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The Safety and Efficacy of Psychedelic-Assisted Therapies for Older Adults: Knowns and Unknowns

Published:September 05, 2022DOI:https://doi.org/10.1016/j.jagp.2022.08.007

      Highlights

      • What is the primary question addressed by this study?
        What is the potential benefit of psychedelic medications in older adults?
      • What is the main finding of the study?
        Psychedelics and related compounds have shown promise in the treatment of a variety of conditions that are prevalent in older adults, including mood disorders, the distress associated with a serious illness, PTSD, substance use disorders, and dementia. Although published research on psychedelic medications has suggested that they are relatively safe when given in controlled conditions, few older people with multimorbidity have been included in clinical trials to date, making the generalizability to older adults with multimorbidity uncertain.
      • What is the meaning of the finding?
        Given the potential of psychedelic compounds to be beneficial to older adults with a variety of conditions, more research is needed to establish the safety and efficacy of psychedelics in older adults, particularly those with multi-morbidity.

      Abstract

      Psychedelics and related compounds have shown efficacy for the treatment of a variety of conditions that are prevalent among older adults, including mood disorders, the psychological distress associated with a serious medical illness, post-traumatic stress disorder (PTSD), and prolonged grief disorder. Psychedelics also have properties that could help provide therapeutic benefits for patients with dementing disorders, as well as promoting personal growth among healthy older adults. This article focuses on psilocybin, a classic psychedelic, and MDMA, a substituted amphetamine with properties similar to classic psychedelics. Both act on the 5HT2A receptor. Psychedelics can be safely administered to healthy adults in controlled conditions. However, both psilocybin and MDMA can increase blood pressure and heart rate, which could be a concern if used in older adults with cardiovascular disease. Very few older adults or patients with serious comorbidities have been included in clinical trials of psychedelics to date, raising the question of how generalizable study results are for the patients that most geropsychiatrists will be treating. Research on the neurophysiologic and mechanistic effects of psychedelics in older adults could also provide insights into the aging brain that could have clinical applications in the future. Given the potential of psychedelic compounds to benefit older adults, more research is needed to establish safety and efficacy among older adults, particularly those with multi-morbidity.

      Keywords

      PSYCHEDELIC-ASSISTED THERAPIES FOR OLDER ADULTS

      The past decade has seen a groundswell of interest in the use of psychedelic medicines for conditions such as post-traumatic stress disorder (PTSD) and the distress associated with a serious medical illness.
      • Reiff CM
      • Richman EE
      • Nemeroff CB
      • et al.
      Psychedelics and Psychedelic-Assisted Psychotherapy.
      The enthusiasm for these compounds is understandable, given the dramatic accounts of improvement reported in both peer-reviewed journals and the popular press.
      • Jacobs A.
      The Psychedelic Revolution is Coming.
      A number of localities have decriminalized psilocybin-containing mushrooms and other psychedelics, and Oregon's measure 109 has established a path for legal “psilocybin services” to be offered in the state starting in 2023. Research is ongoing that may result in reclassification for specific indications of 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin from Schedule 1 of the Controlled Substances Act, paving the way for improved treatment access and expanded research opportunities.
      Professionals who work with older adults are often appropriately skeptical about whether the benefits to younger adults shown in clinical trials can be generalized to older, frailer patients, most of whom are excluded from clinical trials.
      • van Marum RJ
      Underrepresentation of the elderly in clinical trials, time for action.
      That same skepticism should extend to psychedelics. The conditions for which psychedelics appear to be helpful are prevalent among older adults, so it is important that researchers learn more about the safety and efficacy of these compounds in older patients who may be more vulnerable to adverse effects such as cardiovascular events, dysrhythmias, falls, or delirium.
      This paper will review the basic pharmacology of psychedelics, the primary findings of the most important trials that are relevant to older adults, the prevalence of conditions in older adults that might benefit from psychedelic therapies, and what is known about the safety of these substances in older adults, and some thoughts on next steps for studying these medicines in older adults. The term “psychedelic-assisted therapy,” refers to the combination of at least one structured and closely monitored psychedelic dosing session with several hours-worth of psychosocial support provided both before and after the dosing session. Because the most robust recent research that is potentially relevant to older adults has been conducted with MDMA and psilocybin, this paper will focus on those two medications.

      BACKGROUND

      Indigenous peoples have used natural substances containing psychedelic compounds for thousands of years to induce expanded states of consciousness for rites of passage, healing, and to foster spiritual growth and community interconnectedness.
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      Anthropology, Shamanism, and Hallucinogens.
      Western researchers began studying these compounds after the isolation of mescaline in 1897, the chance discovery of LSD's psychoactive properties by Albert Hoffman in 1943, and Hoffman's later synthesis of psilocybin in 1959.
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      Hundreds of research studies involving thousands of doses of psychedelics were conducted in the 1950s and 1960s for alcoholism, depression, war trauma, and the anxiety associated with a terminal diagnosis.
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      Psychiatry & the psychedelic drugs. Past, present & future.
      The drugs were also studied for their potential to induce mystical-type states, spur creativity, improve problem-solving, and enhance well-being. Although the results of many of these studies were promising, many lacked the type of study design that would be expected of an experimental protocol today.
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      • Walter H.
      The History of Psychedelics in Psychiatry.
      In 1970 LSD and other psychedelics were placed into the most restrictive category of drugs in the USA, Schedule 1, effectively halting human research for more than two decades.
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      Effects of Schedule I drug laws on neuroscience research and treatment innovation.
      There has been a so-called renaissance of psychedelic research in the last two decades that has made tremendous strides in furthering understanding of the potential usefulness of these compounds using rigorous scientific protocols. Correctly, it has been pointed out that much of the research has not been inclusive enough of people of color and other marginalized groups.
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      • Labate BC
      Diversity, equity, and access in psychedelic medicine.
      We would add older adults to the list of inadequately represented study participants.

      Pharmacology of the Psychedelics

      The so-called classic psychedelics include psilocybin, derived from certain mushroom species, mescaline, derived from peyote and San Pedro cacti, and LSD, a synthetic compound derived from the ergot fungus, among others. Extensive research has demonstrated that the classic psychedelics are agonists or partial agonists of serotonin (5-HT) receptors, among which the most important for their psychedelics effects appears to be the 5-HT2A receptor, found in brain, particularly the frontal cortex, the claustrum, parts of the limbic system, and the basal ganglia. In the periphery, the 5HT2A receptor is found in vascular smooth muscle, including the gastrointestinal tract.
      • Nichols D
      Hallucinogens.
      MDMA is a novel substituted amphetamine that has some similarity in its effects to classic psychedelics, but primarily produces an enhanced sense of empathy, elevation of mood, and less sensory disruption than classic psychedelics. MDMA stimulates release and inhibits reuptake of serotonin, dopamine, and norepinephrine.
      • de la Torre R
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      Non-linear pharmacokinetics of MDMA ('ecstasy') in humans.
      Similar to classic psychedelics, it has affinity for 5-HT2A receptors.
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      • Hoener MC
      • Liechti ME
      Monoamine transporter and receptor interaction profiles of a new series of designer cathinones.
      Psychedelics may act to suppress typical brain communication functions (e.g., the Default Mode Network DMN). This alteration in brain function is associated with the subjective experiences of timelessness, somatic boundlessness, ego dissolution, and perceptual alterations. The clinical response to psychedelic therapies may be mediated, in part, by the induction of a “mystical-type,” or transcendent, experience in participants.
      • Griffiths R
      • Richards W
      • Johnson M
      • McCann U
      • Jesse R
      Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance.
      • Ross S
      • Bossis A
      • GussRoss J
      • et al.
      Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.
      • Bogenschutz MP
      • Forcehimes AA
      • Pommy JA
      • et al.
      Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study.
      Classic psychedelics may also have anti-inflammatory, analgesic, and other properties that could contribute to their therapeutic effects.
      • Flanagan TW
      • Nichols CD.
      Psychedelics as anti-inflammatory agents.
      ,
      • Castellanos JP
      • Woolley C
      • Bruno K
      • et al.
      Chronic pain and psychedelics: a review and proposed mechanism of action.
      Most adverse effects of psilocybin and MDMA have been reported to be mild-to-moderate in severity when administered to healthy volunteers and clinical populations in an optimal therapeutic environment in conjunction with psychosocial support and careful screening.
      • Bender D
      • Hellerstein DJ.
      Assessing the risk–benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research.
      ,
      • Jerome JL
      • Feduccia AA
      • Wangerome JB.
      Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials.
      From the perspective of physiologic toxicity, psilocybin and MDMA are safe drugs when used at standard doses in healthy adults.
      • Bender D
      • Hellerstein DJ.
      Assessing the risk–benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research.
      • Jerome JL
      • Feduccia AA
      • Wangerome JB.
      Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials.
      • Vizeli P
      • Liechti ME.
      Safety pharmacology of acute MDMA administration in healthy subjects.
      In a review of adult healthy volunteers and patients (N=257) administered psilocybin across 11 clinical trials the most common physical side effects of psilocybin include hypertension, tachycardia, nausea, and headache; most participants were <65 years old, but at least a few were >70 years old.
      • Bender D
      • Hellerstein DJ.
      Assessing the risk–benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research.
      In phase I and II studies of MDMA-assisted psychotherapy for PTSD (N=107, mean age 41), the most commonly reported physical reactions on the day of the medication session were anxiety, bruxism, lack of appetite, headache, and fatigue.
      • Bender D
      • Hellerstein DJ.
      Assessing the risk–benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research.
      • Jerome JL
      • Feduccia AA
      • Wangerome JB.
      Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials.
      • Vizeli P
      • Liechti ME.
      Safety pharmacology of acute MDMA administration in healthy subjects.
      • Mithoefer MC
      • Mithoefer AA
      • Feduccia AA.
      3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial.
      The only drug-related serious adverse event in these trials was a transient increase in pre-existing ventricular ectopy that required overnight monitoring. In a pooled analysis of MDMA trials in healthy adults (N=166, mean age 25), MDMA increased systolic blood pressure to >160 mmHg, heart rate >100 beats/min, and body temperature >38°C in 33%, 29% and 19% of the subjects, respectively.
      • Jerome JL
      • Feduccia AA
      • Wangerome JB.
      Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials.
      In a phase III trial of MDMA for PTSD (N=90, mean age 41) no treatment-emergent serious adverse events were seen in the MDMA group.
      • Mitchell JM
      • Bogenschutz M
      • Lilienstein A
      • et al.
      MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.
      Potential adverse psychological reactions to psychedelics include precipitating protracted psychotic and manic states.
      • Strassman R.
      Adverse reactions to psychedelic drugs: A review of the literature.
      and although the precise risk of inducing such states with psychedelics is unknown, most trials have excluded patients at risk for these reactions. In addition, patients under the influence of psychedelic compounds can be extremely vulnerable, so conducting therapeutic sessions with clear physical and professional boundaries and careful screening of potential clients is critical to safe and therapeutic use.
      • BT Anderson
      • Danforth AL.
      • Grob CS.
      Psychedelic medicine: Safety and ethical concerns.
      Acute adverse psychological reactions remain the biggest concern in classic psychedelic administration, and may include fear, panic, paranoia and aggression. Such experiences have been reported most often in the context of nonmedical use.
      • Carbonaro TM
      • Bradstreet MP
      • Barrett FS
      • et al.
      Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences.
      In a phase III trial of MDMA for PTSD (N=90), suicidal ideation occurred in 3 of 46 patients in the MDMA arm versus 5 of 44 patients in the placebo arm. One participant withdrew from the trial after experiencing negative emotions related to clinical assessment questions and an MDMA session.
      • Mitchell JM
      • Bogenschutz M
      • Lilienstein A
      • et al.
      MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.
      Researchers have learned that “set” (the mental state with which the participant enters the experience), “setting” (the physical environment, support staff, and other features such as music that surround the experience), and the correct dose of the psychedelic are critical elements than can promote a therapeutic experience and reduce the risk of harm from an acute, challenging psychological reaction. Furthermore, the counseling portion of psychedelic therapy is essential. Frequently patients relate that difficult psychological material encountered during a session while distressing at the moment, can nevertheless be therapeutic when managed by a skilled therapist.
      • Belser AB
      • Agin-Liebes G
      • Swift TC
      • et al.
      Patient Experiences of Psilocybin-Assisted Psychotherapy: An Interpretative Phenomenological Analysis.
      While the controlled use of psilocybin and MDMA have been associated with few severe adverse reactions, and almost no serious adverse reactions, in the modern phase I, II, and III trials conducted over the last thirty years, most study participants administered psychedelics have been relatively healthy and very few were over the age of 60.

      Mood Disorders

      Life changes, loss, and declining health can contribute to depression among older adults. Two to 5% of community-dwelling adults aged 65 years and older meet diagnostic criteria for major depression.
      • Unutzer J
      • Park M.
      Older adults with severe, treatment-resistant depression.
      The prevalence of major depressive disorder and overall depressive disorders increases with advancing age and worsening health status.
      • Unutzer J
      • Park M.
      Older adults with severe, treatment-resistant depression.
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      • Konig HH
      • et al.
      Age- and gender-specific prevalence of depression in latest-life–systematic review and meta-analysis.
      • Tetsuka S.
      Depression and Dementia in Older Adults: A Neuropsychological Review.
      Depression and depressive symptoms are associated with poor health outcomes and worse qualify of life in older adults.
      • Unutzer J
      • Park M.
      Older adults with severe, treatment-resistant depression.
      Yet, one-half to two-thirds of depressed older adults fail to remit with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).
      • Cristancho P
      • Lenard E
      • Lenzee EJ
      • et al.
      Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM): Study Design and Treatment Characteristics of the First 396 Participants Randomized.
      • Schatzberg A
      • Roose S.
      A double-blind, placebo-controlled study of venlafaxine and fluoxetine in geriatric outpatients with major depression.
      In addition, SSRIs and taking daily medications are associated with falls and other adverse effects in older adults.
      • Bartlett G
      • Abrahamowicz M
      • Grad R
      • et al.
      Association between risk factors for injurious falls and new benzodiazepine prescribing in elderly persons.
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      • van den Bemt B
      • Weerdesteyn V
      • et al.
      Unraveling the association between SSRI use and falls: an experimental study of risk factors for accidental falls in long-term paroxetine users.
      For all of these reasons, novel approaches for addressing treatment-resistant mood disorders in older adults are clearly needed.
      The FDA recently designated psilocybin as a “breakthrough therapy” for both major depression and treatment-resistant depression, giving it priority consideration in the regulatory process.
      • Reiff CM
      • Richman EE
      • Nemeroff CB
      • et al.
      Psychedelics and Psychedelic-Assisted Psychotherapy.
      Psilocybin-assisted therapy has the potential to be a valuable treatment modality for older adults with treatment-resistant depression if safety and efficacy can be robustly demonstrated in this population. Psychedelic-assisted therapy occurs in a limited number of sessions with a limited number of medication administrations, and instead of being an adjunctive treatment to conventional pharmacotherapies like SSRIs, would theoretically be used as an alternative to these drugs. Results from one open-label pilot trial in treatment-resistant depression (N=20, mean age 44 years) and one randomized double-blind waitlist-controlled trial in major depression (N=24, mean age 40 years) suggest that psilocybin therapy may produce large pre-post improvements in depressive symptoms (Cohen's d >2) that persist for weeks after a single dose of the medication.
      • Carhart-Harris R
      • Bolstridge M
      • Day CMJ
      • et al.
      Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.
      ,
      • Davis AK
      • Barrett FS
      • May DG
      • et al.
      Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.
      A phase II double-blind randomized trial of two doses of psilocybin vs daily escitalopram (both with psychosocial support) in major depression (N=59, mean age 41 years) also resulted in clinically meaningful pre-post changes in depression symptoms, but did not ultimately demonstrate superiority on the primary endpoint at six weeks.
      • Carhart-Harris R
      • Blemings A
      • Nutt DJ.
      Trial of Psilocybin versus Escitalopram for Depression.
      As with other psychedelic trials, few patients in these early phase trials of psilocybin for depressive disorders were over the age of 60, and no patients were above the age of 70.

      Psychological Distress Associated with Serious Medical Illness

      Three-quarters of deaths occur in people aged 65 and older,

      Mortality in the United States, 2019, NCHS Data Brief No. 395 (online). Available at cdc.gov/nchs/products/databriefs/db395.htm. Accessed April 1, 2022

      which means that older adults face terminal illnesses more than any other age group. Patients with cancer and other life-threatening medical illnesses often develop psychological distress with depressed mood, anxiety, demoralization, and reduced quality of life. Demoralization, a form of existential suffering characterized by poor coping and a sense of helplessness, hopelessness, and a loss of meaning and purpose in life, is highly prevalent among patients with serious medical illness.
      • Robinson S
      • Kissane DW
      • Brooker J
      • et al.
      A systematic review of the demoralization syndrome in individuals with progressive disease and cancer: A decade of research.
      Over 30% of cancer patients experience mood and other psychiatric disorders,
      • Caruso R
      • Breitbart W.
      Mental health care in oncology. Contemporary perspective on the psychosocial burden of cancer and evidence-based interventions.
      and such disorders are associated with poor clinical outcomes.
      • Li M
      • Fitzgerald P
      • Rodin G.
      Evidence-based treatment of depression in patients with cancer.
      Standard treatments, including antidepressants, benzodiazepines, and various behavioral therapies, often have limited-to-modest efficacy in these patients.
      • Bauereiss N
      • Obermaier S
      • Ozunal SE
      • et al.
      Effects of existential interventions on spiritual, psychological, and physical well-being in adult patients with cancer: Systematic review and meta-analysis of randomized controlled trials.
      ,
      • Faller H
      • Schuler M
      • Richard M
      • et al.
      Effects of psycho-oncologic interventions on emotional distress and quality of life in adult patients with cancer: systematic review and meta-analysis.
      In addition, possible drug-drug interactions and the long delay in onset of action of typical antidepressants (e.g., weeks) often make them impractical for patients with medical co-morbidities and short life expectancy.
      A pilot trial at UCLA (N=12, age range 36 – 58 years), and two phase II trials at Johns Hopkins University (N=51, mean age 56 years) and NYU (N=29, mean age 56 years) demonstrated that psilocybin therapy can be safe, and can produce sustained improvements in mood, anxiety, and well-being in patients facing a life-threatening cancer diagnosis.
      • Ross S
      • Agin-Liebes G
      • Lo S
      • et al.
      Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer.
      • Griffiths RR
      • Johnson MW
      • Carducciet MA
      • et al.
      Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.
      • Grob CS
      • Danforth AL
      • Chopra GS
      • et al.
      Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer.
      • Agin-Liebes GI
      • Malone T
      • Yalch MM
      • et al.
      Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.
      In both the NYU and the Johns Hopkins studies, a majority of patients receiving high dose psilocybin (0.3 – 0.43 mg/kg po) rated the experience as one of the most personally meaningful of their lives.
      • Ross S
      • Bossis A
      • GussRoss J
      • et al.
      Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.
      ,
      • Grob CS
      • Danforth AL
      • Chopra GS
      • et al.
      Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer.
      There were no treatment-related serious adverse events in any of these trials, and yet there were few patients over the age of 65 in these studies.
      A related, small pilot study (N=18) was conducted at UCSF with demoralized older gay men who were living with long-term HIV/AIDS, all of whom were ≥50 years old (nine were 60-64 years old, one was ≥65 years old), and many of whom had other serious comorbid illnesses. This uncontrolled, open-label pilot study demonstrated the feasibility of administering high-dose psilocybin (0.3–0.36mg/kg po) with adjunctive group therapy to an older and clinically complex patient population, and also resulted in zero treatment-related serious adverse events.
      • Anderson BT
      • Danforth A
      • Daroff PR
      • et al.
      Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study.
      MDMA-assisted psychotherapy has also been assessed in a pilot study for the treatment of anxiety related to a life-threatening illness.
      • Wolfson PE
      • Andries J
      • Feduccia AA
      • et al.
      MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study.
      This small double-blind randomized placebo-controlled trial (N= 18, mean age 55 years) showed a clinically meaningful pre-post improvement in anxiety following two MDMA-assisted therapy sessions with a mean (SD) improvement in STAI-trait score of -23.5 (13.2), but this was not statistically superior to the control arm. There were no reported treatment-related serious adverse events.
      • Wolfson PE
      • Andries J
      • Feduccia AA
      • et al.
      MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study.

      Post-traumatic Stress Disorder (PTSD)

      Epidemiologic data on PTSD in older adults is somewhat limited, but studies examining smaller subsets of the population demonstrate a reduction in the prevalence of PTSD with aging.
      • Clapp JD
      • Beck KG.
      Treatment of PTSD in older adults: Do cognitive-behavioral interventions remain viable?.
      However, older people who do have PTSD tend to have chronic and fluctuating symptoms, and have high rates of comorbid conditions including depression, anxiety, pain, and impairments in quality of life.
      • Chopra MP
      • Zhang H
      • Pless Kaiser A
      • et al.
      PTSD is a chronic, fluctuating disorder affecting the mental quality of life in older adults.
      Treatments for PTSD have included various types of psychotherapy and medications. Only four drugs—sertraline, paroxetine, fluoxetine, and venlafaxine–are approved by the FDA for PTSD. An estimated 40–60% of patients do not have an adequate clinical response to either drugs, therapy, or both, highlighting the need for novel approaches.
      • Nøhr AK
      • Eriksson H
      • Hobart M
      • Moltke I
      • Buller R
      • Albrechtsen A
      • Lindgreen S
      Predictors and trajectories of treatment response to SSRIs in patients suffering from PTSD.
      Six phase II randomized trials of MDMA-assisted psychotherapy for treatment of PTSD were conducted from 2004 to 2017 (total N=107 across six studies). Active doses of MDMA (75–125 mg) or control doses of inactive placebo or low-dose MDMA (25–40 mg) were combined with manualized “inner-directed” psychotherapy in which participants were supported by a male and female therapy team.
      • Jerome JL
      • Feduccia AA
      • Wangerome JB.
      Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials.
      ,
      • Mithoefer MC
      • Mithoefer AA
      • Feduccia AA.
      3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial.
      ,
      • Mithoefer MC
      • Feduccia AA
      • Jerome L
      • et al.
      MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials.
      Patients randomized to the active treatment arm had marked improvements in standard PTSD assessments scales (e.g., CAPS-5) that were both clinically and statistically significant. Due to these promising results, the FDA has also designated MDMA a “breakthrough therapy.”
      • Reiff CM
      • Richman EE
      • Nemeroff CB
      • et al.
      Psychedelics and Psychedelic-Assisted Psychotherapy.
      This was followed by a multi-center phase III trial (N=90) in patients with severe PTSD that found a large and statistically significant greater improvement in PTSD symptoms in patients administered MDMA vs placebo.
      • Vizeli P
      • Liechti ME.
      Safety pharmacology of acute MDMA administration in healthy subjects.
      Nevertheless, the average ages of study participants in both the phase I/II trials and the phase III trial was 41 years, with very few patients over the age of 50, making the generalizability to an older population unknown.

      Substance Use Disorders

      Nicotine and alcohol abuse are significant but sometimes under-recognized problems among older adults. About 10% of people over the age of 60 are current tobacco users, with the percentage decreasing with increasing age.
      • Wallace AE
      • Sairafi NA
      • Weeks WB.
      Tobacco cessation counseling across the ages.
      Approximately 10 – 15% of men and 5 – 7% of women engage in alcohol use that is considered high risk.
      • Sewell DD
      • Koh S
      • Maglione J
      • et al.
      General Topics in Geriatric Psychiatry.
      Pilot studies of psilocybin and MDMA have shown promise in alcohol and nicotine use disorders.
      • Bogenschutz MP
      • Forcehimes AA
      • Pommy JA
      • et al.
      Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study.
      ,
      • Johnson MW
      • Garcia-Romeu A
      • Cosimano MP
      • et al.
      Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction.
      ,
      • Sessa B
      • Higbed L
      • O'Brien S
      • et al.
      First study of safety and tolerability of 3, 4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder.
      The studies done to date have been small but have included some patients over the age of 60.
      • Bogenschutz MP
      • Forcehimes AA
      • Pommy JA
      • et al.
      Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study.
      ,
      • Johnson MW
      • Garcia-Romeu A
      • Cosimano MP
      • et al.
      Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction.
      • Sessa B
      • Higbed L
      • O'Brien S
      • et al.
      First study of safety and tolerability of 3, 4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder.

      Alzheimer Disease and other Dementias

      It is estimated that 11% of people over the age of 65 have dementing illnesses, with Alzheimer disease (AD)as the primary cause. There are theoretical reasons to consider psychedelics as a potential treatment for AD and other dementias.
      • Flanagan TW
      • Nichols CD.
      Psychedelics as anti-inflammatory agents.
      • Vann Jones SA
      • O'Kelly A
      Psychedelics as a Treatment for Alzheimer's Disease Dementia.
      • Garcia-Romeu A
      • Darcy S
      • Jackson H
      • White T
      • Rosenberg P.
      Psychedelics as Novel Therapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms.
      • Harvey JA.
      Role of the serotonin 5-HT2A receptor in learning.
      • Bornemann J.
      The viability of microdosing psychedelics as a strategy to enhance cognition and well-being - an early review.
      Psilocybin has the potential to reduce neuronal and synaptic loss, as well as inflammation. In addition, psychedelics induce brain plasticity and modify connectivity between brain regions.
      • Vann Jones SA
      • O'Kelly A
      Psychedelics as a Treatment for Alzheimer's Disease Dementia.
      • Garcia-Romeu A
      • Darcy S
      • Jackson H
      • White T
      • Rosenberg P.
      Psychedelics as Novel Therapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms.
      • Harvey JA.
      Role of the serotonin 5-HT2A receptor in learning.
      • Bornemann J.
      The viability of microdosing psychedelics as a strategy to enhance cognition and well-being - an early review.
      Classic psychedelics may play a role in learning and memory.
      • Harvey JA.
      Role of the serotonin 5-HT2A receptor in learning.
      There are anecdotal self-reports that micro-dosing of psychedelics is associated with enhanced cognitive function, but there is no high-quality evidence to support this practice for cognitive enhancement.
      • Bornemann J.
      The viability of microdosing psychedelics as a strategy to enhance cognition and well-being - an early review.
      Neuropsychiatric symptoms, such as aggression, agitation, irritability, and depression, are some of the most disturbing symptoms of dementia, occurring in over 40% of patients with dementia.
      • Lyketsos CG
      • Lopez O
      • Jones B
      • et al.
      Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study.
      • Fernandez-Martinez M
      • Castro J
      • Molano A
      • et al.
      Prevalence of neuropsychiatric symptoms in Alzheimer's disease and vascular dementia.
      A reduced serotonergic neurotransmission in AD appears to be one of pathophysiologic correlates with such behaviors.
      • Garcia-Romeu A
      • Darcy S
      • Jackson H
      • White T
      • Rosenberg P.
      Psychedelics as Novel Therapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms.
      Since the classic psychedelics are agonists or partial agonists at the brain serotonin 5-HT2A receptors, they could, theoretically, ameliorate such behaviors. There is currently a pilot study to examine the potential of psilocybin to treat neuropsychiatric symptoms in patients with early-stage dementia or mild cognitive impairment (ClinicalTrials.gov NCT04123314).

      Grief

      Grief is a normal response to the kinds of loss which are common among older adults, including the deaths of spouses, friends, and the loss of functional abilities. Grief can become pathological when it is prolonged and associated with functional impairment.
      • Prigerson HG
      • Shear MK
      • Reynolds CF.
      Prolonged Grief Disorder Diagnostic Criteria—Helping Those With Maladaptive Grief Responses.
      Among bereaved adults, 7–10% are expected to develop prolonged grief disorder.
      • Prigerson HG
      • Shear MK
      • Reynolds CF.
      Prolonged Grief Disorder Diagnostic Criteria—Helping Those With Maladaptive Grief Responses.
      There are anecdotal data and some observational data suggesting that psychedelic therapies may be beneficial for people with prolonged grief disorder. To date, only one psychedelic trial has reported pre-post improvements in grief symptoms, but this was an uncontrolled, open-label pilot study.
      • González D
      • Cantillo J
      • Perez I
      • et al.
      Therapeutic potential of ayahuasca in grief: a prospective, observational study.
      Because prolonged grief disorder shares many clinical features with depression (i.e., dysphoria, guilt, anhedonia), it is plausible that patients with grief might benefit from psychedelic therapies.

      Psychedelic Use for Personal Growth

      Psychedelic therapies might also have benefits for older people who may not meet criteria for a formal psychiatric diagnosis. Normal aging may often be associated with periods of subclinical distress related to loss of function, loss of loved ones, loneliness, coping with a serious illness, or other normal human experiences. Old age in the modern world may be experienced as a time of diminution and loss of status and influence. Older adults’ location in multiple overlapping identities may exacerbate the role of inequities based on race, sexuality and ethnicity. If the social disruptions of aging intersect with stressors associated with other stigmatized identities throughout the lifespan, they may compound experiences of disenfranchisement and marginalization.
      • Bourgois P.
      • Holmes S.M.
      • Sue K.
      • et al.
      Structural vulnerability: operationalizing the concept to address health disparities in clinical care. Academic Medicine.
      Such stressors may trigger older individuals to re-evaluate their purpose in life and spiritual beliefs, or to seek new avenues for meaning-making, interpersonal connection, and personal growth. There is reason to believe that psychedelic therapies may provide psychological benefits even to healthy people seeking psychological and spiritual growth.
      • Griffiths RR
      • Johnson MW
      • Richards WA
      • et al.
      Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors.
      • Bossis A
      Psilocybin, Spirituality, and Palliative Care: Research and Implications.
      The states of consciousness and the mystical-type experiences that psychedelic therapies can produce have been linked with improved clinical outcomes, psychological insight, and general psychological and spiritual well- being.
      • Paloutzian RF
      • Bufford RK
      • Wildman AJ
      Spiritual well-being scale: Mental and physical health relationships.
      However, older adults may historically have categorized psychedelic drug use as dangerous and deviant, and may fear the intersection of legal jeopardy with oppression based on other stigmatized behaviors and identities. More research is needed on whether psychedelics are beneficial, safe, and acceptable for older adults seeking personal growth.

      Potential Concerns about Psychedelics in Older Adults

      Between 2015 and 2050, the proportion of the world's population over 60 years will nearly double from 12% to 22%.

      Ageing and Health Fact Sheet. 2021, World Health Organization (online). Available at: who.int/news-room/fact-sheets/detail/ageing-and-health. Accessed April 2, 2022

      Sixty percent of older adults manage two or more chronic conditions.

      Healthy People 2020, Older Adults (online). Available athealthypeople.gov/2020/topics-objectives/topic/older-adults#2. Accessed April 2, 2020

      Hypertension is the most common disease of older adults, with an estimated 75% of people over the age of 60 carrying the diagnosis.
      • Ostchega Y.
      • et al.
      Hypertension Prevalence amondt adults aged 18 and over: United States, 2017-2018.
      Older adults are vulnerable to syndromes such as falls, frailty, and delirium. As more older adults enroll in psychedelic therapy trials, attention should be paid to the possibility that these comorbidities or syndromes might be exacerbated by these experimental therapies.
      While psychedelics have the potential to aid older adults with depression, demoralization, trauma-related disorders, and other conditions, more needs to be known about the safety and efficacy of these compounds in older adults, particularly those with comorbid conditions. Very few older adults have been included in the clinical trials of psychedelic agents, and those who were included tended to be the “young old” (i.e., less than age 74) and relatively healthy.
      Pharmacokinetics and pharmacodynamics are altered in older adults, and the prevalence of polypharmacy among older adults further complicates the issue of drug safety. There are recommendations for many medications, including antidepressants, to be started at a lower dose and titrated up more slowly than in younger adults. Whether the same is true for psychedelics is unknown and warrants further study. A post hoc analyses of pooled data from several previous studies that administered body weight-adjusted doses of psilocybin of 20mg/70kg and 30mg/70 kg -found no significant associations between age, race, sex, or weight of the participant and psilocybin subjective effects. Nevertheless, associations between these variables and adverse reactions were not assessed. The oldest participant included in this analysis was 71; there were few older participants overall, and it was a relatively healthy population.
      • Garcia-Romeu A
      • Barrett FS
      • Carbonaro TM
      • et al.
      GriffithsRR. Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches.
      Cardiovascular safety is a particular concern, given the prevalence of hypertension, stroke, and heart disease among older adults. For instance, one of the few studies to administer a high-dose of a psilocybin to older, more complex patients found higher rates of moderate-to-severe hypertension during the medication session than were reported in other studies using a similar dose of the drug.
      • Anderson BT
      • Danforth A
      • Daroff PR
      • et al.
      Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study.
      In an escalating dose pharmacokinetic study, psilocybin was shown to increase the QTc interval in a dose-dependent manner, but likely not to a clinically significant extent when administered in doses ≤30 mg orally.
      • Dahmane E
      • Hutson PR
      • Gobburu JVS.
      Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Psilocybin/Psilocin.

      Recommended Next Steps

      The underlying neurophysiologic mechanisms responsible for the clinical effects observed with psychedelic administration are now being investigated in translational and clinical research. How these substances work in older as opposed to younger brains, is an avenue worthy of research. For example, changes seen in the normal aging brain include a loss of connectivity across several brain networks, which psychedelics, as potential promoters of neuroplasticity and synaptogenesis, might impact.
      • de Vos CMH
      • Mason NL
      • Kuypers KPC.
      Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics.
      ,
      • Shafer AT
      • Beason-Held L
      • An Y
      • et al.
      Default mode network connectivity and cognition in the 47aging brain: the effects of age, sex, and APOE genotype.
      Further research into the potential of psychedelic medicines to impact learning, memory, mood, inflammation, neuroplasticity as well as the neurophysiologic mechanisms of those actions, could make important contributions to the basic science of the aging brain, and potentially, clinical geropsychiatry.
      Future studies should include more older adults, as well as other more marginalized populations, with careful attention to addressing safety as well as efficacy concerns. Given the tendency of psilocybin, MDMA and other psychedelics to increase blood pressure and heart rate, for MDMA to increase temperature, and for psilocybin to prolong the QTc interval, protocols should be developed to ensure that cardiovascular harms are avoided. Assuming that phase III trials of psychedelics continue to confirm the promising results found in earlier trials, it would be reasonable for researchers to develop a psychedelic research agenda specifically tailored to the clinical issues facing older adults.

      CONCLUSION

      Older age is associated with many health conditions that could potentially benefit from psychedelic-assisted therapy, including the distress associated with a serious illness, depression, PTSD, prolonged grief disorder, substance use disorders, and dementia. While studies in healthy older adults suggest that psychedelics are safe when used in an optimal, controlled setting, there has not been enough research of older adults with serious comorbidities to establish safety in these populations. More research is needed to guide if and how these substances can be used safely in older adults and older adults with comorbid illness. More research is also needed to understand the mechanistic effects of psychedelics in the aging brain in both health and disease.

      Author Contributions

      All listed authors contributed to the writing and editing of the manuscript. Drs. Johnston and Anderson, as first and senior authors, made the major contributions, with Drs. Grob and Mangini also making significant contributions. The authors would like to thank Dr. Anthony Back, Dr. Tony Bossis, Dr. Ira Byock, and Dr. Mary Cosimano for their assistance in the preparation of this manuscript.

      DISCLOSURES

      None of the authors have significant conflicts of interest related to this paper. Dr. Grob receives research support from The Heffter Research Institute, The Multidisciplinary Association for Psychedelic Studies (MAPS), and The Steven and Alexandra Cohen Foundation. He serves on the Scientific Advisory Panel of Lobe Sciences. In the last three years, Dr. Anderson has received consulting fees from Journey Colab and he has received research support from the Heffter Research Institute and the Steven and Alexandra Cohen Foundation. Drs. Johnston and Mangini have no relevant disclosures.
      The authors would like to thank Dr. Anthony Bossis, Mary Cosimano, LMSW, Dr. Anthony Back, and Dr. Ira Byock for their help in the preparation of this manuscript.

      DATA STATEMENT

      The data has not been previously presented orally or by poster at scientific meetings.

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        Neurobiol Aging. 2021; 104: 10-23

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      • Expending Perspectives on the Potential for Psychedelic-Assisted Therapies to Improve the Experience of Aging
        The American Journal of Geriatric PsychiatryVol. 31Issue 1
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          There has been a resurgence of research into the therapeutic effects of psychedelic-assisted therapies (PAT) within the last two decades, with groundbreaking results for some of the most treatment-resistant psychiatric conditions, including depression, Psot-Traumatic Stress Disorder (PTSD), substance-use disorder, and end-of-life anxiety. Johnston et al. review these data regarding the unmet clinical needs in older adults and emphasize PAT's potential applications in this population.1 However, citing the lack of safety and efficacy data and the potentially heightened risks in patients over the age of 60, the authors rightly highlight that generalization of these findings to the geriatric population would be premature and that further research is warranted to define potential indications and safety guidelines.
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