Treatment of a Complex Personality Disorder Using Repeated Doses of LSD-A Case Report on Significant Improvements in the Absence of Acute Drug Effects

Earlier research has reported that limited administrations of serotonergic hallucinogens and MDMA can produce sustained improvements in anxiety and depressive symptoms, an effect commonly attributed to subjective experiences during the acute drug state. Despite such findings, uncertainty remains about whether the acute phenomenology is necessary for therapeutic benefit and how these compounds behave in patients with complex, treatment-resistant psychopathology. Müller and colleagues report a single-case experimental treatment in a 39-year-old woman with severe, treatment-resistant depression and a mixed personality disorder. The report documents the clinical course following initial MDMA exposures and then repeated, ascending weekly doses of LSD, with attention to both symptomatic change and the unexpected absence of typical acute psychedelic effects despite pharmacokinetic confirmation of drug exposure. The case is presented to explore clinical response patterns and possible mechanisms when symptomatic improvements occur without pronounced acute subjective effects.

This is a single-case, experimental treatment conducted on an inpatient open psychiatric ward after special permission from Swiss authorities. The patient had a long history of severe psychiatric illness and prior treatment resistance; diagnostic assessment during admission included SCID-I and SCID-II, leading to ICD-10 classifications of mixed personality disorder with emotionally unstable, paranoid and compulsive features (F61.0), severe recurrent depression (F33.2), and mixed obsessional thoughts and acts (F42.2). Concomitant psychotropic medications present on admission included bupropion 300 mg/day, venlafaxine 337.5 mg/day, pregabalin 600 mg/day, risperidone 1.5 mg/day and lorazepam 7.5 mg/day, as well as regular nasal racemic ketamine. Prior to the experimental treatment, venlafaxine and olanzapine were tapered to avoid serotonergic interactions; risperidone and clotiapine were paused prior to each administration and lorazepam was tapered for clinical reasons. Treatment began with two single oral administrations of 125 mg MDMA, delivered in a supervised therapeutic setting (morning sessions, quiet room, vital-sign monitoring, music and therapist support) primarily to familiarise the patient with drug-induced mental alterations. After a 3-week washout, LSD dosing started at 50 µg and was escalated weekly to 100, 150 and 200 µg, followed by continuing weekly administrations at 200 µg. Clinical and psychometric monitoring included staff observations, a mood diary, the Symptom Checklist-90 (SCL-90) completed before and after the inpatient course, and the 5D-ASC questionnaire (5 Dimensions of Altered States of Consciousness) to quantify acute subjective effects. After an administration of 200 µg, plasma samples were taken hourly and analysed by validated mass spectrometry to characterise drug concentration and pharmacokinetics. No formal statistical analyses beyond reliable-change assessment on the SCL-90 are reported in the extracted text.

Substantial clinical improvement was observed following LSD administration despite minimal acute psychedelic effects. Clinically notable reductions were seen in depressed mood, emotional instability, loss of energy and suicidal ideation; the ward staff and attending physicians corroborated the patient’s reports of feeling "more calm and stable" and having diminished suicidal thoughts. Improvements typically emerged rapidly after each dose and lasted approximately 7 days. On psychometric assessment, the SCL-90 showed significant decreases according to the reliable change index in the scales somatization, obsessive–compulsive, interpersonal sensitivity, depression, hostility and phobia, and in the global severity index. No significant changes were reported for the SCL-90 scales anxiety, paranoid ideation and psychoticism in the extracted text. The clinical course also included reductions in compulsive thoughts and acts after several administrations, and the improvement appeared to be dose-dependent according to clinicians’ observations and the mood diary. Objective plasma monitoring after a 200 µg dose demonstrated measurable LSD concentrations, but levels were slightly lower than expected and the time-to-peak was delayed; these pharmacokinetic findings did not explain the lack of acute subjective effects. The 5D-ASC assessment showed only small elevations on "blissful state" and "impaired control and cognition," while more typical psychedelic phenomena such as visual alterations were absent. No relevant somatic or psychiatric adverse effects were reported during the inpatient treatment. In outpatient follow-up the patient continued weekly 200 µg administrations with maintained improvement and discontinued benzodiazepine use that she had been taking several times per week for years. The authors report plans for continued close monitoring including cognitive testing, laboratory tests, ECG and echocardiography to screen for serotonin 2B–receptor–related valvular disease given the uncertainty about risks from repeated dosing.

The investigators emphasise two unusual features of this case: clinically meaningful symptomatic improvement in a severe, treatment-resistant condition, and the occurrence of these improvements in the near absence of characteristic acute LSD effects. They note that the time course of benefit—rapid onset with effects waning after about a week—resembles antidepressant responses described after ketamine rather than the prolonged remission reported in some psychedelic studies. Several potential explanations are discussed. The clinical picture has superficial similarity to reports of "microdosing," where sub-perceptual doses are reported to transiently improve mood and energy, but the doses used here were substantially larger than typical microdoses. Biological hypotheses include individual differences such as a serotonin 2A receptor polymorphism that could blunt subjective effects, or pharmacodynamic interactions with concurrent medications (for example, GABAergic effects of pregabalin) that might suppress typical acute phenomena. Non-pharmacological explanations are also considered, including placebo effects or benefits from intensive clinical monitoring and the therapeutic context, though the authors note the patient’s prior limited response to many treatments and a differential response to MDMA that make simple expectancy explanations less compelling. Limitations acknowledged by the authors include the single-case design, which precludes causal inference and generalisability, and the absence of mechanistic data to explain the dissociation between plasma exposure and subjective effects. The authors recommend cautious continuation with stringent monitoring and suggest the case raises questions for future research about whether acute subjective psychedelic experiences are necessary for therapeutic benefit and about the safety and efficacy of repeated dosing schedules. No firm clinical recommendations are made beyond the careful observation and planned assessment described in the report.