Effect of Ketanserin, Olanzapine, and Lorazepam After LSD Administration on the Acute Response to LSD in Healthy Subjects

The main objective of this study is to determine whether administration of ketanserin (40 mg), olanzapine (10 mg), and lorazepam (2 mg) after administration of LSD (150 µg) attenuates and shortens the subjective LSD response (any drug effect) compared to administration of LSD (150 µg) alone

LSD is investigated as treatment for various psychiatric (e.g., depression and anxiety) but also somatic disorders (e.g., cluster headache). In Switzerland, compassionate use of psychedelics including LSD is possible based on single authorizations of the federal office of public health in treatment-resistant patients. Additionally, current social and political changes demonstrate a shift of how psychedelics are seen and how they might be used in therapy in the future.

Despite the good safety profile of LSD, a broader use might increase the number of adverse psychological reactions to LSD. For such occasions, health professionals should have a tool to not only psychologically but also pharmacologically interfere and end states of acute psychedelic-induced distress. In clinical practice, the gamma-butyric acid (GABA) agonistic acting benzodiazepine lorazepam or the atypical neuroleptic olanzapine with affinity to the 5-HT2A, 5-HT2C and dopamine D1-4 receptors are primarily used for the treatment of drug-induced psychotic symptoms. However, the ability of these drugs to block these effects after LSD intake remains to be investigated.

The primary goal of the present study is therefore to investigate whether ketanserin, olanzapine and lorazepam administration after LSD administration might attenuate and shorten the LSD response compared to administration of LSD alone. Additionally, the present study examines changes in quality of the LSD experience after administration of ketanserin, olanzapine or lorazepam and effects on sensorimotor gating and sleep. The study provides insight into the receptor mechanisms involved in alterations of consciousness and specifically the relevance of ongoing 5-HT2A receptor stimulation in the mediation of the psychedelic response to LSD and psychotic symptoms.

Eligibility Criteria:
Inclusion Criteria:

1. Age between 25 and 65 years
2. Sufficient understanding of the German language
3. Understanding of procedures and risks associated with the study
4. Willing to adhere to the protocol and signing of the consent form
5. Willing to refrain from the consumption of illicit psychoactive substances during the study
6. Abstaining from xanthine-based liquids and foods from the evenings prior to the study sessions to the end of the study days, limit coffee drinking ≤ 3 cups per day for 7 days prior to study day
7. Participants must be willing not to drive a traffic vehicle or to operate machines within 48 h after substance administration
8. Willing to use effective contraceptive measures throughout study participation (according to Clinical Trial Facilitation Group (CTFG): Recommendations related to contraception and pregnancy testing in clinical trials)
9. Women of childbearing potential must have a negative pregnancy test at the beginning of the study. Pregnancy tests are repeated before each study session.
10. Body mass index between 18 - 29 kg/m2

Exclusion Criteria:

1. Chronic or acute medical condition
2. Current or previous major psychiatric disorder including psychotic disorder, mania / hypomania, borderline personality disorders.
3. Psychotic disorder or bipolar disorder in first-degree relatives
4. Known hypersensitivity to LSD, ketanserin, olanzapine or lorazepam
5. Hypertension (\>140/90 mmHg) or hypotension (SBP \< 85 mmHg)
6. Hallucinogenic substance use (not including cannabis) more than 10 times or any time within the previous two months
7. Pregnancy or current breastfeeding
8. Participation in another clinical trial (currently or within the last 30 days)
9. Use of medication that may interfere with the effects of the study medication
10. Current substance use disorder (within the last 2 months)
11. Tobacco smoking (\>1 cigarette/day)
12. Consumption of alcoholic beverages (\>15 drinks/week)
13. Not exhibiting consistent startle responding on the screening day (i.e., over 75% discernible responses to six 108 dB 40 ms startle pulses), as this would preclude the ability to measure fear potentiated startle.
14. Use of strong CYP2D6 inhibitor
15. Use of strong CYP1A2 inhibitor or inducer