Treating posttraumatic stress disorder and alcohol use disorder comorbidity: Current pharmacological therapies and the future of MDMA-integrated psychotherapy

Abstract

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur in patients who have experienced trauma. This comorbidity leads to a vicious cycle where PTSD symptoms beget heavy drinking and vice versa. There are no FDA-approved medications to treat PTSD-AUD; therefore, individuals suffering from this comorbidity are treated with medication approved to treat the disorders separately or with off-label pharmacological interventions. However, these medications are limited in their efficacy for treating PTSD-AUD comorbidity. Emerging research on the nonclassical psychedelic drug 3,4-methylenedioxymethamphetamine (MDMA) suggests that it may be an effective drug used in conjunction with psychotherapy. The following reviews the current research for clinical pharmacotherapies, as well as MDMA-integrative psychotherapy as they pertain to PTSD and AUD in isolation and co-occurrence. Future directions for the role of psychedelic-integrative therapy for the treatment of this comorbidity are discussed.

Keywords

Alcohol use disorder posttraumatic stress disorder comorbidity psychedelics

Introduction

Alcohol use disorder (AUD) is a condition with longstanding prominence in the United States (Grant, 1994). The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (American Psychiatric Association, 2013) characterizes AUD by the meeting of 2 out of 11 criteria in which levels of alcohol consumption negatively affect one’s physical, mental, and/or social health (Haass-Koffler and Kenna, 2013; Kranzler and Soyka, 2018). Furthermore, in severe cases, physical dependence on alcohol may keep one from stopping drinking without experiencing physical withdrawal and craving (Liang and Olsen, 2014). The epidemiological prevalence of AUD in a nationally representative sample is 13.9% at 12-months pre-interview and 29.1% in lifetime occurrence (Grant et al., 2015). Health risk assessment of AUD denotes that much of the burden and mortality associated with alcohol may come indirectly via liver disease, as well as in the form of economic and social loss (Rehm and Shield, 2019).

Posttraumatic stress disorder (PTSD) was defined in early psychological sciences as detriments to physical and mental well-being following experiences of extreme shock (Solomon and Davidson, 1997). Veteran mental health advocacy groups caring for individuals who fought in the Vietnam War brought PTSD into medical and psychiatric parlance in the United States (Helzer et al., 1987). Later, PTSD became understood to include far more traumatic events than those related to combat, including domestic violence, sexual violence, and childhood abuse (Solomon and Davidson, 1997). Current epidemiological data cite sexual assault as the most prevalent type of trauma exposure in the United States (Zohar et al., 2022). The clinical definition of PTSD evolved to include the experiencing of a significant traumatic event that has caused impairment to occupational and social functioning for longer than 1 month (Schrader and Ross, 2021). The DSM-5 denotes four distinguishing features: traumatic exposure, reexperiencing, avoidance, and heightened arousal. Symptoms that may be displayed include intrusion of traumatic memories, negative alterations in cognition and mood, sleep disturbances, hypervigilance, heightened arousal states, irritability, and exaggerated startle responses (American Psychiatric Association, 2013).

While PTSD and AUD are important to examine in isolation, the occurrence of AUD following a traumatic life event is highly prevalent irrespective of a formal PTSD diagnosis (Fetzner et al., 2011). Epidemiological review of PTSD-AUD comorbidity shows that alcohol is the most commonly used substance in patients with PTSD, culminating in a threefold risk of developing AUD and a twofold risk of lifetime prevalence compared to patients without a PTSD diagnosis (Gilpin and Weiner, 2017). The impact of this comorbidity is particularly troubling as AUD increases the severity of PTSD symptoms (Dworkin et al., 2018), diminishes neuropsychological functioning (Samuelson et al., 2006), and increases attrition rates in treatment and clinical research (Straus et al., 2018). Suicidal ideation and suicide attempts were more significantly associated with PTSD-AUD than with either PTSD or major depression alone (Rojas et al., 2014). This cycle appears to permeate on a lifelong and generational level, as exposure to a family history of AUD is associated with adult PTSD, particularly in females with corresponding early sexual trauma (Subbie-Saenz de Viteri et al., 2020). The burden of this comorbidity may be elucidated by its effect on quality of life. Men in treatment for AUD who meet the criteria for lifelong PTSD exhibit detriments in physical and mental quality of life, particularly in patients who experience dissociative symptoms (Evren et al., 2011).

Treatments for PTSD and AUD include psychotherapy and psychopharmacological interventions (Debell et al., 2014; Maria-Rios and Morrow, 2020; Mavranezouli et al., 2020; Witkiewitz et al., 2019). The following is a narrative review of pharmacological and psychodynamic treatments for PTSD and AUD as primary and comorbid disorders. Current limited research on this approach will also be reviewed and compared to currently available pharmacotherapies. The primary aim of the current paper is to briefly summarize current treatment practices for PTSD, AUD, and their comorbidity to contextualize upcoming research on the novel approach of using the psychedelic compound 3,4-methylenedioxymethamphetamine (MDMA), in conjunction with psychotherapy, as a treatment for PTSD-AUD.

Pharmacological interventions for AUD and PTSD

AUD primary

In the United States, there are four FDA-approved pharmacological interventions for AUD. Disulfiram, the first FDA-approved pharmacotherapy for AUD, creates an aversive physical response when combined with alcohol, causing nausea and vomiting, thereby promoting abstinence through an induced aversion to drinking (Mutschler et al., 2016). A systematic review of 11 randomized control trials (RCT) indicated that this medication is effective in promoting abstinence compared to placebo over short periods of time (Jorgensen et al., 2011). However, a careful review of its long-term usage shows limitations as an effective agent, as disulfiram relies on strict adherence to promote abstinence (Suh et al., 2006). In reviewing over 60 years of research since disulfiram’s introduction an emergent theme is that the medication works well when administered under supervision, but lack of supervision leads to a lack of compliance, and thereby lack of efficacy (Fuller and Gordis, 2004).

The opiate antagonist naltrexone is used to decrease alcohol craving in heavy drinkers, thereby preventing or limiting drinking recurrence during periods of abstinence. A 6-month RCT showed significant decreases in heavy drinking and craving when patients (n = 118) were treated with naltrexone (Balldin et al., 2003). Like disulfiram, limitations in naltrexone’s efficacy are related to medication adherence. A long-lasting intramuscular (IM) injection form of naltrexone is also approved for the treatment of AUD. IM naltrexone circumvents shortcomings by reducing medication regimens to monthly administration. One RCT (n = 624) showed a significant decrease in heavy drinking compared to placebo over 6 months when naltrexone IM was administered in conjunction with 12 sessions of low-intensity supportive therapy (Garbutt et al., 2005). This study did not exclude patients who were actively drinking. The most dramatic decreases in heavy drinking days were in those who were drinking the heaviest upon enrollment.

Lastly, acamprosate reduces overall heavy drinking and manages protracted alcohol withdrawal symptoms (Mason and Crean, 2007). Protracted withdrawal is distinct from acute symptoms like delirium tremens, which typically last between 5 and 7 days. Protracted withdrawal is characterized by sleep disturbance and anxious cravings that may lead to drinking. A meta-analysis of 17 RCTs found robust support for acamprosate’s ability to promote abstinence rates of at least 6 months (Mann et al., 2004). Limitation again lies in adherence as acamprosate must be taken three times a day.

While the above medications are the only options approved for AUD, other drugs are prescribed off-label based on emerging clinical evidence (Litten et al., 2016). Research examining outpatient AUD treatment in the United States between 2014 and 2016 suggest that off-label medications are more commonly prescribed than those with FDA approval (Wallach et al., 2022). These findings suggest that many potential pharmacological treatments for AUD are yet to be fully explored. For a more in-depth review of pharmacotherapies for AUD, see Bahji et al. (2022).

PTSD primary

There are only two FDA-approved pharmacological interventions for PTSD as a primary disorder—the selective serotonin reuptake inhibitors sertraline and paroxetine. Other medications, such as the selective serotonin and norepinephrine reuptake inhibitor (SSNRI) venlafaxine, are used off-label (Ralevski et al., 2014). The antihypertensive prazosin (α1-antagonist) (Petrakis et al., 2016) and the antiepileptic topiramate (Yeh et al., 2011) are also currently being investigated for PTSD treatment, particularly in regard to symptoms that disrupt sleep.

Sertraline use in patients with PTSD has been shown to reduce a broad range of symptoms compared to placebo, especially symptoms that relate to psychological or emotional regulation (Davidson et al., 2002). Results from RCTs indicate significant decreases in reported symptom intensity and investigator-rated clinical impressions after 12 weeks of use (Brady et al., 2000). Sertraline was studied alongside prolonged exposure (PE) therapy, which teaches patients to gradually approach trauma-related triggers, in a doubly randomized preference trial where 200 participants were randomized to either their choice of treatment or no choice (Zoellner et al., 2019). Some comparable beneficial effects were found between sertraline and PE, but advantages for PE emerged over time (which was also the preferred treatment by participants).

Research on the efficacy of paroxetine has yielded similar results. A pilot study contrasted 3 months of treatment with paroxetine with cognitive behavioral therapy (CBT) (Frommberger et al., 2004). Initial results indicated comparable effects between the two treatments, with slight differences at 6-month follow-up where CBT’s effects appeared marginally more enduring. In parallel with sertraline research, paroxetine was also studied alongside PE for individuals with PTSD from motor vehicle accidents (Popiel et al., 2015). Again, PE yielded greater remission results than pharmacotherapy. Furthermore, paroxetine’s efficacy has been examined in mitigating the onset of PTSD in civilian patients (Borrelli et al., 2019). Patients receiving paroxetine showed marginal improvement in quality of life and social functioning from baseline, but no difference from placebo in other PTSD outcomes.

Venlafaxine is an SSNRI commonly prescribed for depression and examined as a potential agent for PTSD. One short-term trial comparing the medication to both placebo and sertraline found that it was superior to the placebo, and broadly similar in efficacy to sertraline in reexperiencing, avoidance/numbing, and hyperarousal subscales (Davidson et al., 2006). These symptom reductions, as well as secondary effects of remission on the clinician-administered PTSD scale (CAPS), were observed after 24 weeks of treatment compared to placebo.

Prazosin has mixed evidence in RCTs for reducing PTSD sleep disturbances. A low dose of prazosin for patients with PTSD was associated with night-terror reduction and, in some cases, a mean increase in total sleeping time by 94-min (Green, 2014). These findings were extended to combat veteran populations within multiple studies, wherein prazosin was administered thrice a day and titrated up to dosages between 9 and 16 mg (Raskind et al., 2002, 2013). In a secondary analysis, the treatment effects of prazosin were shown to be particularly evident in participants with higher baseline blood pressure (Raskind et al., 2016). Taken together, these promising results offer a pathway for how prazosin may be most effectively used to treat PTSD. Limitations to consider are hypotensive effects that may arise, especially at higher doses.

Topiramate is well tolerated in RCTs among civilians with PTSD. Along with reducing CAPS total severity scores, one study reported efficacy in reducing specific clusters of symptoms compared to placebo: traumatic event re-experiencing and psychological numbing (Yeh et al., 2011). Limitations include the modest statistical power of some results supporting topiramate, along with other research suggesting that combat-related PTSD symptoms may not be as responsive to topiramate as other types of trauma in civilian populations (Tucker et al., 2007).

In summary, while sertraline and paroxetine are effective to an extent, they are not guaranteed to forge a path to remission (Krystal et al., 2017). Prazosin and topiramate are promising new medications with differing action mechanisms for varying symptom clusters, but their specificity offers only modest strength in treatment potential.

PTSD-AUD comorbidity

Pharmacological trials discussed thus far have focused on PTSD in isolation, often requiring participants to not have co-occurring substance use disorders (SUDs) as a criterion for participation. While this type of inclusion criteria may make for a more uniform sample in the laboratory, it does not reflect the reality of differentiating trauma cases in the real world (Haass-Koffler, 2023). There are varying hypotheses that attempt to explain the reason behind PTSD and AUD comorbidity. Chronic stress-inducing dysregulation of the hypothalamic–pituitary–adrenal axis has been shown to lead to increased alcohol use (Zhang et al., 2020), with PTSD symptom severity serving as a moderating factor in this process (Goldstein et al., 2023). A self-medication hypothesis is posited to play a role in the development of PTSD and AUD comorbidity, with repeated trauma exposure and further alcohol use perpetuating cyclically. Also, early trauma exposure by way of childhood maltreatment may be at the root of this cycle (Schimmenti et al., 2022). Others hypothesize that a general predisposition to anxiety may make an individual equally vulnerable to developing PTSD and AUD, compounded by potential trauma exposure when self-medicating with alcohol (Maria-Rios and Morrow, 2020).

Because AUD is such a prevalent comorbidity with PTSD, the role existing medications play in the treatment of this dual diagnosis is key in the review and discussion of what treatment is available thus far. Currently approved AUD medications have been tested in some studies with a PTSD-AUD population (Petrakis et al., 2006). While only a subgroup of this study’s sample was diagnosed with PTSD-AUD, the group’s abstinence from alcohol was aided by either or both study medications and was reported to have led to improvements in their PTSD symptoms.

Sertraline was tested in a PTSD-AUD sample (n = 94) with mixed results that varied based on severity and onset of diagnoses (Brady et al., 2005). In this study, AUD with later onset and lower severity, coupled with early-onset PTSD, showed the most significant decreases in drinking behavior. These findings may support the use of sertraline in early intervention among patients with PTSD at risk of developing severe AUD.

Paroxetine has been examined among multiple AUD comorbidities including PTSD, social anxiety, and major depression with mixed drinking and trauma outcomes (Book et al., 2008, Na et al., 2021). In PTSD-AUD, paroxetine showed no difference in decreasing trauma symptoms when compared to the drug for depression desipramine. In this subsample, paroxetine was shown to be less effective than desipramine. Analyses of differing comorbidities and medication combinations in this study demonstrated the varying outcomes that emerge with differing diagnoses (Petrakis et al., 2012).

Prazosin has been evaluated as a treatment option for PTSD-AUD comorbidity, but results remain mixed. A 6-week pilot study (n = 30) found prazosin was effective in reducing the number of drinking days in PTSD-AUD patients, although trauma symptomatology did not show improvement (Simpson et al., 2015). A 13-week RCT with a veteran sample (n = 96) titrated prazosin to 16 mg, the standard maximum recommended dose (Petrakis et al., 2016). Results did not support prazosin treatment, as neither drinking behavior nor PTSD symptoms showed a significant reduction that could be linked to the medication. Despite the results in single disorder samples, the limited number of AUD-PTSD comorbidity studies, and their mixed results, the efficacy of α1-adrenergic receptor antagonists is still under investigation for PTSD-AUD. Interestingly, secondary analyses of two independent trials that used one of two α1-receptor antagonists reported that high blood pressure was a predictor of prazosin’s response on PTSD symptoms in US veterans with PTSD (Raskind et al., 2016) and of doxazosin’s response on alcohol consumption in individuals with AUD (Haass-Koffler et al., 2017, 2018).

Topiramate has also been examined for its efficacy in treating PTSD-AUD. One study (n = 30) examined drinking behavior as a primary outcome of topiramate treatment but found no support for the decrease in drinking frequency (Batki et al., 2014). Secondary PTSD outcomes of topiramate were supported, particularly in decreases in re-experiencing symptoms. The cluster of PTSD symptoms related to hyperarousal were decreased in this trial due to topiramate but were not examined in previous trials. The authors suggest that the efficacy of topiramate may vary depending on comorbidities.

Integrated psychotherapy and pharmacotherapy

A meta-analysis of 36 studies on comorbid PTSD and AUD highlights the importance of augmenting pharmacological treatment with psychotherapeutic approaches, particularly trauma-focused behavioral health therapies (Hien et al., 2023). A number of therapies previously used to treat either PTSD or AUD have been implemented in comorbid populations. These styles include CBT, cognitive processing therapy (CPT), relapse prevention training, and seeking safety (SS) (Schafer et al., 2019; Taylor et al., 2017). CPT is similar in practice to CBT but with a trauma-informed therapist. SS can be best defined by its focus on safety for the patient as an overarching goal. Current literature endorses the safety and efficacy of exposure-based therapies to not exacerbate PTSD, AUD, or other substance symptoms (Lancaster et al., 2020; Norman et al., 2019). By combining these treatments with pharmacotherapy, a patient may remove symptomatic obstacles and become better equipped with the necessary tools to make therapeutic progress.

An integrated therapy for PTSD-AUD, as well as other SUDs, is concurrent treatment of PTSD and substance use disorders using prolonged exposure (COPE) (Back et al., 2019). Although this model does not incorporate pharmacotherapy, it does attempt to treat PTSD-AUD via combined approaches of relapse prevention and exposure to triggers (Najavits et al., 2020). A trial comparing COPE to relapse prevention alone in a military population found beneficial results in all conditions, but greater efficacy for COPE in reducing participants’ number of drinks per drinking day and the severity of PTSD symptoms (Back et al., 2019). Another study tested the integration of PE and motivational enhancement therapy in either an integrated or staggered approach, finding modest differences, but overall general benefits for comorbid PTSD-SUD from any version of therapeutic intervention (Kehle-Forbes et al., 2019).

In the first RCT to combine psychotherapy with pharmacotherapy in PTSD-AUD veterans, PE with either naltrexone or placebo was compared to supportive counseling with matched naltrexone/placebo conditions (Foa et al., 2013). In both conditions, naltrexone decreased daily alcohol consumption compared to placebo. Participants in both conditions also showed a decrease in PTSD symptom severity. However, no significant difference between PE and supportive counseling was found. This null finding is contrary to the sizable literature supporting PE’s efficacy in reducing PTSD symptoms. Reasoning for this contradiction varies from adherence to traits of supportive counseling. Importantly, no alcohol or PTSD symptom increases were found in this study regardless of condition.

Another integrated treatment trial of PTSD-AUD combined sertraline treatment with weekly SS therapy (Hien et al., 2015). All participants (n = 69) were enrolled in 12 sessions of SS and randomized to receive sertraline titrated from 50 to 200 mg or a matched placebo. Results revealed clinically significant improvements in PTSD and AUD for all participants regardless of medication; however, PTSD symptomology was significantly decreased when sertraline was added compared to placebo. Bolstering psychotherapeutic treatment with pharmaco-intervention may allow patients to move beyond barriers that would normally stand in the way of the therapeutic process.

While the above study is promising, it is one of the very few integrated treatment trials for PTSD-AUD. Such a scarcity in this literature is crucial to address considering the prevalence of this comorbidity. Alternative treatments include mindfulness meditation practice, yoga, and acupuncture (Ralevski et al., 2014). At this time, these may be considered alternative or complementary, but a growing interest in these approaches from both the scientific community and patient populations may reveal their utility. Similarly, one such example of a renaissance can be seen in the field of psychedelics.

MDMA integrative therapy for PTSD, AUD, and beyond

MDMA was synthesized in the early 20th century but rose to prominence over 60 years later when it was utilized as a tool by psychotherapists to promote openness and therapeutic alliance with their patients (Garcia-Romeu et al., 2016). The drug garnered attention and subsequent illicit Schedule 1 status due to its recreational prevalence and structural similarity to methylenedioxyamphetamine, which holds neurotoxic properties (Latimer et al., 2021). During the new psychedelic renaissance in recent years, MDMA has been broadly labeled as a “nonclassic” psychedelic due to its chemical structure and emotional effects distinct from psilocybin or lysergic acid diethylamide (LSD). It has been described as an “entactogen” a word derived to represent the process of reaching within oneself to grasp things that have otherwise been repressed (Nichols, 2022). In human subjects, MDMA is known to induce an altered state of consciousness accompanied by feelings of euphoria, closeness to others, mental stimulation, and empathy. It has been described as a “heart” trip for its prevalence of positive effect, as opposed to the “head” trip of classic psychedelics.

On a neurochemical level, MDMA is primarily effective as an agonist to the serotonergic system, releasing and inhibiting reuptake of presynaptic serotonin as well as dopamine, norepinephrine, and oxytocin (Kolbrich et al., 2008). Potential neurotoxicity for repeated use of MDMA has been examined in some animal populations; however, the generalizability of these findings to humans has been called into question (de la Torre and Farre, 2004). In light of the reevaluation of MDMA’s risks and benefits, there is a renewed interest in its clinical usage. Most significant in this reevaluation is MDMA’s potential to adjunctively bolster the efficacy of psychotherapy. Some benefits have been examined in novel areas of study, like social anxiety disorder and socialization on the autism spectrum (Danforth et al., 2018). The most well-documented clinical usage of MDMA-assisted therapy (MDMA-AT) to date is in the area of PTSD.

MDMA and PTSD

Phase 2 clinical trials established a standard design of MDMA-AT in research settings. This design involves three preparatory non-drug psychotherapy sessions, leading to 2-to-3 eight-hour experimental MDMA therapy sessions. Each experimental session is followed by three non-drug therapy sessions to integrate insights gained from drug sessions into daily life. The efficacy of these interventions is typically measured with the CAPS (Blake et al., 1995). Interventions in early trials were shown to be significantly more effective compared to placebo (Feduccia et al., 2019, Ot’Alora et al., 2018). It should be noted that placebo-controlled conditions in psychedelic trials are difficult to mask if the placebo is inactive (Luoma et al., 2020). Active placebo options or Subtherapeutic levels of MDMA have been used in attempts to address this issue Oehen, P., et al. (2013).

Promising phase 2 results have led to the expansion of MDMA research into multi-site phase 3 trials, which have found significant reductions in CAPS scores and secondary measures of impairment via the Sheehan Disability Scale (Mitchell et al., 2021). Approximately 65% of participants had a history of sertraline/paroxetine use, speaking to the growing body of evidence in favor of psychedelic intervention for treatment-resistant PTSD. To add further robustness to this evidence, future research will need to directly compare MDMA-AT with sertraline and paroxetine in a head-to-head design.

The mechanisms of action leading to changes in PTSD symptoms are not well understood. Preclinical trials examining the effects of MDMA in animal models offer key insights into the drug’s impact on traumatic memory processing. One study examining conditioned fear responses in 200 male rats found that MDMA administration did not necessarily extinguish fear responses during exposure, but rather altered the reconsolidation of those fear memories after recall so that they became more manageable over time (Hake et al., 2019). A study using male and female rodents of varying ages found that a single dose of MDMA reopened critical learning periods and promoted reintegration into optimal conditions (Nardou et al., 2019). Taken together, plasticity appears crucial in disrupting the maladaptive maintenance of PTSD.

MDMA and AUD

Research examining MDMA specifically as a potential AUD treatment is limited. The first study to examine its safety, tolerability, and efficacy in treatment included patients diagnosed with AUD who recently underwent a medical detox (Sessa et al., 2021). This study was conducted in an open-label feasibility paradigm. Outcomes examined were the drug’s tolerability during an 8-week course of intervention, and subsequent drinking behaviors at follow-up interviews. Results indicated no serious adverse reactions to MDMA or intent to use MDMA illicitly/recreationally following therapeutic intervention. At 9-months post-intervention, the number of alcoholic drinks consumed by participants averaged at 18.7 per week, compared to the average 130.6 pre-intervention. While this study did employ a small sample size (n = 14), results are promising with regard to MDMA as a feasible treatment with potentially significant results.

There is some history of other psychedelic interventions being utilized to address SUD, particularly AUD. An observational research study queried individuals about their substance use before and after a self-administered naturalistic use of classic psychedelics, like LSD and psilocybin (Garcia-Romeu et al., 2019). This study found a 69% decrease in participants who met self-reported criteria for SUD following their psychedelic experience.

When deciding whether to employ classic psychedelics or enactogens, the extent to which a participant is willing to undergo classic psychedelic experiences ought to be considered. While the potential of a mystical-like experience with ego dissolution may be enticing to some, it may be daunting for others. MDMA’s ability to increase mindful awareness of the “here and now” without affecting the ego makes it a valuable tool for psychotherapeutic insight.

MDMA in PTSD-AUD comorbidity

Examined in isolation, there is strong evidence for the use of MDMA-AT in the treatment of PTSD, and some emerging evidence for its safety and potential value in AUD treatment. Previous MDMA-AT trials also suggest that benefits derived from this intervention for PTSD still occur in the presence of various comorbidities including AUD, major depression, and others. A key next step in future research will be to examine whether PTSD with comorbid AUD can be treated concurrently using MDMA-AT. One such study is in development and set to begin shortly at Brown University (NCT05943665). This study will examine the efficacy of MDMA-AT in a veteran population with comorbid PTSD-AUD. No other MDMA research has been conducted on this comorbidity. Findings from this study will provide important information regarding MDMA’s potential benefits in treating PTSD-AUD.

Conclusions

The narrative of a “miracle drug” as a de facto cure to a disease is not useful in regard to PTSD and AUD. It is unlikely that one treatment approach will be appropriate or effective for all affected patients. The purpose of reviewing existing pharmacotherapies for these disorders is to identify their uses as well as their shortcomings when addressing such complex and debilitating disorders as AUD and PTSD. The current evidence indicates that existing pharmacotherapies have been relied on to manage symptoms of these disorders, thereby reducing harm. This alleviation of symptoms may lead to remission and eventual flourishing. However, the issue for existing pharmacotherapies appears to lie in their strength, duration, and failure to integrate with other forms of treatment.

MDMA’s value in the treatment of PTSD and AUD is not a mere result of its pharmacological action or influence on symptoms, but in its removal of barriers so that a patient may turn toward distressing memories and emotions and subsequently address areas that would otherwise be unavailable to them. The ability to integrate MDMA into a highly supportive therapeutic environment makes it a valuable tool, but by no means is the only viable option. Various treatment options for PTSD-AUD, from psychotherapeutic, pharmacological, and other alternatives, are all aimed in the same direction. The integration of psychedelics into treatment may be compared to a bullet train in said direction, the speed of which may be tolerated or not depending on the individual. The current revitalization of psychedelic research has yielded promising results. By comparing and contrasting these results directly with other treatment options, diverse avenues of care are elucidated.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is supported by funds from the Brown University Office of the Vice President for Research (OVPR) and the National Institute of General Medical Sciences (NIGMS), Center of Biomedical Research Excellence (COBRE, P20 GM130414). Dr. Haass-Koffler is also supported by the National Institute on Alcohol Abuse and Alcoholism (R01 AA026589; R01 AA027760; R21 AA027614).

ORCID iDs

Christy Capone

Carolina L. Haass-Koffler

References

American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychiatric Association.

Back

Killeen

Badour

, et al (2019). Concurrent treatment of substance use disorders and PTSD using prolonged exposure: A randomized clinical trial in military veterans. Addict Behav 90: 369–377.

Bahji

Bach

Danilewitz

, et al (2022) Pharmacotherapies for adults with alcohol use disorders: A systematic review and network meta-analysis. J Addict Med 16: 630–638.

Balldin

Berglund

Borg

, et al (2003). A 6-month controlled naltrexone study: Combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence. Alcohol Clin Exp Res 27: 1142–1149.

Batki

Pennington

Lasher

, et al (2014) Topiramate treatment of alcohol use disorder in veterans with posttraumatic stress disorder: A randomized controlled pilot trial. Alcohol Clin Exp Res 38: 2169–2177.

Blake

Weathers

Nagy

, et al (1995) The development of a clinician-administered PTSD scale. J Trauma Stress 8: 75–90.

Book

Thomas

Randall

, et al (2008) Paroxetine reduces social anxiety in individuals with a co-occurring alcohol use disorder. J Anxiety Disord 22: 310–318.

Borrelli

Jr Starr

Downs

, et al (2019) Prospective study of the effectiveness of paroxetine on the onset of posttraumatic stress disorder, depression, and health and functional outcomes after trauma. J Orthop Trauma 33: e58–e63.

Brady

Pearlstein

Asnis

, et al (2000) Efficacy and safety of sertraline treatment of posttraumatic stress disorder: A randomized controlled trial. JAMA 283: 1837–1844.

10.

Brady

Sonne

Anton

, et al (2005) Sertraline in the treatment of co-occurring alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res 29: 395–401.

11.

Danforth

Grob

Struble

, et al (2018) Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study. Psychopharmacology (Berl) 235: 3137–3148.

12.

Davidson

Landerman

Farfel

, et al (2002). Characterizing the effects of sertraline in post-traumatic stress disorder. Psychol Med 32: 661–670.

13.

Davidson

Rothbaum

Tucker

, et al (2006) Venlafaxine extended release in posttraumatic stress disorder: a sertraline- and placebo-controlled study. J Clin Psychopharmacol 26: 259–267.

14.

Debell

Fear

Head

, et al (2014) A systematic review of the comorbidity between PTSD and alcohol misuse. Soc Psychiatry Psychiatr Epidemiol 49: 1401–1425.

15.

de la Torre

Farre

(2004) Neurotoxicity of MDMA (ecstasy): The limitations of scaling from animals to humans. Trends Pharmacol Sci 25: 505–508.

16.

Dworkin

Wanklyn

Stasiewicz

, et al (2018). PTSD symptom presentation among people with alcohol and drug use disorders: Comparisons by substance of abuse. Addict Behav 76: 188–194.

17.

Evren

Sar

Dalbudak

, et al (2011). Lifetime PTSD and quality of life among alcohol-dependent men: Impact of childhood emotional abuse and dissociation. Psychiatry Res 186: 85–90.

18.

Feduccia

Jerome

Yazar-Klosinski

, et al (2019) Breakthrough for trauma treatment: Safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline. Front Psychiatry 10: 650.

19.

Fetzner

Mcmillan

Sareen

, et al (2011) What is the association between traumatic life events and alcohol abuse/dependence in people with and without PTSD? Findings from a nationally representative sample. Depress Anxiety 28: 632–638.

20.

Foa

Yusko

Mclean

, et al (2013) Concurrent naltrexone and prolonged exposure therapy for patients with comorbid alcohol dependence and PTSD: A randomized clinical trial. JAMA 310: 488–495.

21.

Frommberger

Stieglitz

Nyberg

, et al (2004) Comparison between paroxetine and behaviour therapy in patients with posttraumatic stress disorder (PTSD): A pilot study. Int J Psychiatry Clin Pract 8: 19–23.

22.

Fuller

Gordis

(2004) Does disulfiram have a role in alcoholism treatment today? Addiction 99: 21–24.

23.

Garbutt

Kranzler

O’Malley

, et al (2005) Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: A randomized controlled trial. JAMA 293: 1617–1625.

24.

Garcia-Romeu

Davis

Erowid

, et al (2019) Persisting reductions in cannabis, opioid, and stimulant misuse after naturalistic psychedelic use: An online survey. Front Psychiatry 10: 955.

25.

Garcia-Romeu

Kersgaard

Addy

(2016) Clinical applications of hallucinogens: A review. Exp Clin Psychopharmacol 24: 229–268.

26.

Gilpin

Weiner

(2017) Neurobiology of comorbid post-traumatic stress disorder and alcohol-use disorder. Genes Brain Behav 16: 15–43.

27.

Goldstein

Schick

Weyandt

, et al (2023) Posttraumatic stress as a moderator of the association between HPA-axis functioning and alcohol use disorder among a community sample of women currently experiencing intimate partner violence. Exp Clin Psychopharmacol 31: 163–173.

28.

Grant

(1994) Alcohol consumption, alcohol abuse and alcohol dependence. The United States as an example. Addiction 89: 1357–1365.

29.

Grant

Goldstein

Saha

, et al (2015) Epidemiology of DSM-5 alcohol use disorder: results from the national epidemiologic survey on alcohol and related conditions III. JAMA Psychiatry 72: 757–766.

30.

Green

(2014) Prazosin in the treatment of PTSD. J Psychiatr Pract 20: 253–259.

31.

Haass-Koffler

(2023) Utilizing precision medicine to treat alcohol use disorder: A commentary on the alpha1 receptor antagonist. Alcohol Clin Exp Res 47: 432–434.

32.

Haass-Koffler

Goodyear

Zywiak

, et al (2017). Higher pretreatment blood pressure is associated with greater alcohol drinking reduction in alcohol-dependent individuals treated with doxazosin. Drug Alcohol Depend 177: 23–28.

33.

Haass-Koffler

Kenna

(2013) Bacchus by caravaggio as the visual diagnosis of alcohol use disorder from the fifth edition of the diagnostic and statistical manual of mental disorders (DSM-5). Front Psychiatry 4: 86.

34.

Haass-Koffler

Swift

Leggio

(2018) Noradrenergic targets for the treatment of alcohol use disorder. Psychopharmacology (Berl) 235: 1625–1634.

35.

Hake

Davis

JKP

Wood

, et al (2019) 3,4-methylenedioxymethamphetamine (MDMA) impairs the extinction and reconsolidation of fear memory in rats. Physiol Behav 199: 343–350.

36.

Helzer

Robins

Mcevoy

(1987) Post-traumatic stress disorder in the general population. Findings of the epidemiologic catchment area survey. N Engl J Med 317: 1630–1634.

37.

Hien

Levin

Ruglass

, et al (2015). Combining seeking safety with sertraline for PTSD and alcohol use disorders: A randomized controlled trial. J Consult Clin Psychol 83: 359–369.

38.

Hien

Morgan-Lopez

Saavedra

, et al (2023) Project harmony: A meta-analysis with individual patient data on behavioral and pharmacologic trials for comorbid posttraumatic stress and alcohol or other drug use disorders. Am J Psychiatry 180: 155–166.

39.

Jorgensen

Pedersen

Tonnesen

(2011) The efficacy of disulfiram for the treatment of alcohol use disorder. Alcohol Clin Exp Res 35: 1749–1758.

40.

Kehle-Forbes

Chen

Polusny

, et al (2019) A randomized controlled trial evaluating integrated versus phased application of evidence-based psychotherapies for military veterans with comorbid PTSD and substance use disorders. Drug Alcohol Depend 205: 107647.

41.

Kolbrich

Goodwin

Gorelick

, et al (2008) Plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine after controlled oral administration to young adults. Ther Drug Monit 30: 320–332.

42.

Kranzler

Soyka

(2018) Diagnosis and pharmacotherapy of alcohol use disorder: A review. JAMA 320: 815–824.

43.

Krystal

Davis

Neylan

, et al (2017) It is time to address the crisis in the pharmacotherapy of posttraumatic stress disorder: A consensus statement of the PTSD psychopharmacology working group. Biol Psychiatry 82: e51–e59.

44.

Lancaster

Gros

Mullarkey

, et al (2020) Does trauma-focused exposure therapy exacerbate symptoms among patients with comorbid PTSD and substance use disorders? Behav Cogn Psychother 48: 38–53.

45.

Latimer

Stocker

Sayers

, et al (2021) MDMA to treat PTSD in adults. Psychopharmacol Bull 51: 125–149.

46.

Liang

Olsen

(2014) Alcohol use disorders and current pharmacological therapies: The role of GABA(A) receptors. Acta Pharmacol Sin 35: 981–993.

47.

Litten

Wilford

Falk

, et al (2016) Potential medications for the treatment of alcohol use disorder: An evaluation of clinical efficacy and safety. Subst Abus 37: 286–298.

48.

Luoma

Chwyl

Bathje

, et al (2020) A meta-analysis of placebo-controlled trials of psychedelic-assisted therapy. J Psychoactive Drugs 52: 289–299.

49.

Mann

Lehert

Morgan

(2004) The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals: Results of a meta-analysis. Alcohol Clin Exp Res 28: 51–63.

50.

Maria-Rios

Morrow

(2020) Mechanisms of shared vulnerability to post-traumatic stress disorder and substance use disorders. Front Behav Neurosci 14: 6.

51.

Mason

Crean

(2007) Acamprosate in the treatment of alcohol dependence: clinical and economic considerations. Expert Rev Neurother 7: 1465–1477.

52.

Mavranezouli

Megnin-Viggars

Daly

, et al (2020) Psychological treatments for post-traumatic stress disorder in adults: A network meta-analysis. Psychol Med 50: 542–555.

53.

Mitchell

Bogenschutz

Lilienstein

, et al (2021) MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study. Nat Med 27: 1025–1033.

54.

Mutschler

Grosshans

Soyka

, et al (2016) Current findings and mechanisms of action of disulfiram in the treatment of alcohol dependence. Pharmacopsychiatry 49: 137–141.

55.

Najavits

Clark

Diclemente

, et al (2020) PTSD / substance use disorder comorbidity: Treatment options and public health needs. Curr Treat Options Psychiatry 7: 544–558.

56.

Ralevski

Jegede

, et al (2021) Depression and/or PTSD comorbidity affects response to antidepressants in those with alcohol use disorder. Front Psychiatry 12: 768318.

57.

Nardou

Lewis

Rothhaas

, et al (2019) Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature 569: 116–120.

58.

Nichols

(2022) Entactogens: How the name for a novel class of psychoactive agents originated. Front Psychiatry 13: 863088.

59.

Norman

Trim

Haller

, et al (2019) Efficacy of integrated exposure therapy vs integrated coping skills therapy for comorbid posttraumatic stress disorder and alcohol use disorder: A randomized clinical trial. JAMA Psychiatry 76: 791–799.

60.

Oehen

, et al. (2013). “A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD).” J Psychopharmacol 27(1): 40–52.

61.

Ot’Alora

Grigsby

Poulter

, et al (2018) 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: A randomized phase 2 controlled trial. J Psychopharmacol 32: 1295–1307.

62.

Petrakis

Desai

Gueorguieva

, et al (2016) Prazosin for veterans with posttraumatic stress disorder and comorbid alcohol dependence: A clinical trial. Alcohol Clin Exp Res 40: 178–186.

63.

Petrakis

Poling

Levinson

, et al (2006) Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder. Biol Psychiatry 60: 777–783.

64.

Petrakis

Ralevski

Desai

, et al (2012) Noradrenergic vs serotonergic antidepressant with or without naltrexone for veterans with PTSD and comorbid alcohol dependence. Neuropsychopharmacology 37: 996–1004.

65.

Popiel

Zawadzki

Praglowska

, et al (2015) Prolonged exposure, paroxetine and the combination in the treatment of PTSD following a motor vehicle accident. A randomized clinical trial–The “TRAKT” study. J Behav Ther Exp Psychiatry 48: 17–26.

66.

Ralevski

Olivera-Figueroa

Petrakis

(2014) PTSD and comorbid AUD: A review of pharmacological and alternative treatment options. Subst Abuse Rehabil 5: 25–36.

67.

Raskind

Millard

Petrie

, et al (2016) Higher pretreatment blood pressure is associated with greater posttraumatic stress disorder symptom reduction in soldiers treated with prazosin. Biol Psychiatry 80: 736–742.

68.

Raskind

Peterson

Williams

, et al (2013) A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry 170: 1003–1010.

69.

Raskind

Thompson

Petrie

, et al (2002) Prazosin reduces nightmares in combat veterans with posttraumatic stress disorder. J Clin Psychiatry 63: 565–568.

70.

Rehm

Shield

(2019) Global burden of alcohol use disorders and alcohol liver disease. Biomedicines 7: 99.

71.

Rojas

Bujarski

Babson

, et al (2014) Understanding PTSD comorbidity and suicidal behavior: associations among histories of alcohol dependence, major depressive disorder, and suicidal ideation and attempts. J Anxiety Disord 28: 318–325.

72.

Samuelson

Neylan

Metzler

, et al (2006) Neuropsychological functioning in posttraumatic stress disorder and alcohol abuse. Neuropsychology 20: 716–726.

73.

Schafer

Lotzin

Hiller

, et al (2019) A multisite randomized controlled trial of seeking safety vs. relapse prevention training for women with co-occurring posttraumatic stress disorder and substance use disorders. Eur J Psychotraumatol 10: 1577092.

74.

Schimmenti

Billieux

Santoro

, et al (2022) A trauma model of substance use: Elaboration and preliminary validation. Addict Behav 134: 107431.

75.

Schrader

Ross

(2021) A review of PTSD and current treatment strategies. Mo Med 118: 546–551.

76.

Sessa

Higbed

O’Brien

, et al (2021) First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder. J Psychopharmacol 35: 375–383.

77.

Simpson

Malte

Dietel

, et al (2015) A pilot trial of prazosin, an alpha-1 adrenergic antagonist, for comorbid alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res 39: 808–817.

78.

Solomon

Davidson

(1997) Trauma: Prevalence, impairment, service use, and cost. J Clin Psychiatry 58: 5–11.

79.

Straus

Haller

Lyons

, et al (2018) Functional and psychiatric correlates of comorbid post-traumatic stress disorder and alcohol use disorder. Alcohol Res 39: 121–129.

80.

Subbie-Saenz de Viteri

Pandey

, et al (2020) Pathways to post-traumatic stress disorder and alcohol dependence: Trauma, executive functioning, and family history of alcoholism in adolescents and young adults. Brain Behav 10: e01789.

81.

Suh

Pettinati

Kampman

, et al (2006) The status of disulfiram: A half of a century later. J Clin Psychopharmacol 26: 290–302.

82.

Taylor

Petrakis

Ralevski

(2017) Treatment of alcohol use disorder and co-occurring PTSD. Am J Drug Alcohol Abuse 43: 391–401.

83.

Tucker

Trautman

Wyatt

, et al (2007) Efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 68: 201–206.

84.

Wallach

Rhee

Edelman

, et al (2022). U.S. prescribing of on-and-off-label medications for alcohol use disorder in outpatient visits: NAMCS 2014 to 2016. J Gen Intern Med 37: 495–498.

85.

Witkiewitz

Litten

Leggio

(2019) Advances in the science and treatment of alcohol use disorder. Sci Adv 5: eaax4043.

86.

Yeh

Mari

Costa

, et al (2011) A double-blind randomized controlled trial to study the efficacy of topiramate in a civilian sample of PTSD. CNS Neurosci Ther 17: 305–310.

87.

Zhang

Price

Leonard

, et al (2020) Alcohol use disorder masks the effects of childhood adversity, lifetime trauma, and chronic stress on hypothalamic-pituitary-adrenal axis reactivity. Alcohol Clin Exp Res 44: 1192–1203.

88.

Zoellner

Roy-Byrne

Mavissakalian

, et al (2019) Doubly randomized preference trial of prolonged exposure versus sertraline for treatment of PTSD. Am J Psychiatry 176: 287–296.

89.

Zohar

Amital

Cropp

, et al (2022) Update on the epidemiology, diagnosis, and treatment of posttraumatic stress disorder. Dialogues Clin Neurosci 2: 37–43.