Frontiers in Pharmacology
March 31, 2022
Roberta Murphy, Roberta Murphy, Hannes Kettner et al.
229 citations
In a trial comparing psilocybin-assisted therapy to escitalopram for moderate-to-severe depression, a stronger therapeutic alliance with the therapist predicted greater emotional breakthrough and mystical-type experiences during psilocybin sessions, and these experiences in turn predicted larger reductions in depression symptoms six weeks after treatment. Emotional breakthrough during the first session strengthened the alliance before the second session, while a weaker alliance before the second session directly predicted higher depression scores at the endpoint, independent of the acute psychedelic experience. The findings suggest the therapeutic relationship plays a key role in shaping both the quality of the psychedelic experience and clinical outcomes.
Elife
March 2, 2021
Balázs Szigeti, Laura Kärtner, Allan Blemings et al.
192 citations
A self-blinding citizen science trial with 191 participants tested whether microdosing psychedelics produces psychological benefits beyond a placebo. All psychological outcomes improved from baseline to after the four-week dose period in the microdose group, but the placebo group also improved, and no significant between-group differences were observed. Small, significant differences in acute measures (emotional state, drug intensity, mood, energy, creativity) and post-acute anxiety appeared, but these could be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.
Psychopharmacology
August 8, 2022
Rosalind Watts, Hannes Kettner, Dana Geerts et al.
159 citations
A new scale, the Watts Connectedness Scale (WCS), measures a three-dimensional sense of connectedness to self, others, and the wider world. Analysis of data from 1,226 participants in online surveys and a randomized controlled trial of 52 people with major depressive disorder showed the scale has good internal consistency and construct validity. After psychedelic use, total connectedness scores increased significantly, and acute experiences of mystical experience, emotional breakthrough, and communitas correlated with these changes. In the trial, psilocybin-assisted therapy produced greater increases in WCS scores than daily escitalopram. The WCS may sensitively capture therapeutically relevant psychological changes.
The Lancet Psychiatry
December 12, 2023
Gerhard Gründer, Manuela Brand, Lea J. Mertens et al.
103 citations
Treatment of psychiatric disorders with psychedelic substances is promising, but there is debate over whether therapeutic effects come solely from the drug or require psychotherapy. Some recent studies suggest the substance alone may be responsible, with therapists providing only safety support. This Personal View argues that viewing psychedelic treatment as a purely biological intervention with psychological support for safety reflects an outdated, reductionistic dualism that has long dominated psychiatry. The discussion has important implications for how these compounds are studied and regulated.
Frontiers in Neuroscience
October 6, 2023
Tobias Buchborn, Hannes S. Kettner, Laura Kärtner et al.
21 citations
The ego is central to psychedelic research and therapy but remains poorly defined. This theoretical review examines the ego through a psychodynamic lens, focusing on ego boundaries, defenses, and synthesis. Psychedelics can induce regressed ego states with reduced defenses, allowing early-life conflicts that created maladaptive patterns to emerge. The authors argue that lasting change requires psycholytic therapy to permeate the characterological core—the chronic, habitual patterns the ego uses to cope—not just transient ego regression. Emotional integration of formative early events is key to reshaping rigid character and defenses, aiming for more flexible ego patterns. This approach is compatible with third-wave cognitive behavioral therapies.
JAMA Psychiatry
March 18, 2026
Lea J. Mertens, Michael Koslowski, Felix Betzler et al.
9 citations
A phase 2b randomized clinical trial tested 25 mg of psilocybin with psychotherapy against a 5 mg dose and a placebo (nicotinamide) in 144 adults aged 25 to 65 with treatment-resistant depression who had stopped antidepressants. The primary outcome—a 50% or greater reduction in depression scores at six weeks—was not statistically significant: 17.0% of those receiving 25 mg responded, versus 12.5% on 5 mg and 10.6% on placebo. Exploratory analyses suggested a clinically meaningful reduction in depressive symptoms with the 25 mg dose. The treatment was generally well tolerated, but safety signals included higher reports of suicidal ideation on dosing days and two serious adverse reactions, one case of hallucinogen persisting perception disorder.
December 11, 2020
Balázs Szigeti, Laura Kärtner, Allan Blemings et al.
1 citation
A self-blinding citizen science study tested whether psychedelic microdosing improves well-being and cognition beyond placebo. 191 participants who already planned to microdose were randomly assigned to receive four weeks of microdoses, placebos, or a mix. All psychological outcomes—including well-being, mindfulness, and life satisfaction—improved from baseline in the microdose group, but the placebo group also improved, and no significant differences emerged between groups. Small acute differences in mood, energy, and creativity were observed, but these could be explained by participants correctly guessing whether they took a microdose. The findings suggest that the anecdotal benefits of microdosing are likely due to the placebo effect.
Psychotherapy and psychosomatics
May 27, 2026
Lea J Mertens, Felix Betzler, Manuela Brand et al.
A single 25 mg dose of psilocybin, or two such doses given six weeks apart, combined with psychotherapy produced a stable and clinically meaningful reduction in depression symptoms for up to twelve months in people with treatment-resistant depression. The average improvement on the Hamilton Rating Scale for Depression was about 7.9 points at six months and 7.7 points at twelve months, with no significant difference between dosing groups. Restarting standard antidepressant medication during follow-up was strongly linked to higher depression scores. This naturalistic follow-up of a phase 2b trial is the largest and most complete long-term assessment of psilocybin for depression to date.
Der Nervenarzt
March 1, 2025
Moritz Spangemacher, Jonathan Reinwald, Hana Adolphi et al.
Classical and novel antidepressants may share a common mechanism: promoting long-term neuroplasticity and improving negative bias in emotional processing. Extrapharmacological factors—body, environment, and social interaction—appear necessary for these biological changes to produce an antidepressant effect. Rather than dismissing such factors as placebo, the authors argue they should be tested as essential components of treatment and integrated into clinical practice.
Der Nervenarzt
March 1, 2022
Gerhard Gründer, Manuela Brand, Laura Kärtner et al.
Psychedelics like psilocybin are among the most promising new treatments for depression, potentially working within one day. A review of clinical studies from before the 1960s prohibition and after the 2000s revival—mostly using psilocybin—shows small sample sizes (total depressed patients <200) and some methodological weaknesses. Nevertheless, the evidence suggests a pronounced, very rapid antidepressant effect within one day for depression, treatment-resistant depression, and depression in life-threatening cancer, often lasting several months. Ongoing studies with hundreds of patients will clarify psilocybin's potential.