did not result in a recurrence of PTSD symptoms (most recently nightmares and insomnia) in a patient admitted for AUD-associated pancreatitis, but they did not discuss the effects of alpha-1 antagonists on alcohol use [32]. It was not documented whether the IR or XL formulation was used in the case report, but given that prazosin 2 mg was switched to doxazosin 4 mg, it can be assumed that the XL formulation was used, as there would be no indication for doubling the dose upon switching. Overall, there is not enough quality evidence to make any recommendations about doxazosin’s use for dual diagnoses. AUD may alter doxazosin’s effect on PTSD symptoms, especially with studies showing that doxazosin’s effect on alcohol use may be moderated by genetics and other physiological factors, but this would need to be researched further.