Psychedelics for the treatment of depression, anxiety, and existential distress in patients with a terminal illness: a systematic review

In the paper

“Furthermore, it is important to note that besides Falk et. al. (2020), none of the ketamine studies included an active placebo other than lower doses of ketamine.”

What the sources say

• Disputed

  The Methods (Study design; page unavailable) describe a retrospective comparison, not an active-placebo-controlled study. Falk et al. state that the control group received the same specialized palliative care but was not treated with S-ketamine; the paper therefore does not support the claim that Falk et al. were an exception that used an active placebo. It does not establish what placebos the other ketamine studies used. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites Falk et al., 2020 sourceExperimental — accuracy not yet measured

In the paper

“After crossover, 12 months later (n = 9), both groups reported a decrease in anxiety.”

What the sources say

• Partly supported

  The Results > Clinical Response and Discussion (pages unavailable in our copy) say anxiety decreased after the experimental dose in both the blinded-treatment and crossover groups, with benefits sustained at the 12-month follow-up. Our copy does not substantiate the stated n = 9, and the Methods > Experimental Intervention specifies that follow-up was 12 months after each participant’s last LSD session, not 12 months after crossover for both groups. (LLM, conf=0.83)

  cites Gasser et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“The evidence for the pharmacological and psychological treatment of anxiety and depression in patients with a life-threatening illness is ambiguous (Rosenstein, 2011).”

What the sources say

• Partly supported

  In “Treatment of depression in end-of-life cancer care” (page unavailable), the paper says it is unknown whether established drug and psychotherapeutic treatments for depression work as well in cancer patients, and that antidepressant trials have yielded mixed results. The claim extends this uncertainty to anxiety treatment and to all life-threatening illnesses, neither of which the cited discussion evaluates. (LLM, conf=0.87)

  cites Rosenstein, 2011 sourceExperimental — accuracy not yet measured

In the paper

“To our knowledge, there is no published data regarding the effects of anxiolytic treatment in advanced cancer patients (Spencer et al., 2010).”

What the sources say

• Partly supported

  The Discussion says the authors were unaware of published randomized clinical trials of anxiety treatment in advanced cancer patients and calls for research on treatment effects. That supports a gap in trial evidence, but not the broader claim that no published data exist on the effects of anxiolytic drugs specifically. (LLM, conf=0.88)

  cites Spencer et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“No drug-related severe adverse events were reported.”

What the sources say

• Supported

  The Results > Safety passage explicitly states that neither the 200 μg LSD dose nor the 20 μg active placebo produced any drug-related severe adverse events. It distinguishes these from the less severe related adverse events that were reported. (LLM, conf=0.95)

  cites Gasser et al., 2014 source

In the paper

“Hence, there is a serious need for effective interventions with a sustained effect on existential distress, depression, and anxiety in patients with an incurable illness (Rosenbaum et al., 2019).”

What the sources say

• Supported

  In the main text (page unavailable), Rosenbaum et al. describe existential distress, anxiety, and depression in people facing cancer or other life-threatening illnesses and state that additional effective treatments are needed. They also emphasize the lasting benefits observed in trials for anxiety and depression, supporting the citing sentence’s call for sustained effects. (LLM, conf=0.87)

  cites Rosenbaum et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Improvements remained stable after 6 months and 1 year.”

What the sources say

• Supported

  Results, Table 3 (page not provided), shows that the improvement in the primary anxiety measure persisted at both follow-ups: the total STAI trait score was 61.1 at baseline, 36.4 at treatment exit, 33.6 at six months, and 34.2 at twelve months. This supports the claim that improvements remained stable through one year. (LLM, conf=0.92)

  cites Wolfson et al., 2020 source

In the paper

“Statistically significant improvements were found in anxiety, depression, sleep, global functioning, well-being, self-compassion, mindfulness, and attitudes regarding death, compared to baseline.”

What the sources say

• Partly supported

  The Results report statistically significant changes over time in anxiety, depression, sleep, global functioning, self-compassion, mindfulness, and several well-being measures. The claim overstates the baseline comparison: Table 3 does not show significant baseline-to-treatment-exit improvements for the death-attitude subscales, and some well-being subscales were also nonsignificant. (LLM, conf=0.88)

  cites Wolfson et al., 2020 sourceExperimental — accuracy not yet measured

In the paper

“They found robust reductions in self-reported demoralization, grief, and psychological trauma from baseline to end-of-treatment and after 3 months.”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Anderson et al., 2020 sourceExperimental — accuracy not yet measured

In the paper

“Depression scores after 1, 2, and 3 days decreased significantly more in all treatment groups than in the control group.”

What the sources say

• Supported

  The Results section, “Comparison of HAMD-17 scores” (page not provided), reports that depression scores in all treatment groups were significantly lower than in the control group at 1, 2, and 3 days. (LLM, conf=0.94)

  cites Wang et al., 2020 source

In the paper

“In one patient, decreased pain and panic attacks were reported after 1 week and lasted for the remaining months of the patients' life.”

What the sources say

• Supported

  Case Study 1 describes W as a hospice patient with fear of impending death. The account of her ketamine-enhanced psychotherapy reports that the following week she said her pain and recurrent panic attacks were gone; she remained comfortable without painkillers or psychotropic medication until her death seven months later. (LLM, conf=0.93)

  cites Kolp et al., 2007 sourceExperimental — accuracy not yet measured

In the paper

“Two studies from the same research group (Liu et al., 2020;Wang et al., 2020) compared racemic and S-ketamine and found S-ketamine to be superior to racemic ketamine in treating pain and depression”

What the sources say

• ?Not checked — no full text of the sourcecites Liu et al., 2020 source
• Supported

  The Conclusions state that this study found S-ketamine more effective than racemic ketamine for pain and depression in cervical carcinoma patients with mild or moderate depression. The Results clarify that the advantage was short-term and was significant for the high-dose group, not the low-dose group. This citation supports the finding from Wang et al.; it does not establish what the separately cited Liu et al. study found. (LLM, conf=0.90)

  cites Wang et al., 2020 source

In the paper

“Since 2008, 11 case studies were published in which ketamine was administered in varying dosages to a total of 12 palliative-or hospice care patients to treat anxiety, depression, and suicidality”

What the sources say

• ?Not checked — no full text of the sourcecites Stefanczyk-Sapieha et al., 2008 source
• Partly supported

  The Discussion (page not provided) reports two hospice patients whose depression and anxiety symptoms decreased after a single oral dose of ketamine. It does not document 11 case studies involving 12 patients, varying dosages, or treatment of suicidality. (LLM, conf=0.90)

  cites Irwin and Iglewicz, 2010 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Zanicotti et al., 2012 source

In the paper

“On day one, a significant effect of ketamine compared to midazolam was found on suicidality and depression.”

What the sources say

• Supported

  The ‘Ketamine reduces acute suicidal ideation and overall depression’ results report significantly lower suicidal-ideation scores in the ketamine group than in the midazolam group on day 1. They also report a significant day-1 effect on overall depression, measured by MADRS. The Participants section identifies the patients as newly diagnosed with cancer. (LLM, conf=0.95)

  cites Fan et al., 2017 source

In the paper

“On day seven, both effects were no longer significant.”

What the sources say

• Partly supported

  The Results section (“Ketamine reduces acute suicidal ideation and overall depression”; page unavailable) explicitly says the antidepressant effect was no longer significant at seven days. It reports significant reductions in suicidal-ideation scores on days one and three, but does not state whether the anti-suicidal effect was significant on day seven. Thus, the claim about both effects is only partly supported. (LLM, conf=0.83)

  cites Fan et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“Griffiths et al. (2016)(n = 51) reported significantly larger response (92% versus 32%) and remission (60% versus 1%) on depression and anxiety (76% vs. 24%; 52% vs. 12%, respectively) in the high-dose group compared to active placebo after 5 weeks.”

What the sources say

• Partly supported

  Table 6 (Results > Outcome measures) supports the five-week depression response rates of 92% versus 32% and the higher high-dose remission rate. But the low-dose depression remission rate was 16%, not the cited 1%; the cited anxiety rates match the table. The table marks the between-group differences as significant. (LLM, conf=0.94)

  cites Griffiths et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“In the first 3 days after the initial dose, 93% had a positive effect on the Global Clinical Impression Scale (GCI).”

What the sources say

• Supported

  The Results (Response to Ketamine; page not provided) report that 93% of patients had positive results on the CGI therapeutic-effect scale during days 0–3 after ketamine dosing. The paper abbreviates Clinical Global Impression as CGI, rather than GCI. (LLM, conf=0.93)

  cites Iglewicz et al., 2015 source

In the paper

“One month after the second session, the MDMA group had a borderline significant larger reduction in trait anxiety compared to the placebo group.”

What the sources say

• Supported

  The Results report a larger reduction in STAI-Trait anxiety in the MDMA group than in the placebo group one month after the second blinded session (−23.5 versus −8.8). The difference was close to, but did not reach, conventional statistical significance (p = 0.0558), consistent with the claim’s “borderline” qualifier. (LLM, conf=0.88)

  cites Wolfson et al., 2020 source

In the paper

“With one exception (Kolp et al., 2007), none of these studies included psychotherapy.”

What the sources say

• Supported

  The Introduction describes this paper as presenting two case studies of ketamine-enhanced psychotherapy for patients with end-of-life issues. This confirms the cited study as the psychotherapy exception; the comparison with the citing paper’s other studies is not attributed to Kolp et al. (LLM, conf=0.93)

  cites Kolp et al., 2007 source

In the paper

“Evidence of enduring effects of conventional psycho-or pharmacotherapy is limited or ambiguous (Akechi et al., 2008;Ostuzzi et al., 2018).”

What the sources say

• Partly supported

  The Actual method section says the meta-analysis used change from baseline to immediate post-treatment scores, so its findings do not establish enduring effects of psychotherapy. The review concerns patients with advanced cancer; it does not assess enduring effects of pharmacotherapy or support the claim across other populations. No page numbers are available in our copy. (LLM, conf=0.82)

  cites Akechi et al., 2008 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) says no trials assessed antidepressant follow-up response beyond 12 weeks, supporting limited evidence for enduring effects of pharmacotherapy. The review concerns people with cancer, so it does not establish the broader, unqualified claim about conventional therapy; it does not assess psychotherapy. (LLM, conf=0.85)

  cites Ostuzzi et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“Results of this study should be interpreted with caution due to study limitations such as a small sample size and lack of a control group after crossover.”

What the sources say

• Supported

  The Discussion identifies the small sample and study design as limitations. It also says that results after all participants received MDMA were limited in interpretation by the lack of a control group after crossover. (LLM, conf=0.95)

  cites Wolfson et al., 2020 source

In the paper

“However, studies indicate that ketamine dependence is not frequently observed in either chronic pain patients and depressed patients who receive daily ketamine dosages (Blonk et al., 2010;Schoevers et al., 2016).”

What the sources say

• ?Not checked — no full text of the sourcecites Blonk et al., 2010 source
• Partly supported

  The Safety and abuse potential section says addiction or misuse were not described as side-effects in the pain studies, and the Discussion says such problems were not prominent in the reviewed depression and pain studies. The paper does not establish how frequently dependence occurred specifically among patients receiving daily doses; it also notes that few studies systematically examined longer-term consequences. Page numbers were not available in our copy. (LLM, conf=0.83)

  cites Schoevers et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“Findings from clinical studies on ketamine for the treatment of addiction support the notion that spiritual (Krupitsky and Grinenko, 1997) or mystical-type experiences (Rothberg et al., 2021;Dakwar et al., 2018) may also mediate its therapeutic effect.”

What the sources say

• ?Not checked — no full text of the sourcecites Krupitsky and Grinenko, 1997 source
• ?Not checked — no full text of the sourcecites Rothberg et al., 2021 source
• Supported

  The Discussion reports a mediating role for mystical-type experience in ketamine’s behavioral effects on cocaine use disorder. It cautions that the study cannot establish whether the experience caused the benefit, consistent with the citing sentence’s qualified “may.” Dakwar et al. (2018) is cited for mystical-type, not spiritual, experiences. (LLM, conf=0.92)

  cites Dakwar et al., 2018 source

In the paper

“These psychedelic effects are usually either not addressed (Grabski et al., 2020;Mathai et al., 2020) or regarded as unwanted 'psychotic' side adverse effects in clinical trials (Romeo et al., 2015).”

What the sources say

• Supported

  Grabski et al. report that only a small number of studies assessed mystical experiences during ketamine administration (Discussion, p. 14). This supports the part attributed to Grabski et al.—that these psychedelic-type effects are usually not addressed. The separate claim about unwanted psychotic adverse effects is cited to Romeo et al., not Grabski et al. (LLM, conf=0.87)

  cites Grabski et al., 2020 source
• ?Not checked — no full text of the sourcecites Mathai et al., 2020 source
• ?Not checked — no full text of the sourcecites Romeo et al., 2015 source

In the paper

“Indeed, there appears to be little qualitative research on patient experiences with ketamine for the treatment of any mental disorder (Breeksema et al., 2020a).”

What the sources say

• Supported

  The Results (Study Characteristics, Table 2) list one qualitative ketamine study, concerning depressive disorder. The Discussion explicitly says there were “insufficient qualitative data” for ketamine, supporting the claim that little such research was available. (LLM, conf=0.93)

  cites Breeksema et al., 2020a source

In the paper

“Bladder dysfunction and lower urinary tract impairment have been described in long-term (˃ 2 years and ˃ 6 years, respectively) recreational ketamine use (Mak et al., 2011;Chen et al., 2018).”

What the sources say

• ?Not checked — no full text of the sourcecites Mak et al., 2011 source
• Supported

  The Discussion reports Mak et al.’s finding of bladder dysfunction among people using ketamine for more than two years. It also reports a mean use duration of 79.6 months among users with lower urinary tract symptoms and hypothesizes that use for more than six years may be associated with lower urinary tract impairment. The citing sentence describes these observations without asserting a causal threshold. (LLM, conf=0.87)

  cites Chen et al., 2018 source

In the paper

“Since all psychedelics exert effects rapidly and are known to induce mystical-type, peak, or transcendental effects that are correlated with therapeutic outcomes (Dore et al., 2019;Johnson et al., 2019;Barrett and Griffiths, 2018), these treatments may be especially helpful in the context of existential distress (Rosenbaum et al., 2019).”

What the sources say

• Supported

  In “Psychedelics for psychological and existential distress in palliative and cancer care” (page not provided), the authors describe psychedelic-assisted therapy as potentially highly effective for existential distress associated with life-threatening illness. They also say its psychospiritual effects appear well suited to the concerns of people facing cancer and nearness to death, supporting the citing sentence’s hedged claim. (LLM, conf=0.94)

  cites Rosenbaum et al., 2019 source

In the paper

“Finally, a recent exploratory pilot study that used MDMA-assisted psychotherapy to treat existential distress in patients with a life-threatening illness found lasting positive change on anxiety, depression, and attitudes towards death (Wolfson et al., 2020).”

What the sources say

• Supported

  The Discussion reports improvements in anxiety, depression, and attitudes regarding death after MDMA-assisted psychotherapy, with outcomes maintained at 6- and 12-month follow-up. It also notes that the long-term follow-up lacked a control group, so other factors could have contributed to the lasting changes. (LLM, conf=0.91)

  cites Wolfson et al., 2020 source

In the paper

“In a 1979 open-label pre-post study (Richards et al.), 30 cancer patients with depression, anxiety, and/or psychological isolation received DPT (75-127,5 mg, intramuscular [IM]) as an adjunct to brief psychotherapy.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Richards et al.

In the paper

“Seven of these participants were less anxious (about death)”

What the sources say

• ?Not checked — no full text of the sourcecites Gasser et al., 2015 source

In the paper

“Observer-rated pre-post comparisons showed significant improvements in depression, psychological isolation, anxiety, fear, and acceptance of death.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Kurland et al., 1972

In the paper

“All classical psychedelic treatment programs included some form of psychotherapy.”

In the paper

“The pre-post study by Pahnke et al. (1969) studied the effect of 'psychedelic peak therapy' (PPT) on 22 depressed terminal cancer patients.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Pahnke et al., 1969

In the paper

“Patients whose somatic state pre-treatment was graver showed fewer positive changes compared to the less severely ill patients.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Pahnke et al., 1969

In the paper

“According to the authors, the occurrence of a 'psychedelic peak experience' seemed positively correlated with therapeutic effect.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Pahnke et al., 1969

In the paper

“No serious adverse effects were reported.”

What the sources say

• ?Not checked — no full text of the sourcecites Richards et al., 1972
• ?Not checked — no full text of the sourcecites Grof et al., 1973 source

In the paper

“No (serious) adverse effects were reported.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Richards et al.

In the paper

“Setting, therapeutic context, and the role of 'mystical' or 'peak' experiences were considered as significant mediators of treatment effect and were thus given central roles.”

In the paper

“and six reported improved quality of life.”

What the sources say

• ?Not checked — no full text of the sourcecites Gasser et al., 2015 source

In the paper

“No (serious) adverse effects were reported.”

What the sources say

• ?Not checked — no full text of the sourcecites Grob et al., 2011 source

In the paper

“At the first and third postoperative day, depression scores in the ketamine group were significantly lower compared to the control group.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Xu et al., 2017

In the paper

“Regarding atypical psychedelics, it is interesting that none of the RCTs combined ketamine treatment with psychotherapy.”

In the paper

“In both studies, mystical experiences correlated significantly with therapeutic outcomes.”

In the paper

“These effects tended to wear off after some time (several hours to 1 week) if the ketamine administration was not repeated.”

In the paper

“After 6 months, this was also the case for symptoms of depression.”

What the sources say

• ?Not checked — no full text of the sourcecites Grob et al., 2011 source

In the paper

“This effect was no longer significant at day seven.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Xu et al., 2017

In the paper

“Psilocybin treatment did not reduce pain or the need for analgesic medication.”

What the sources say

• ?Not checked — no full text of the sourcecites Grob et al., 2011 source

In the paper

“After 4 years, 60-80% of the patients still showed significant reductions in depression and anxiety compared to baseline (Agin-Liebes et al., 2020).”

What the sources say

• ?Not checked — no full text of the sourcecites Agin-Liebes et al., 2020 source

In the paper

“Positive psychological changes included increased relaxation, equanimity, self-assurance, and mental strength.”

What the sources say

• ?Not checked — no full text of the sourcecites Gasser et al., 2015 source

In the paper

“Adverse events, such as nausea, psychological discomfort, and anxiety, were transient and did not persist beyond 1 day after treatment.”

In the paper

“No adverse effects were reported in the studies that used classical psychedelics.”

In the paper

“Before crossover, the psilocybin group (n = 6) reported a larger, yet statistically non-significant reduction of depression and anxiety symptoms compared to the placebo group (n = 6).”

What the sources say

• ?Not checked — no full text of the sourcecites Grob et al., 2011 source

In the paper

“After 3 months, trait anxiety was significantly decreased in both groups compared to baseline.”

What the sources say

• ?Not checked — no full text of the sourcecites Grob et al., 2011 source

In the paper

“Across the board, large effects were found on depression and anxiety.”

In the paper

“Group differences were no longer significant after 3 months.”

What the sources say

• ?Not checked — no full text of the sourcecites Liu et al., 2020 source

In the paper

“In the second crossover RCT (n = 29) (2018), significant differences in response were found between the high-dose first and the low-dose group.”

In the paper

“All eight remaining patients showed significant responses on depression.”

What the sources say

• ?Not checked — no full text of the sourcecites Irwin et al., 2013 source

In the paper

“No (serious) adverse events were reported in the ketamine studies included in this review.”

In the paper

“No (S)AEs occurred. AEs during session: nausea/vomiting, tremors, palpitations, respira-tory issues”

In the paper

“Integrative psycho-therapy PT: improvements on observer-rated depression anxiety, fear of death, isolation, and management of disease (all: < .001) p”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Richards et al. 1972; Grof et al. 1973

In the paper

“No (S)AEs occurred”

In the paper

“In contrast with classic psychedelics, we found that the effects of ketamine on mood emerge but also diminish rapidly if not repeatedly administered.”

In the paper

“A subsequent study by Kast with LSD in patients with terminal cancer reported that 89% gained”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Kast, 1966

In the paper

“Surprisingly, they also found that patients showed more open and positive attitudes towards their condition after LSD treatment.”

What the sources say

• ?Not checked — no full text of the sourcecites Kast and Collins, 1964 source

In the paper

“Evidence for the use of antidepressants is inconclusive (Price and Hotopf, 2009).”

What the sources say

• ?Not checked — no full text of the sourcecites Price and Hotopf, 2009 source

In the paper

“Due to the large differences in study designs and outcome measurements, no meta-analyses were performed.”

In the paper

“However, this line of research was abruptly discontinued following the worldwide prohibition of psychedelics in 1968 (Grob et al., 2013).”

What the sources say

• ?Not checked — no full text of the sourcecites Grob et al., 2013 source

In the paper

“The effects of methylphenidate for the treatment of depression in (advanced) cancer were minimal (Andrew et al., 2018).”

What the sources say

• ?Not checked — no full text of the sourcecites Andrew et al., 2018 source

In the paper

“A review on the efficacy of ketamine for depression and pain in palliative care patients found antidepressant effects (Goldman et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Goldman et al., 2019 source

In the paper

“Ketamine seems to be mainly offered as a stand-alone pharmacological treatment, like conventional antidepressants (Greenway et al., 2020).”

What the sources say

• ?Not checked — no full text of the sourcecites Greenway et al., 2020 source

In the paper

“Like classical psychedelics, ketamine can induce short-term changes in consciousness and perception that may have therapeutic relevance.”

In the paper

“MDMA has been reported to induce cardiovascular effects such as increased blood pressure and heart rate (Fonseca et al., 2021).”

What the sources say

• ?Not checked — no full text of the sourcecites Fonseca et al., 2021 source

In the paper

“However, side effects such as ketamine-induced ulcerative cystitis and dependence may pose a concern, especially when ketamine use is frequent and of prolonged duration (Short et al., 2018;Morgan et al., 2012).”

What the sources say

• ?Not checked — no full text of the sourcecites Short et al., 2018 source
• ?Not checked — no full text of the sourcecites Morgan et al., 2012 source

In the paper

“However, they do not address important existential domains of distress, such as lack of meaning and dignity, death anxiety, and coping with overwhelming changes.”

In the paper

“Population differences therefore may have contributed to some of the observed differences.”