Examining the Rationale for Studying Psychedelic-Assisted Psychotherapy for the Treatment of Caregiver Distress

Abstract

Background:

More than 50 million people in the United States serve as uncompensated informal caregivers to chronically ill friends or family members. Providing care to a sick loved one can contribute to personal growth but can also cause significant strain. Caregiver distress refers to a constellation of physiological, psychological, interpersonal, and spiritual impairments that typically result when an individual's own health becomes affected while caring for another. Caregiver distress is highly prevalent, affecting an estimated 30–70% of individuals across various caregiver populations. Although evidence-based treatments for caregiver distress exist, they do not sufficiently address all its components. In recent years, clinical trials have demonstrated that psychedelic-assisted psychotherapy (PAP) may have applications for treating a range of medical and psychiatric conditions that have significant overlap in symptoms to those seen in caregiver distress. While no studies to date have examined PAP for caregiver distress, this article provides a rationale for investigating PAP as a potential novel treatment for this indication.

Methods:

A narrative review on the effects and clinical applications of PAP that significantly overlap with the dimensions of caregiver distress was conducted. Safety considerations, psychedelic selection, and therapeutic structure for studying PAP in the treatment of caregiver distress were also examined.

Results:

Psychologically, PAP has been shown to treat anxiety, depression, and reduce suicidal ideation. Physiologically, evidence suggests that psychedelics have anti-inflammatory properties, which may aid caregivers suffering from chronic inflammation. Interpersonally, PAP has been demonstrated to enhance feelings of empathy, connectedness, and strengthen social relationships, which can often become strained while caregiving. Spiritually, PAP has been shown to ameliorate existential distress and hopelessness in cancer patients, which may similarly benefit demoralized caregivers.

Conclusion:

PAP has the potential to comprehensively treat all biopsychosocial–spiritual dimensions of caregiver distress.

Introduction

Informal caregivers provide uncompensated physical, emotional, and financial support to family members or friends suffering from a range of chronic illnesses, including cancer and degenerative conditions such as dementia. According to a 2020 report on caregiving in the United States, 21.3% of all adults (53 million) identified as having served as an unpaid caregiver in the past 12 months, including 16.8% who cared for an adult aged 50 years or older.¹ As the world's population ages, the incidence of age-related disease is similarly expected to increase. For example, cases of dementia are forecasted to nearly triple globally from 2019 to 2050,² and cases of cancer are expected to grow by 47% between 2020 and 2040.³ Growing in parallel to the population of patients with age-related and degenerative diseases is a population of individuals, often family members, who serve as their caregivers. A recent report published by the Alzheimer's Association found that dementia caregivers spent an estimated collective 16 billion hours caregiving in 2021, valued at $271.6 billion.⁴

Caregiving, when successfully managed, has been associated with delayed institutionalization of the care recipient⁵ and can provide the patient more time with family and friends. While caregiving can contribute to personal growth for some,⁶ it can also dominate caregivers' time and attention, which may lead to the neglect of their own mental and physical health. For example, caregiving can be physically demanding and may result in fatigue, sleep disturbances, and chronic inflammation.^7–10 Psychologically, caregiving can be emotionally distressing, especially when the care recipient has cognitive impairments or a neurodegenerative illness, which has been shown to correlate with higher rates of depression and anxiety in caregivers.¹¹

Constantly being “on call” can affect the interpersonal lives of caregivers by limiting their participation in leisure activities and other social functions.¹² This, in turn, can generate feelings of loneliness and may even foster resentment between the caregiver and care recipient.^13,14 It is also common for caregivers to reduce their working hours, which can lead to financial hardship and familial–professional role conflict.¹⁵ Finally, existential distress and demoralization are commonly reported in caregivers of patients with advanced cancer and neurodegenerative illnesses.^13,16 These impairments can eventually result in a condition known as caregiver distress.

While there is currently no specific International Classification of Diseases-10th Revision or Diagnostic and Statistical Manual of Mental Disorders-5th Edition-Text Revision code for caregiver distress, it is generally defined as “the extent to which caregivers perceive that caregiving has had an adverse effect on their emotional, social, financial, physical, and spiritual functioning”¹⁷ and is understood to be a significant clinical condition.^18–20 This definition attempts to encompass the multidimensional aspects of caregiver distress, which comprises a constellation of psychological, physiological, interpersonal, and spiritual components. Furthermore, caregiving is a highly individualized experience and caregivers tolerate different levels of burden before developing clinically significant distress. To better quantify caregiver distress, the validated, revised 12-item Zarit Burden Interview (ZBI) is a commonly employed rating scale that uses a threshold score of ≥17 to indicate high levels of burden, suggesting clinically significant distress.^21,22

Most studies have estimated the prevalence of caregiver distress to be very high. A large prospective cohort study (n = 732) conducted over 3 years found that 57.7% of caregivers of someone with dementia experienced significant caregiver burden, with 22.8% of this sample enduring moderate-to-severe symptoms according to the ZBI.²³ A more recent trial found this value to be more than 70% among caregivers of cancer patients undergoing chemotherapy.²⁴ The COVID-19 pandemic has further exacerbated caregiver burden; upward of 70% of family caregivers report increased caregiving roles due to the pandemic or pandemic-related policies, and over half emphasized feelings of worry and of being overwhelmed by their responsibilities.²⁵

These observations, coupled with the expected growth in informal caregiving, underscore the pressing need for effective treatments. In this article, we present a narrative review on existing interventions for caregiver distress and highlight current shortcomings in treatment. Furthermore, we examine the rationale for why psychedelic-assisted psychotherapy (PAP) may be useful for treating this condition and how it could be effectively studied in future clinical trials.

Standard of Care for Caregiver Distress

Psychosocial interventions

Evidence-based treatments for caregiver distress include psychotherapy, psychoeducation, and multicomponent interventions.^26–28 These psychosocial treatments alleviate caregiver distress by targeting one or more elements of the condition. For instance, cognitive-behavioral therapy (CBT), a time-limited manualized treatment conducted within a patient–therapist dyad or group setting, has been commonly studied as a treatment for caregiver distress to reduce depressive symptoms, adjust behavioral patterns, and reduce dysfunctional thinking.²⁷

Psychoeducational programs aim to expand informal caregivers' clinical repertoire by educating caregivers on the care recipient's illness and by teaching caregivers emotion regulation skills.²⁹ Psychoeducation also typically emphasizes the importance of prioritizing time for oneself through hobbies, relaxation, and self-care.²⁹ Support groups are another commonly utilized intervention and often consist of peers empathizing over shared experiences or hardships.³⁰ Multicomponent treatments also exist and include various combinations of psychoeducation, skills training, CBT, problem solving, counseling, and support groups.²⁹

Multiple systematic reviews and meta-analyses have been published over the past two decades evaluating the effectiveness of various psychosocial interventions for treating caregiver distress.^18,19,31 The results of these studies have generally revealed small-to-moderate improvements in perceived caregiver burden and associated distress with effect sizes ranging from 0.09 to 0.23¹⁸ and more significant improvements in depressive symptoms with effect sizes ranging up to 0.70.³¹ These reviews have generally highlighted the effectiveness of CBT as well as multicomponent treatments, which are often more comprehensive and patient-tailored, to be the most effective.^31,32

For example, one rigorously studied and widely used multicomponent intervention—the NYU Caregiver Intervention—combines individual counseling, family counseling, and support groups, tailoring therapy to the needs of each caregiver.³³ This intervention has been shown to delay the institutionalization of the care recipient^34,35 by improving caregiver well-being, reducing caregiver depression,³⁶ and has been successfully adapted across multiple communities in the United States^37,38 and elsewhere.³⁹

However, a review of the literature on caregiver distress has also revealed two important limitations. The first limitation is that most treatments focus on a singular core dimension or outcome (e.g., depression, anxiety, spiritual distress, inadequate social support).^5,27 The second limitation is the mild to modest efficacy of available treatments, which have been shown to diminish over time.¹⁸ For example, Hepburn et al.⁴⁰ found that the interventional effects of psychoeducation last for up to 6 months, and more broadly, Pinquart and Sörensen⁵ observed that the benefits of most psychotherapeutic interventions are maintained for ∼11 months. The short-term effectiveness of most current treatments is concerning since sustained clinical benefit is of particular importance for caregivers; while interventions may conclude after weeks or months, caregiving often persists for years, and responsibilities often increase with time as the condition of the care recipient deteriorates.¹⁵

Pharmacological interventions

To the best of our knowledge, there is only one published randomized controlled trial that has investigated pharmacological treatment for caregiver distress. This pilot study (n = 45) compared standard of care (basic psychoeducation and referral to support groups) with standard of care in conjunction with escitalopram, a selective-serotonin reuptake inhibitor (SSRI), to target caregiver burden, symptoms of depression, and related outcomes in family caregivers of patients with Alzheimer's disease.⁴¹ Results showed that escitalopram produced significant improvements in depression, anxiety, subjective distress, and resilience, with 86% of the caregivers receiving escitalopram achieving remission of their depression compared with only 44% in the control group. Furthermore, the authors noted faster and more consistent results with their pharmacologically enhanced treatment compared with psychosocial interventions alone.⁴¹ These promising findings support continued investigation into pharmacologically enhanced psychotherapeutic treatments for caregiver distress.

Psychedelic-Assisted Psychotherapy

History of classic psychedelics

Plant-based psychedelics including psilocybin, mescaline, and N,N-dimethyltryptamine (DMT) have likely been used by indigenous communities for various spiritual and healing purposes for thousands of years.⁴² These compounds primarily function as serotonin 2A (5-HT_2A) receptor agonists⁴³ and induce profound perceptual, affective, and consciousness-altering effects.⁴⁴ The psychoactive properties of psychedelics took until 1943 to be discovered by the West following Albert Hoffman's accidental consumption of lysergic acid diethylamide (LSD), which eventually ushered in a new era of clinical research.⁴⁵

During the 1950s and 1960s, an estimated tens of thousands of patients were treated with psychedelic therapy^45,46 for a variety of clinical conditions, including alcohol use disorder,⁴⁷ existential distress in advanced cancer,^48,49 pain,⁵⁰ and more. However, this initial wave of research ended following the passage of the Controlled Substances Act of 1970, which classified all classic psychedelics as Schedule I substances.⁵¹ Nevertheless, research with psychedelics continued both in vitro⁵² and in vivo,⁵³ and human subjects research gradually resumed in the 1990s^54–56 in the United States and Europe, which eventually led to the rapid resurgence of clinical research seen today.⁵⁷

History of 3,4-methylenedioxyl-methamphetamine

Related to the classic psychedelics (e.g., psilocybin, LSD, and DMT), 3,4-methylenedioxyl-methamphetamine (MDMA) is an empathogenic “para-psychedelic” compound that similarly induces alterations in perception and consciousness.⁵⁸ MDMA promotes the release of the neurotransmitters serotonin, dopamine, and norepinephrine⁵⁹ and was first synthesized in 1912 by the company Merck. However, MDMA was not used for clinical purposes until the mid 1970s when its psychoactive properties were discovered by Alexander Shulgin.⁶⁰ Following this discovery, MDMA was used first as an adjunct to psychotherapy during the late 1970s and eventually for recreational purposes during the 1980s, which continued until 1985 when widespread recreational use resulted in MDMA becoming a Schedule I controlled substance.

After 1985, MDMAs use in the clinic and in clinical trials came to a halt. Animal studies resumed first, and eventually, clinical trials restarted in the 1990s and early 2000s.⁶¹ More recently, the Food and Drug Administration (FDA) has granted breakthrough therapy designation to MDMA-assisted psychotherapy for the treatment of posttraumatic stress disorder (PTSD) in light of a growing evidence base spearheaded by the nonprofit Multidisciplinary Association for Psychedelic Studies.⁶²

Modern research with psychedelics

Unlike the less structured formats of many of the early psychedelic studies, modern clinical trials have employed psychedelics as part of a therapeutic package known as PAP. This model typically consists of a co-therapist dyad providing psychotherapeutic support before, during, and after the psychedelic dosing session(s). Using this approach, multiple research groups have demonstrated promising preliminary results suggesting that psychedelics may have therapeutic applications for a variety of conditions,⁶³ including major depressive disorder (MDD),^64,65 advanced cancer-related psychiatric and existential distress,^66–68 and substance use disorders.^69–71 Additionally, PAP has been or is currently being investigated for its potential to treat eating disorders (NCT04505189, NCT05481736),⁷² obsessive-compulsive disorder (NCT03356483),⁷³ psychiatric distress in Alzheimer's disease (NCT04123314)⁷⁴ and Parkinson's disease (NCT04932434), as well as cluster headaches (NCT02981173) and migraines (NCT04218539).⁷⁵

Rationale for studying PAP in caregivers

A number of symptoms of the aforementioned conditions overlap significantly with the phenomenology of caregiver distress, including depression and anxiety,⁷⁶ existential distress,^13,16 and chronic inflammation.^77,78 It thus stands to reason that PAP may also be effective at treating caregiver distress, but no research to date has studied PAP for this indication. In alignment with recent studies that have characterized the dimensions of caregiver distress using a biopsychosocial model,^79,80 in this study, we review the potential beneficial effects of PAP on the (1) psychological, (2) physiological, (3) interpersonal, and (4) spiritual components of caregiver distress. Furthermore, we examine how PAP may be feasibly and safely studied within the context of caregiver distress in future clinical trials.

Biopsychosocial–Spiritual Effects of PAP

Psychological effects

High rates of anxiety and depression have been well documented in caregivers of patients with Alzheimer's disease, advanced cancer, amyotrophic lateral sclerosis, and in caregivers of stroke survivors.^81–83 The prevalence of anxiety and depression in caregivers is routinely found to be more than 20%,⁷⁶ with certain populations including those caring for someone with Alzheimer's disease or cancer demonstrating prevalence as high as 40%⁸⁴ or 50%,⁸¹ respectively.

PAP using LSD and psilocybin has shown promise for rapidly improving symptoms of depression and anxiety in patients with life-threatening diseases⁸⁵ and cancer.^{48,66–68,86} More recently, in non-cancer patients, PAP has shown promise for treating MDD^64,65 and even treatment-resistant depression (TRD).^87,88 There is also some evidence that PAP may be associated with sustained improvements in affective symptoms, ranging from 1 year in MDD⁸⁹ to 4.5 years in advanced-cancer related depression and anxiety.⁹⁰

However, in TRD, the therapeutic effects of PAP may diminish more rapidly, lasting on the order of months, indicating a potential need for periodic re-dosing for certain treatment-resistant conditions.⁸⁸ Longitudinal studies will ultimately be needed to better understand the time course of treatment effects. Additionally, using data collected from the National Survey on Drug Use and Health of more than 190,000 respondents in the United States, Hendricks et al.⁹¹ found that any lifetime use of a classic psychedelic was correlated with reduced suicidal ideation, suicidal planning, and suicide attempts in the year preceding survey completion, as well as lower psychological distress in the preceding month.

In one recent study comparing an SSRI (escitalopram) with psilocybin, PAP was found to be at least as effective as standard of care for the treatment of MDD, with secondary outcomes generally favoring psilocybin over escitalopram.⁶⁴ Additionally, participants who received escitalopram more frequently reported persistent side effects, such as sexual dysfunction and reduced emotional responsiveness. In contrast, participants who received psilocybin more commonly experienced transient side effects such as headaches during the psychedelic dosing day.⁶⁴

Another potential advantage of PAP is the infrequent need for medication dosing. SSRIs need to be taken daily for 4–6 weeks to take full effect,^92,93 whereas PAP may achieve significant symptom reduction following a single 8-h medication session when paired with therapy.^66,89,94 For an already strained and fatigued population, this treatment model may be particularly favorable.

Physiological effects

A systematic review of 192 research articles identified numerous physical complications of caregiving, including impaired sleep, loss of appetite, and weight loss.⁹⁵ Caregiver distress can also lead to chronic inflammation and impaired immune function.⁹⁶ Two recent studies demonstrated elevated levels of cytokines in caregivers and found that cytokine levels were correlated with the severity of caregiver distress as well as decreased quality of life.^78,97 Another trial identified shorter telomere lengths in caregivers, indicating accelerated biological aging in this vulnerable population.⁷⁷ It is widely thought that the combination of a weakened immune system,⁹⁸ chronic inflammation, and premature biological aging^77,96 puts caregivers at risk for age-related illnesses.^20,99,100 However, it should also be noted that the increased physical and cognitive demands of caregiving may be beneficial for some caregivers who would otherwise be less active.^101–105

Psychedelic compounds are currently being explored for their physiological effects, including anti-inflammatory and immunomodulatory properties.^106,107 Multiple preclinical studies as well as emerging evidence in humans suggest that psychedelics possess potent anti-inflammatory properties, possibly due to downstream effects from activating 5-HT_2A or sigma-1 receptors.^108–111 Specifically, psychedelics have been found to suppress the production of various inflammatory molecules including cytokines interleukin (IL)-2, IL-4, IL-6,^107,112,113 which have been shown to be elevated in individuals experiencing caregiver distress.^77,99,114 It has also been hypothesized that psychedelics might slow or even reverse telomere shortening and decelerate the aging process,¹¹⁵ although this has yet to be experimentally tested.

While the anti-inflammatory and immunomodulatory properties of psychedelics will require further validation in human clinical trials, they may serve as novel alternatives to steroids, opiates, and other anti-inflammatory agents^116–118 due to their preferable side effect profile and lower abuse potential.^43,119

Interpersonal effects

Caregivers commonly experience feelings of social isolation and loneliness.¹²⁰ A large review of well over 1,000 caregivers found that nearly half (43.7%) of caregivers report feelings of loneliness, with 17.7% of this sample reporting severe symptoms.¹⁴ These symptoms may stem from caregiving time-demands, distress-induced anhedonia, and reduced effort to participate in social functions.¹²⁰ Experiences of caregiver loneliness are associated with other aspects of caregiver distress including poorer physical health, reduced physical activity, increased depressive symptoms, and helplessness,¹²¹ highlighting the important clinical relevance of considering social impacts.

Of note, one study found that over half of their caregiver sample reported having inadequate time for themselves, often felt criticized by other family members in relation to their caregiving, and experienced changes in their relationship with the care recipient.¹²² Over time, caregivers may even develop feelings of anger and resentment toward their care recipient, leading to relational strain and possibly even harmful behavior toward the care recipient.¹²³

Preliminary data suggest that classic psychedelic compounds could potentially enhance social relationships and support prosocial and altruistic behaviors,^124,125 as reported by both participant and community observers.¹²⁶ Psilocybin has also been reported to enhance feelings of social connectedness and may possibly even reduce quarrelsome behaviors.¹²⁷ Furthermore, the interpersonal effects of PAP may be long-lasting, and feelings of love, life enjoyment, and enhanced emotional connectedness have been reported up to 4.5 years following psilocybin administration.⁹⁰

Psychedelic experiences can often induce a lasting increase in empathy and social connectedness, which may play a role in mediating improvements in social behaviors.¹²⁸ Preliminary data from animal models and in humans suggest that classic psychedelics may facilitate greater involvement in maintaining social relationships.^127,129 This is an important consideration for potentially burnt-out and socially isolated caregivers who may lack motivation to engage socially with others. As with various other changes observed following treatment with psychedelic compounds, improvements in relationships and prosocial behaviors have been found to persist for up to 14 months.¹²⁶

This suggests that PAP may be a useful tool in remedying caregivers' social distress by directly improving empathy, enhancing feelings of interpersonal connectedness, increasing motivation to interact with others, and by promoting prosocial as well as altruistic behaviors. Furthermore, improving the well-being of caregivers themselves as well as increasing their altruism and prosocial behaviors may have reciprocal effects on the care recipient by improving the quality of care they receive.¹³⁰ These improvements may even strengthen the relationship between caregiver and care recipient, leading to a more cohesive family dynamic.

Additionally, MDMA-assisted psychotherapy has been studied as a treatment for improving relational issues among couples,^131,132 as well as for the treatment of PTSD.^62,133 Due to the anger, strain, and resentment that can develop between caregiver and care recipient, MDMA has a potential role in facilitating both relational improvements and reducing symptoms of anxiety and trauma that could have developed over the course of caregiving. Moreover, MDMA-assisted psychotherapy has been shown to promote prosocial and altruistic behaviors, similar to those seen in classic psychedelics.¹³⁴

Spiritual effects

Spirituality, defined broadly, is an innate aspect of the human experience involving connection to meaning, purpose, and something greater than oneself.^135,136 Spirituality may support individuals in deepening their connection with themselves, others, nature, the systems they inhabit, and with the sacred (uniquely defined by each individual according to their lived experience or religious tradition). Spirituality may also assist individuals in enhancing their sense of meaning and purpose in life and may serve as an inner source of guidance during challenging times.

Spirituality is emphasized in palliative care and has been widely studied in populations experiencing serious illness,¹³⁵ yet there is far less research exploring the effects of spirituality on caregivers. Like patients experiencing serious illness, caregivers often endorse demoralization and spiritual distress¹⁶ as they are often in close proximity to suffering and death, making existential themes more salient. Like terminally-ill patients, caregivers also grapple with complicated forms of grief related to past, present, and future loss.¹³⁷ Applebaum et al.¹³⁸ identified caregivers' death anxiety and existential distress as critically unmet needs that can be experienced early in the caregiving process, as well as guilt which can linger well past the care recipient's death. In caregiver distress, existential issues relating to self-identity,¹³⁸ challenging emotions and meaning-making,^139,140 as well as quality of life are common.¹⁴¹

Spiritual well-being has also been shown to buffer negative mental health outcomes that are often associated with caregiver distress.^142,143 Specifically, caregivers who reported a high sense of spirituality reported lower rates of emotional distress and a higher amount of time devoted to caregiving.¹⁴⁴ Spirituality and religious coping have also been shown to minimize certain depressive and anxious symptoms in caregivers.^145,146 Furthermore, studies have demonstrated that caregivers reporting lower spiritual well-being reported greater difficulty accepting and being present to their own emotions.¹⁴⁷

Classic psychedelics have been shown to occasion mystical experiences, a subjective and often ineffable quality of the psychedelic state that has been described as involving an experience of oneness or unity.¹⁴⁸ This phenomenon has been observed across multiple studies and has been associated with robust and persistent improvements in spiritual well-being.^149–151 Furthermore, participants of these studies report these mystical experience to be among the most personally meaningful of their lives.^149,150 Psychedelic compounds have also been shown to enhance spiritual well-being and to minimize existential distress in cancer populations.^66,67 In a randomized controlled clinical trial of patients with advanced cancer, psilocybin was found to rapidly improve symptoms of demoralization, existential distress, and feelings of hopelessness,⁶⁶ with results persisting for 4.5 years.⁹⁰

The spiritually rich nature of the psychedelic experience may support individuals in exploring meaning related to their caregiving experience. Psychedelics are thought to induce a transient period of neuroplasticity and cognitive flexibility during which individuals are particularly open to new ideas and making changes to their belief systems and behaviors.¹⁵² When combined with psychotherapy, persistent changes to beliefs and behaviors may be helpful in aiding caregivers reappraise their caregiving experience and allow them to be more present for the care recipient.

Considerations for Studying PAP for Caregiver Distress

Safety

Modern clinical trials have demonstrated that under medical supervision, classic serotonergic psychedelics, such as psilocybin, LSD, and DMT, are non-addictive and safe to administer to most patients.¹⁵³ The most commonly reported side effects include bodily discomforts such as headaches and nausea¹⁵⁴ as well as transient increases in heart rate and blood pressure.¹⁵⁵ For these reasons, individuals with preexisting cardiac risk factors have generally been excluded from clinical trial participation.¹¹⁹

Psychedelics may also induce acute psychological discomforts such as fear, anxiety, or paranoid ideation pertaining to the subjective psychedelic experience.¹⁵⁴ These discomforts are usually successfully managed by trained therapists and rarely necessitate treatment with medications such as benzodiazepines.¹⁵⁶ Additionally, there is some concern that psychedelics may worsen or induce psychosis in individuals with a primary psychotic disorder or family history of such, and so, these patients have also been excluded from participation in clinical trials.¹¹⁹ However, for most individuals, psychedelics taken under medical supervision rarely cause psychosis and are psychologically and physiologically well tolerated.^157,158

Psychedelic selection for caregiver distress research

Psilocybin and MDMA have been the most rigorously studied psychedelics in clinical trials and have recently been granted breakthrough therapy designation by the FDA for the treatment of MDD and TRD as well as for PTSD, respectively.¹⁵⁹ As previously discussed, psilocybin and MDMA-assisted therapies have shown promise for treating a wide array of symptoms that significantly overlap with the phenomenology of caregiver distress, which provides a clinical rationale to study these therapies in caregivers. Therefore, the nuance of psychedelic compound selection may come down to the particulars of the clinical trial design and treatment goals.

For example, if the emphasis of the trial is focused around targeting psychological or psychospiritual distress, then there may be a stronger rationale for psilocybin-assisted psychotherapy. However, if improving relational dynamics, social relationships, and accompanying behaviors are emphasized, a stronger case might be made for MDMA-assisted psychotherapy. Given the heterogeneous nature of caregiver distress, there may also be benefit in using both psilocybin and MDMA-assisted psychotherapy within the same clinical trial design to comprehensively address all components of this clinical condition.

Other psychedelics such as LSD, mescaline, and DMT are beginning to be explored for their therapeutic potential; however, these compounds have not been thoroughly studied in modern trials.¹⁵⁹ Additionally, some psychedelics such as LSD and mescaline have acute effects that can last up to 12 h or longer and therefore pose practical issues to their study in outpatient clinical trials.¹⁶⁰ DMT also poses its own unique challenges; it is orally inactive unless coadministered with a monoamine oxidase inhibitor, and there are very little clinical data from investigating other routes of administration.¹⁶¹ For these reasons, psilocybin and MDMA are currently the most promising agents with which to begin investigation of psychedelic-assisted treatment for caregiver distress.

Therapeutic structure

The model of PAP used most widely in modern clinical trials involves a co-therapist dyad and consists of a nondirective and client-centered approach that combines preparatory therapy, a psychedelic dosing session(s), and integrative psychotherapy. The preparatory therapy before dosing is designed to build rapport, establish safety and trust between the participant and facilitators, define treatment goals and intentions, and make ready the individual for the psychedelic experience. Psychedelic dosing sessions themselves are typically administered with the proper “set and setting” to ensure safety and maximize the therapeutic benefit of the session.¹⁶²

This structure typically involves the participant maintaining an inward focus while lying down on a couch or bed, wearing eyeshades, and listening to a pre-prepared musical playlist via headphones—with the co-therapist dyad present in the room and ready to provide support if challenging experiences arise.¹⁶³ Following the dosing day, participants usually receive integration therapy to support contextualizing the content of the psychedelic experience and to learn how to apply relevant insights into their daily life.

Another model of PAP that has recently been studied in a clinical trial for patients suffering from HIV and AIDS incorporated group psychotherapy.¹⁶⁴ In addition to individual preparatory therapy, medication dosing, and integration therapy, all study participants attended twice weekly group psychotherapy throughout the duration of the trial. Using this approach, significant improvements in emotional distress and demoralization were reported along with strong praise from study participants for the group therapy, which allowed them to quickly connect, empathize, and feel closer to fellow participants, and ultimately improved outcomes.¹⁶⁴ Group psychotherapy will also be studied in an upcoming trial using MDMA-assisted psychotherapy for veterans with PTSD (NCT05173831).

Caregiving often affects entire families and involves complex interpersonal dynamics. Therefore, incorporating group or even family-wide psychotherapy into PAP may be useful for treating caregiver distress and for supporting the family unit. Some of the earliest trials with psychedelics included elements of family and group therapy, which were felt to improve patient outcomes.^49,165 Studies with MDMA have also demonstrated that it is not only safe but may also be beneficial to relationships when two individuals share the dosing experience.^131,166 Pertinent to caregivers, an upcoming clinical trial will investigate the use of MDMA-assisted therapy for the treatment of adjustment disorder in dyads of cancer patients and their concerned significant other (NCT05584826). Therefore, it may be helpful in some circumstances to consider including both the caregiver and care recipient in a combined medication session or a joint psychotherapy process, assuming that the care recipient has no contraindications to treatment and is willing to participate.

Conclusions

This is the first article to specifically propose the integration of pharmacotherapy with psychotherapy in the form of PAP for the treatment of caregiver distress. Unlike current interventions, which typically target only certain symptoms of the condition, PAP could potentially address all biopsychosocial–spiritual dimensions of caregiver distress and should therefore be rigorously studied for this indication.

Authors' Contributions

Conception of project: N.D.G. and P.D.P. Literature review: N.D.G., S.K.P., L.A.W., C.M., and P.D.P. Analysis of literature: all authors. Wrote the article: N.D.G., S.K.P., L.A.W., and P.D.P. Assisted in writing and critically revised the article: all authors.

Author Disclosure Statement

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding Information

The authors received no financial support for the research, authorship, and/or publication of this article.