Biological psychiatry
February 1, 2023
Friederike Holze, Peter Gasser, Felix Müller et al.
294 citations
LSD-assisted therapy produced long-lasting reductions in anxiety and comorbid depression symptoms up to 16 weeks in patients with anxiety related to a life-threatening illness. In a double-blind, placebo-controlled crossover trial with 42 patients, LSD treatment led to significant decreases in anxiety scores compared to placebo, with a large effect size. Similar improvements were seen in depression ratings. Positive acute subjective drug effects and mystical-type experiences correlated with long-term anxiety reductions. Mild, transient side effects occurred in 19% of patients, and one serious adverse event (acute transient anxiety) was reported.
Neuropsychopharmacology
November 16, 2019
Friederike Holze, Patrick Vizeli, Felix Müller et al.
250 citations
LSD, MDMA, and d-amphetamine all increased heart rate, blood pressure, body temperature, and pupil size, but LSD produced the strongest alterations in consciousness, mystical experiences, ego dissolution, and emotional excitation. MDMA increased feelings of good drug effects, liking, and high more than d-amphetamine, and only MDMA raised oxytocin levels. d-Amphetamine boosted activity and concentration relative to LSD. None of the substances changed brain-derived neurotrophic factor. The findings highlight distinct subjective and endocrine profiles that may inform dosing in psychedelic-assisted therapy.
Neuropsychopharmacology
October 15, 2020
Friederike Holze, Patrick Vizeli, Laura Ley et al.
243 citations
Lysergic acid diethylamide (LSD) produces dose-dependent subjective effects starting at 25 µg, with a ceiling for good drug effects at 100 µg, while ego dissolution and anxiety increase further at 200 µg. The average duration of subjective effects lengthens from 6.7 to 11 hours across the 25–200 µg range. LSD moderately raises blood pressure and heart rate. The serotonin 5-HT2A receptor antagonist ketanserin (40 mg) given before 200 µg LSD prevents the response, indicating that LSD's full psychedelic effects are primarily mediated by 5-HT2A receptor activation. These results assist dose finding for future LSD research.
Neuropsychopharmacology
February 25, 2022
Friederike Holze, Laura Ley, Felix Müller et al.
223 citations
In healthy volunteers, 100 and 200 micrograms of LSD and 30 milligrams of psilocybin produce comparable subjective effects, including alterations of mind that are qualitatively and quantitatively very similar. The 15 milligram psilocybin dose produces clearly weaker subjective effects. The 200 microgram dose of LSD induces higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 microgram dose. LSD at both doses has clearly longer effect durations than psilocybin. Psilocybin increases blood pressure more than LSD, whereas LSD increases heart rate more than psilocybin, though both show comparable overall cardiostimulant properties. Any differences between LSD and psilocybin appear dose-dependent rather than substance-dependent, except for the differential effects on heart rate and blood pressure.
Clinical Pharmacology & Therapeutics
November 7, 2021
A. Becker, Friederike Holze, Tanja Grandinetti et al.
177 citations
In healthy volunteers, taking the antidepressant escitalopram for two weeks before a 25 mg dose of psilocybin did not reduce the positive mood effects of the psychedelic, but it significantly lessened bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects compared to placebo pretreatment. Escitalopram did not alter psilocin's pharmacokinetics; the half-life of free psilocin was 1.8 hours. It also did not change HTR2A or SCL6A4 gene expression, QTc intervals, or BDNF levels. Longer antidepressant pretreatment and studies in patients are needed to further define interactions between antidepressants and psilocybin.
ACS Pharmacology & Translational Science
August 31, 2020
Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder et al.
134 citations
Low doses of LSD (5, 10, and 20 μg) increase brain-derived neurotrophic factor (BDNF) levels in blood plasma, a marker of neuroplasticity. In a placebo-controlled within-subject study with healthy volunteers, BDNF levels rose at 4 hours after 5 μg and at 6 hours after both 5 and 20 μg, compared to placebo. This suggests that even low doses of LSD can acutely enhance neuroplasticity, supporting further research in patient populations for psychiatric conditions.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2023
Laura Ley, Friederike Holze, Denis Arikci et al.
127 citations
At equally strong doses, the classic psychedelics mescaline, LSD, and psilocybin produce comparable subjective experiences, with no evidence of qualitative differences in altered states of consciousness. Autonomic effects were moderate; psilocybin increased diastolic blood pressure more than LSD, while LSD showed a trend toward higher heart rate than psilocybin. Mescaline had the longest effect duration (mean 11.1 hours), followed by LSD (8.2 hours) and psilocybin (4.9 hours). Mescaline and LSD, but not psilocybin, raised circulating oxytocin. None altered brain-derived neurotrophic factor. Tolerability was similar, though mescaline caused slightly more subacute adverse effects 12–24 hours later.
European Neuropsychopharmacology
October 17, 2020
Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder et al.
121 citations
Taking very low doses of LSD, known as microdosing, can selectively improve mood and cognition. In a placebo-controlled experiment with 24 healthy adults, doses of 5, 10, and 20 micrograms of LSD were tested. The 20 mcg dose increased positive mood, while 5 mcg and 20 mcg increased friendliness and reduced attentional lapses. Arousal increased at 5 mcg. Negative effects included increased confusion at 20 mcg and increased anxiety at both 5 and 20 mcg. Altered states of waking consciousness occurred at 10 and 20 mcg. The minimal dose producing noticeable effects was 5 mcg, with the clearest effects at 20 mcg.
Clinical Pharmacology & Therapeutics
December 12, 2022
Friederike Holze, Urs Duthaler, A. Becker et al.
116 citations
Psilocybin is being studied as a treatment for psychiatric and neurological disorders. After oral administration of 15, 25, or 30 mg to healthy subjects, peak psilocin concentrations averaged 11, 17, and 21 ng/mL, reached after about 2 hours, with elimination half-lives around 1.4–1.8 hours. Subjective effects lasted 5.5–6.4 hours, and maximal 'any drug' effects ranged from 58% to 80%. Psilocin showed dose-proportional pharmacokinetics, and both duration and intensity of effects were dose-dependent. Body weight did not influence pharmacokinetics or response.
The International Journal of Neuropsychopharmacology
November 4, 2022
Aaron Klaiber, Friederike Holze, Ioanna Istampoulouoglou et al.
100 citations
Lysergic acid diethylamide (LSD) produces its acute psychedelic effects by stimulating the serotonin 5-HT2A receptor. In a double-blind, randomized, placebo-controlled, crossover study with 24 healthy participants, the 5-HT2A antagonist ketanserin (40 mg orally) was given one hour after LSD (100 µg orally). Ketanserin reversed the acute response to LSD, reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. It also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution, and reduced adverse cardiovascular effects and mydriasis. Ketanserin did not alter LSD's pharmacokinetics or its elevation of brain-derived neurotrophic factor levels. The findings indicate that LSD produces its psychedelic effects only when occupying 5-HT2A receptors, and ketanserin can shorten and attenuate the LSD experience for research and therapy.
Journal of Psychopharmacology
August 25, 2020
Johannes G. Ramaekers, Nadia R. P. W. Hutten, Natasha L. Mason et al.
95 citations
A low dose of LSD (20 micrograms) that does not cause a psychedelic experience can increase pain tolerance and reduce the unpleasantness of pain in healthy volunteers. In a controlled experiment with 24 participants, those given 20 µg of LSD kept their hand in cold (3°C) water longer and reported less pain than when given a placebo. Smaller doses (5 and 10 µg) did not produce the same effect. The 20 µg dose caused slight increases in blood pressure, anxiety, and dissociation, but no profound mind-altering effects. These findings suggest that very low doses of LSD may offer a new approach to pain management without the intense psychological effects of higher doses.
Translational psychiatry
May 23, 2023
Severin B Vogt, Laura Ley, Livio Erne et al.
85 citations
Intravenous DMT can produce a psychedelic state that is short-lasting and controllable. A double-blind, placebo-controlled crossover trial with 27 healthy participants tested five DMT regimens: low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus plus low infusion (15 mg + 0.6 mg/min), and high bolus plus high infusion (25 mg + 1 mg/min). Bolus doses induced very intense effects within 2 minutes, with more negative feelings and anxiety than infusions. Infusions produced slowly increasing, dose-dependent effects that plateaued after 30 minutes. All effects subsided within 15 minutes of stopping the infusion. Acute tolerance developed, with stable subjective effects from 30 to 90 minutes despite rising plasma concentrations. Intravenous DMT infusion is a promising tool for tailored psychedelic therapy.
British Journal of Clinical Pharmacology
March 19, 2019
Friederike Holze, Urs Duthaler, Patrick Vizeli et al.
72 citations
After a 100 μg oral dose of LSD, plasma levels peak at about 1.7 hours and decline with a half-life of 3.6 hours. The main metabolite O-H-LSD peaks later, around 5 hours, and has a longer half-life of 5.2 hours. No sex differences in pharmacokinetics were observed. Subjective effects last an average of 8.5 hours, peaking at 2.5 hours. The concentration needed to produce half-maximal effects is 1.0 ng/mL for good effects and 1.9 ng/mL for bad effects, showing that subjective experiences closely track plasma concentrations over time.
Frontiers in Pharmacology
July 13, 2021
Friederike Holze, Isidora Avedisian, Nimmy Varghese et al.
66 citations
Lysergic acid diethylamide (LSD) dose-dependently increased both implicit and explicit emotional empathy in 16 healthy subjects, with the highest 200 µg dose producing a significant effect compared with placebo. The 200 µg dose also moderately increased plasma oxytocin levels. Blocking the serotonin 5-HT2A receptor with ketanserin reduced the LSD-induced oxytocin release but did not reduce the increases in emotional empathy. These results indicate that LSD enhances empathy through mechanisms that may be partially independent of its primary action on 5-HT2A receptors, whereas the oxytocin release depends on 5-HT2A receptor stimulation and aligns with the psychedelic effect of LSD.
Psychopharmacology
January 25, 2022
Felix Müller, Elias Kraus, Friederike Holze et al.
64 citations
Up to 9.2% of healthy volunteers reported reoccurring drug-like experiences after taking LSD or psilocybin in controlled studies, but none met the criteria for hallucinogen-persisting perception disorder (HPPD). The experiences were mostly mild, visual, brief, and perceived as neutral or pleasant, with no impairment in daily life. Distressing experiences occurred in two subjects but subsided spontaneously. The findings suggest that flashbacks are not a clinically relevant problem in controlled settings with healthy participants.
Clinical Pharmacology & Therapeutics
September 25, 2020
Friederike Holze, Matthias E. Liechti, Nadia R. P. W. Hutten et al.
63 citations
Very low doses of LSD (5, 10, and 20 µg) were given to 23 healthy participants in a double-blind, placebo-controlled crossover trial. LSD concentrations in the blood increased in proportion to dose, with maximal levels reached after about 1.1 hours and an average elimination half-life of 2.7 hours. The 5 µg dose produced no significant subjective effects. The 10 µg dose significantly increased feelings of being under the influence and good drug effect, starting at 1.1 hours, peaking at 2.5 hours, and lasting until 5.1 hours. The 20 µg dose also increased bad drug effects. The threshold for psychotropic effects was 10 µg.
Psychopharmacology
September 13, 2021
Friederike Holze, Toya V Caluori, Patrick Vizeli et al.
57 citations
LSD dose-dependently increased subjective, physiologic, and adverse effects in healthy subjects. Positive subjective effects (good drug effect) were more pronounced than negative ones (bad drug effect), with maximal ratings of >50% good drug effects reached in 37%, 91%, 96%, and 91% of administrations at 25, 50, 100, and 200 µg, respectively, versus 0%, 9%, 27%, and 31% for bad drug effects. Physiologic effects were moderate: no systolic blood pressure exceeded 180 mmHg, peak heart rate >100 beats/min occurred in up to 25% of subjects at the highest dose, and peak body temperature >38°C in up to 34%. Kidney and liver function remained unaltered. Six subjects reported transient flashbacks. Single-dose LSD is safe regarding acute psychological and physical harm in healthy subjects in a controlled research setting.
Biological Psychiatry Cognitive Neuroscience and Neuroimaging
February 1, 2024
Friederike Holze, Nirmal Singh, Matthias E. Liechti et al.
50 citations
Psychedelic compounds such as psilocybin, LSD, DMT, 5-MeO-DMT, and mescaline, all serotonin 2A receptor agonists, are under investigation as potential treatments. This review summarizes current clinical research on these five compounds, covering mechanisms of action, pharmacokinetics, pharmacodynamics, efficacy, and safety. Evidence for therapeutic indications remains scarce except for psilocybin for depression. No differences in psychedelic effects were noted beyond effect duration, and it is unclear whether different receptor profiles contribute to therapeutic potential. More research is needed to differentiate these compounds for various therapeutic uses.
Neuropsychopharmacology
April 25, 2023
Peter Bedford, Daniel J. Hauke, Zheng Wang et al.
43 citations
Lysergic acid diethylamide (LSD) predominantly strengthens interregional connections and reduces self-inhibition across the brain, except in occipital and subcortical regions where connections weaken and self-inhibition increases. These patterns suggest LSD perturbs the brain's excitation/inhibition balance. Whole-brain effective connectivity, assessed via regression dynamic causal modelling of resting-state fMRI data from 45 participants in two placebo-controlled trials, discriminated LSD from placebo with 91.11% accuracy and correlated with global subjective effects, indicating potential for decoding subjective experiences.
Biological Psychiatry Cognitive Neuroscience and Neuroimaging
April 29, 2022
Mihai Avram, Felix Müller, Helena Rogg et al.
43 citations
Psychedelics, empathogens, and psychostimulants produce increased connectivity between the thalamus and sensorimotor areas of the brain, a pattern similar to that observed in individuals with psychotic disorders. This suggests a shared neural mechanism across these substances and certain psychiatric conditions, linking altered thalamocortical communication to changes in perception and behavior.
Neuropsychopharmacology
November 20, 2020
Felix Müller, Friederike Holze, Patrick C. Dolder et al.
43 citations
The non-hallucinogenic drug MDMA reduces functional connectivity within several resting-state brain networks, including the default mode network, visual networks, and the sensorimotor network. These decreases closely match those previously reported for hallucinogenic drugs like LSD. The findings suggest that such connectivity changes are not specific to serotonergic hallucinogens but can be induced by monoaminergic stimulation without marked subjective drug effects. However, alterations within the default mode network may help explain the antidepressant effects of some of these substances.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
December 1, 2023
Isabelle Straumann, Laura Ley, Friederike Holze et al.
41 citations
Co-administering MDMA (100 mg) with LSD (100 µg) does not improve the quality of the acute subjective effects compared with LSD alone in healthy adults. The combination prolongs the duration of subjective effects and increases blood pressure, heart rate, and pupil size more than LSD alone. Oxytocin levels rise more with MDMA alone or the combination than with LSD alone. The findings suggest that combining MDMA with LSD offers no relevant benefits over LSD alone for psychedelic-assisted therapy.
Current topics in behavioral neurosciences
January 1, 2022
Matthias E Liechti, Friederike Holze
35 citations
Proper dosing is crucial for the clinical use of classic psychedelics and entactogens, which are being studied for psychiatric conditions such as anxiety, depression, cluster headache, and posttraumatic stress disorder. Controlled study data on dosing with well-characterized pharmaceutical formulations are scarce. The dose equivalence of different substances, dose-response effects, and subjective effects at various doses are important for their use in psychotherapy. Microdosing has gained popularity, and the first placebo-controlled studies of LSD have been published. This chapter covers pharmaceutical aspects, definitions of different doses including microdoses, personalized dosing, and non-pharmacological factors that influence response.
The British journal of psychiatry : the journal of mental science
September 1, 2024
Friederike Holze, Peter Gasser, Felix Müller et al.
32 citations
A long-term follow-up of a double-blind, placebo-controlled crossover trial found that LSD-assisted therapy produced sustained reductions in anxiety and depression for up to 94 weeks after the last treatment. Participants who received LSD first showed a decrease of 21.6 points on the State-Trait Anxiety Inventory, and those who received LSD second showed a decrease of 16.5 points, both statistically significant. Comorbid depression also improved, with Beck Depression Inventory scores dropping by 8.1 and 8.9 points in the two groups. Personality traits shifted toward lower neuroticism and higher extraversion. Patients attributed lasting positive effects to the psychedelic experience.
Frontiers in Psychiatry
October 22, 2020
Felix Müller, Markus Mühlhauser, Friederike Holze et al.
31 citations
A woman with severe, treatment-resistant depression and a complex personality disorder received weekly, ascending doses of LSD in an open psychiatric ward. Despite adequate dosing confirmed by blood tests, she experienced no substantial acute subjective drug effects. However, she showed rapid and significant improvements in depressed mood, emotional instability, low energy, and suicidal thoughts. Questionnaire scores also decreased in global severity and various psychopathological subscales. Improvements lasted about 7 days after each dose. The case suggests that LSD can induce rapid but transient beneficial effects on several symptoms, and that these improvements can occur without acute drug experiences, resembling the time course of ketamine's antidepressant effects.