Absolute Oral Bioavailability and Bioequivalence of LSD Base and Tartrate in a Double‐Blind, Placebo‐Controlled, Crossover Study

Abstract

Lysergic acid diethylamide (LSD) is currently being investigated as a potential treatment for psychiatric and neurological disorders. Different LSD formulations (base or tartrate, oral or intravenous) are being used. Unclear is whether LSD base and tartrate pharmacokinetics are equivalent. Additionally, LSD's absolute oral bioavailability is unknown. Therefore, we tested the bioequivalence of different oral LSD base and tartrate formulations and defined LSD's absolute oral bioavailability at a dose of ~80 μg freebase equivalent. We used a randomized, double‐blind, placebo‐controlled, five‐period crossover design in 20 healthy participants to investigate an ethanolic drinking solution of LSD base, a watery drinking solution of LSD tartrate, a rapid dissolvable tablet of LSD base, an intravenous formulation of LSD tartrate, and corresponding placebos. We assessed pharmacokinetic parameters and acute subjective, autonomic, and adverse effects up to 24 hours. All oral formulations were bioequivalent, with the ethanolic base solution as a reference. The area under the concentration–time curve from zero to infinity and maximum plasma concentration were within a 90% confidence interval of 80–125%. The absolute bioavailability of oral LSD was 80% and similar for all tested formulations. Overall, the oral formulations showed comparable pharmacokinetic and pharmacodynamic parameters. Intravenous LSD administration produced higher “any drug effect,” “good drug effect,” and “ego dissolution” compared with oral LSD tartrate, more “anxiety” compared with all oral formulations, and more “nausea” and “bad drug effect” compared with oral LSD base and tartrate. In conclusion, dosing with LSD base and tartrate can be considered bioequivalent with high and similar oral bioavailability.

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Psychedelics are currently being investigated as novel treatments for various psychiatric and neurological disorders. In research, LSD is given as a freebase or tartrate formulation. However, it is unclear whether these LSD formulations differ in their pharmacokinetic properties. Additionally, LSD's absolute oral bioavailability is unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The present study investigated the bioequivalence of different LSD base and tartrate formulations and determined LSD's absolute oral bioavailability using a dose‐equivalent intravenous LSD tartrate formulation.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Oral LSD base and tartrate were bioequivalent and shared similar pharmacodynamic profiles. The absolute oral bioavailability of LSD base and tartrate was similarly high at ~80%.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Independent of whether LSD base or tartrate are used, both can be considered bioequivalent when dosed equivalently. LSD has a good absolute oral bioavailability. These findings are important for the interpretation of findings of past, present, and future LSD studies.

Lysergic acid diethylamide (LSD) is a classic psychedelic that induces alterations of the state of consciousness via serotonin (5‐HT) 2A receptor agonism. ¹ , ² , ³ LSD is currently under investigation for several psychiatric and neurological disorders ⁴ (NCT03866252, NCT05883540, and NCT03781128), and it was recently granted a breakthrough designation by the Food and Drug Administration for the treatment of generalized anxiety disorders. In addition to its clinical investigational status, LSD is widely used for recreational and spiritual purposes. ⁵

LSD is used either as freebase or tartrate salt. In recreational settings, the water‐soluble and more stable form of tartrate is widely used, and both forms have been used in clinical research. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ Most modern research to date, including studies that characterized the pharmacokinetics of LSD, have used LSD base, ⁶ , ⁷ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ formulated as capsules or an ethanolic solution. However, more recently completed, ongoing, and planned studies have used LSD tartrate (NCT05407064, NCT05883540, and NCT05953038). The bioequivalence of different formulations has not yet been examined. Unclear is whether LSD base and tartrate have similar pharmacokinetic properties and result in comparable acute effects when dosed equivalently with regard to LSD base content. Additionally, the absolute oral bioavailability of LSD is unknown and has been indirectly estimated to be ~71%. ¹⁶ , ²⁰ Furthermore, modern research data on the pharmacokinetics and pharmacodynamics of intravenous LSD tartrate administration are lacking. An early study reported an immediate effect onset that peaked ~1 hour after the administration of ~120 μg LSD tartrate. ²¹ Therefore, we conducted a randomized, double‐blind, placebo‐controlled, crossover trial in 20 healthy participants to test the bioequivalence of LSD tartrate, LSD freebase as an ethanolic drinking solution, and LSD freebase in the form of a rapid dissolvable tablet (RDT) and determined the absolute oral bioavailability of these LSD formulations using an additional administration of intravenous LSD tartrate.

METHODS

Study design

The present study used a double‐blind, placebo‐controlled, crossover design with five experimental test sessions to test ~80 μg LSD freebase equivalent in the forms of (i) a drinking solution that contained LSD freebase in 96% ethanol (v/v), (ii) a drinking solution of LSD tartrate that was dissolved in water for injection (WFI), (iii) a solid RDT formulation that contained LSD freebase, (iv) an intravenous LSD tartrate administration that was identical to the oral LSD tartrate formulation, and (v) corresponding placebos for each formulation (double‐dummy design). The order of administration was random and counterbalanced. Washout periods between test sessions were at least 10 days. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines in Good Clinical Practice (GCP) and was approved by the Ethics Committee of Northwest Switzerland (EKNZ) and Swiss Federal Office for Public Health (BAG). The study was registered at ClinicalTrials.gov (NCT04865653).

Participants

Twenty healthy participants (10 men and 10 women; mean age ± SD: 37 ± 11 years; range: 25–57 years; mean body weight ± SD: 70 ± 12 kg; range: 50–93 kg) completed the study and were included in the final analysis (Details can be found in the CONSORT flow chart in the Supplement S1 ). Participants were recruited by word of mouth and from a pool of volunteers who had contacted our research group with interest in participating in a psychedelic trial. All participants provided written informed consent and were paid for their participation. Exclusion criteria were age < 25 years or > 65 years, pregnancy and/or breastfeeding, personal or family (first‐degree relative) history of major psychiatric disorders (assessed by the Semi‐structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4^th edition, Axis I disorders, performed by a psychologist or physician), the use of medications that may interfere with the study medication (e.g., antidepressants, antipsychotics, and sedatives), chronic or acute physical illness (e.g., abnormal physical examination or hematological and chemical blood analyses), tobacco smoking (> 10 cigarettes/day), lifetime prevalence of psychedelic drug use > 20 times, illicit drug use within the last 2 months (except for Δ⁹‐tetrahydrocannabinol), and illicit drug use during the study period. Participants were required to consume no more than 20 standard alcoholic beverages per week and have no more than one drink on the day before the test sessions. Eleven participants (55%) had previously used a psychedelic, including mescaline (two participants, once), LSD (10 participants, of which three referred to their previous use as a “microdose,” 1–10 times), and psilocybin (four participants, 1–10 times). Excluding those who only once had consumed a “microdose,” 40% previously had a full‐dose psychedelic experience. Seven participants (35%) had previously used 3,4‐methylenedioxymethamphetamine (MDMA; 1–12 times). Six participants (30%) had used a stimulant, including amphetamine (two participants, 2–6 times) and cocaine (two participants, 1 to ~200 times). Eight participants (40%) had never used any illicit drugs except cannabis.

Study drugs

LSD base and LSD tartrate were obtained from Lipomed AG (Arlesheim, Switzerland) and formulated according to Good Manufacturing Practice (GMP) by Apotheke Dr Hysek (Biel, Switzerland). The LSD base drinking solution vials contained 80 μg LSD freebase in 1 mL of 96% ethanol (v/v). The exact analytically confirmed LSD freebase content (mean ± SD) was 83.1 ± 1.59 μg (n = 3 samples). The corresponding placebo consisted of identical vials that were filled with 1 mL of 96% ethanol. The LSD RDTs contained 80 μg LSD freebase. The corresponding placebo consisted of identical RDTs. The RDTs showed an LSD content decline from initially 88.7 ± 1.02 μg (111%; n = 10 samples) to 75.6 ± 8.64 μg (95%; n = 3 samples) after 12 months and to 72.3 ± 1.8 μg (90%; n = 5 samples) after 18 months. This information was used to estimate the individual RDT LSD doses for each participant using the date of dosing and assuming a linear decrease in content, resulting in an estimated mean (range) dose of 80.5 ± 4.1 μg (86.5–73.8 μg). Oral and intravenous LSD tartrate was formulated as an aqueous solution that contained 117 μg LSD tartrate that was diluted in 1 mL of WFI. The analytically confirmed LSD base content was 81.0 ± 1.43 μg LSD freebase (101%; n = 10 samples). For intravenous administration, the solution was diluted in saline to a final volume of 2 mL before administration. The corresponding placebo consisted of identical vials that were filled with 1 mL of WFI. Stability for the aqueous tartrate formulation and ethanolic base formulation was confirmed for the entire study duration.

Administration was ensured by two investigators. Administrations were separated by 1 minute: (i) oral LSD tartrate at t = −1 minute and (ii) LSD base RDT at t = 0 minute, followed by the simultaneous administration of (iii) oral LSD base at t = 1 minute and intravenous LSD tartrate through an arm vein catheter. Intravenous LSD tartrate was administered over 9 minutes (four times ~20 μg LSD base equivalent every 3 minutes) for safety reasons. The participants were asked to guess their treatment allocation at the end of each study session and again at the end‐of‐study visit to evaluate blinding.

Study procedures

The study included a screening visit, five 25‐h test sessions, and an end‐of‐study visit. The sessions were conducted in a calm hospital room. One participant and one or two investigators were present during each test session. The sessions began at 8:00 a.m. A urine sample was taken at least once randomly to verify abstinence from drugs of abuse, and a urine pregnancy test was performed in women before each test session. Participants received a standardized breakfast (two croissants) and underwent baseline measurements. LSD or placebo was administered at 9:00 a.m. Outcome measures were repeatedly assessed for 24 h. The order of assessment for the repeated outcomes was plasma sampling, vital parameters, and assessment of subjective drug effects. The participants remained under constant supervision during the acute effect phase (up to 8–12 h). An investigator was present in the room next to the participant during the night. Participants were released ~24 h after drug administration.

Plasma LSD concentrations

Blood was collected in lithium heparin tubes before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, and 24 h after drug administration. Samples were centrifuged immediately, and plasma was stored at −80°C until analysis. Plasma LSD and 2‐oxo‐3‐hydroxy‐LSD (O‐H‐LSD) concentrations were determined by high‐performance liquid chromatography–tandem mass spectrometry in the range of 10–10,000 pg/mL using a previously validated method. ⁷ The validated linear range for LSD and O‐H‐LSD was 5–10,000 pg/mL, with a correlation coefficient (R ²) of ≥ 0.998. For LSD, the inter‐assay accuracy across all QC levels ranged from 89% to 108%, with a coefficient of variation (CV) ≤ 7.4%. For O‐H‐LSD, inter‐assay accuracy ranged from 92% to 101%, with CV ≤ 8.9%. For this study, 10 pg/mL was used as LLOQ. Based on previous pharmacokinetic data, plasma concentration sampling up to 24 h was expected to cover > 90% of LSD's area under the concentration–time curve from zero to infinity (AUC_∞). ¹⁸

Pharmacokinetic analyses

All pharmacokinetic analyses were conducted using Phoenix WinNonlin 8.4 (Certara, Princeton, NJ, USA). Pharmacokinetic parameters were estimated using non‐compartmental methods. ⁷ Dosing time was adjusted to the respective formulation. Dosing time for intravenous LSD tartrate was set to t = 5.5 minutes (mean of dosing interval). The actual analytically determined dose was used for the subsequent correction of relevant pharmacokinetic parameters. Bioequivalence for the oral formulations was tested based on European Medicines Agency guidelines for bioequivalence studies, ²² with the LSD base solution as a reference. For maximum plasma concentrations (C _max) and AUC_∞, a 90% confidence interval (CI) for the ratio of the log‐transformed test and reference values with an acceptance interval of 80.00–125.00% were defined. Absolute oral bioavailability (F) was calculated as the ratio between AUC_∞ oral and AUC_∞ intravenous.

An additional compartmental analysis was conducted. For the oral formulations, we applied a one‐compartment model, featuring first order input and elimination without any lag time, a method previously reported in detail and used for several different LSD doses. ³ , ⁷ , ¹⁸ For the intravenous application, we applied a two‐compartment micro model to separate the distribution from elimination phase.

Furthermore, we conducted a formal PK‐PD analysis, where predicted individual concentrations were used as input for the PD model. A sigmoid maximum effect (E _max) model (EC₅₀, E _max, γ) was selected for all PD effects. The procedure was previously reported in detail elsewhere. ³ , ⁷ , ¹⁸

Subjective drug effects and effect durations

Subjective effects were assessed repeatedly using Visual Analog Scales (VASs) ³ , ²³ , ²⁴ , ²⁵ before and 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, and 24 hours after drug administration. The Adjective Mood Rating Scale (AMRS) ²⁶ was administered before and 3, 6, 9, 12, and 24 hours after drug administration. The 5 Dimensions of Altered States of Consciousness (5D‐ASC) scale ²⁷ , ²⁸ and Psychedelic Experience Scale (PES), which includes the Mystical Effect Questionnaire (MEQ), ²⁹ , ³⁰ , ³¹ were administered 24 hours after drug administration to retrospectively rate peak psychedelic and mystical‐type effects. A detailed description of the administered questionnaires can be found in the Supplementary Methods S1 .

Time to onset, maximal effect, time to maximal effect, time to offset, effect duration, and area under the effect‐time curve (AUEC) were assessed using individual effect‐time plots of the VAS item “any drug effect,” with a threshold of 10% of the maximum response. For maximal ratings, < 50% the threshold was set to 5. Analyses were conducted using Phoenix WinNonlin 8.4.

Autonomic and adverse effects

Blood pressure, heart rate, and tympanic body temperature were repeatedly measured before, and at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, and 24 hours after drug administration. ³² Adverse effects were assessed before, and at 12 and 24 hours after drug administration using the List of Complaints (LC) ³³ and in the form of spontaneously reported adverse events between study sessions.

Data analysis

Peak maximum effect (E _max) and/or minimum effect (E _min) or peak change from baseline (ΔE _max) values were determined for repeated measures. The values were analyzed using repeated‐measures analysis of variance (ANOVA), with formulation as the within‐subjects factor, followed by Tukey post hoc tests using RStudio, PBC, Boston, MA, USA. The criterion for significance was p < 0.05.

RESULTS

Pharmacokinetics

Plasma concentrations of LSD and O‐H‐LSD could be quantified at all timepoints after treatment. The concentration–time curves of the LSD base and tartrate formulations are shown in Figure 1 . Concentration–time curves of the main metabolite, O‐H‐LSD, are shown in Figure S1 . The corresponding pharmacokinetic parameters are presented in Table 1 . Individual curves are presented in Figure S2 . The bioequivalence analysis is depicted in Figure S3 . Results from the compartmental analysis are presented in Figure S4 and Table S1 .

Figure 1.

Plasma concentration–time curves of the tested lysergic acid diethylamide (LSD) formulations. Oral LSD formulations showed similar concentration–time curves and shared similar pharmacokinetic profiles with comparable parameters for maximum plasma concentration (C _max), time to reach maximum plasma concentration (t _max), plasma elimination half‐life (t _1/2), and area under the concentration–time curve (AUC). Oral absolute bioavailability was around 80% of intravenous LSD tartrate. The data are expressed as the mean ± SD in 20 participants. The corresponding parameters are presented in Table 1 .

Table 1.

Pharmacokinetic parameters based on non‐compartmental analyses (geometric mean (95% CI), range), N = 20

	C max (pg/mL)	C max/D (pg/mL/μg)	t max (h)	t 1/2 (h)	AUC24 (pg h/mL)	AUC∞ (pg h/mL)	AUC∞/D (pg h/mL/μg)	AUC %extrapol (%)	CL(/F) (L/h)	Vz(/F) (L)	F (%)
LSD base oral 83 μg
LSD	1760 (1530–2020)	21 (18–24)	2.0 (1.7–2.4)	4.0 (3.6–4.4)	13,500 (11,400–16,000)	14,100 (11,900–16,800)	170 (143–202)	3.7 (2.9–4.8)	5.9 (4.9–7.0)	34 (30–39)	80 (71–89)
	957–3470	12–42	1.0–4.0	2.9–5.8	7160–28,700	7250–29,600	87–357	1.2–9.7	2.8–11	15–50	45–108
O‐H‐LSD	127 (112–145)		5.6 (5.0–6.2)	7.1 (6.3–8.0)	1680 (1480–1910)	2020 (1750–2320)		16 (13–18)
	84–208		3.5–8.0	4.4–12	1120–2600	1300–3700		7.2–30
LSD tartrate oral 81 μg
LSD	1880 (1610–2180)	23 (20–27)	1.7 (1.4–2.1)	3.9 (3.6–4.3)	13,300 (11,000–16,100)	13,900 (11,400–16,900)	171 (140–209)	3.3 (2.4–4.5)	5.8 (4.8–7.1)	33 (28–38)	80 (72–90)
	1170–4840	14–60	0.8–4.0	2.7–5.5	6110–33,600	6180–35,000	76–432	1.0–13	2.3–13	15–56	39–176
O‐H‐LSD	128 (112–146)		5.3 (4.7–6.0)	7.2 (6.4–8.1)	1700 (1480–1950)	2060 (1770–2400)		16 (13–19)
	84–193		3.5–8.0	4.3–12	1110–2770	1290–3400		5.9–39
LSD base RDT oral 81 μg
LSD	1760 (1560–2000)	22 (19–25)	2.0 (1.6–2.4)	3.9 (3.6–4.3)	13,300 (11,300–15,600)	13,800 (11,700–16,400)	172 (145–204)	3.2 (2.4–4.2)	5.8 (4.9–6.9)	33 (29–37)	81 (72–91)
	1150–3610	15–42	0.5–4.0	2.9–6.7	7940–29,000	8090–29,900	98–347	1.1–13	2.9–10	16–50	49–114
O‐H‐LSD	132 (117–148)		5.4 (4.8–6.2)	7.5 (6.4–8.8)	1750 (1550–1990)	2140 (1850–2470)		16 (13–20)
	87–223		3.5–9.0	4.1–17	1150–2950	1340–3590		6.3–41
LSD tartate i.v. 81 μg
LSD	5940 (4950–7120)	73 (61–88)	0.16 (0.15–0.17)	3.8 (3.6–4.1)	16,800 (14,600–19,300)	17,200 (14,900–20,000)	213 (184–246)	2.4 (1.8–3.1)	4.7 (4.1–5.4)	26 (23–29)
	2890–10,100	36–125	0.16–0.19	3.0–5.6	8800–26,600	8870–27,500	110–340	0.8–7.3	2.9–9.1	16–42
O‐H‐LSD	134 (117–153)		4.8 (4.1–5.7)	6.7 (6.0–7.5)	1760 (1550–2010)	2070 (1810–2370)		13 (11–16)
	74–201		3.0–8.0	5.0–11	1000–2750	1190–3600		6.6–28

AUC, area under the plasma concentration–time curve; AUC₂₄, AUC from time 0–24 h; AUC_∞, AUC from time zero to infinity; AUC∞/D, dose‐corrected AUC∞; AUC %extrapol, extrapolated AUC; CL, total clearance; CL(/F), apparent total clearance; C _max, maximum observed plasma concentration; C _max/D, dose‐corrected C _max; T _1/2, plasma half‐life; Tmax, time to reach C _max; 95% CI, 95% confidence interval; Vz, volume of distribution; Vz(/F), apparent volume of distribution; F, absolute oral bioavailability; LSD, lysergic acid diethylamide.

All oral formulations met the criteria for bioequivalence. For the LSD base RDT, the 90% CI values were 93–111% and 94–114% for AUC_∞ and C _max, respectively. For oral LSD tartrate, the 90% CI values were 92–111% and 99–120% for AUC_∞ and C _max, respectively. The oral formulations shared similar pharmacokinetic profiles when comparing C _max, plasma half‐life (t _1/2), and AUC_∞. Oral LSD tartrate showed a numerically slightly shorter time to reach maximum plasma concentration (t _max) compared with both oral LSD base formulations. Absolute oral bioavailability values (F) of all oral LSD base and tartrate formulations are presented in Table 1 and were 80–81% of intravenously administered LSD tartrate. The intravenous LSD tartrate formulation produced higher C _max and AUC_∞ values.

Subjective drug effects

Subjective effects over time, assessed by VASs, are shown in Figure 2 and Figure S5 . Parameters that characterize the overall subjective drug effects over time based on the VAS item “any drug effect” are presented in Table 2 . Results from the formal PK‐PD analysis are presented in Figure S6 and Table S2 . Alterations of mind and mystical‐type effects, assessed by the 5D‐ASC and PES, are shown in Figure 3 and Figure S7 . Acute effects on mood, assessed by the AMRS, are shown in Figure S8 . The corresponding statistics are presented in Tables S3 – S6 . Sex differences assessed by the VAS are presented in Table S7 .

Figure 2.

Acute subjective effects on the Visual Analog Scale (VAS) induced by oral and intravenous lysergic acid diethylamide (LSD) formulations and placebo. Oral LSD base and tartrate formulations had comparable pharmacodynamic profiles. Intravenous LSD tartrate showed a rapid onset and an earlier peak of subjective effects and induced higher anxiety than oral LSD formulations. Intravenously administered LSD induced higher nausea compared with oral LSD base and tartrate but not LSD base ODT. The data are expressed as the mean ± SD ratings in 20 participants. The corresponding statistics are presented in Table 2 and Table S3 .

Table 2.

Parameters characterizing the subjective drug effect‐time curves of tested oral and intravenous lysergic acid diethylamide (LSD) base and tartrate formulations

	LSD base oral	LSD base RDT oral	LSD tartrate oral	LSD tartrate i.v.
Time to onset (h)	0.7 ± 0.4*** (0.3–1.8)	0.8 ± 0.4*** (0.3–2.1)	0.7 ± 0.3*** (0.1–1.2)	0.04 ± 0.04 (0.02–0.2)
Time to offset (h)	8.9 ± 1.7 (5.6–12)	9.1 ± 3.9 (2.2–20)	8.3 ± 2.2 (3.6–14)	8.1 ± 1.8 (4.7–11)
Time to maximal effect (h)	2.4 ± 0.7*** (1.0–4.4)	2.5 ± 0.9*** (1.0–4.0)	2.6 ± 0.8*** (1.0–3.5)	1.2 ± 0.8 (0.2–2.4)
Effect duration (h)	8.1 ± 2.0 (4.0–11)	8.3 ± 3.9 (2.0–20)	7.6 ± 2.2 (2.5–13)	8.0 ± 1.8 (4.6–11)
Maximal effect (%)	85 ± 20 (39–100)	82 ± 27 (12–100)	79 ± 24** (33–100)	94 ± 12 (61–100)
AUEC (h pg/mL)	454 ± 197 (186–905)	437 ± 236 (30–920)	418 ± 208 (80–874)	482 ± 165 (222–801)

Parameters are for “any drug effects.” The threshold to determine times to onset and offset was set at 10% of the individual maximal possible response. If the individual maximal response was ≤ 50% the threshold was set to 5%. Values are mean ± SD (range). **P < 0.01, ***P < 0.001 compared with LSD tartrate i.v.; AUEC, area under the effect curve; N = 20.

Figure 3.

Acute alterations of mind on the 5 Dimensions of Altered States of Consciousness (5D‐ASC) scale. All oral lysergic acid diethylamide (LSD) formulations induced comparable alterations of mind. Intravenously administered LSD induced significantly higher effects of “oceanic boundlessness” compared with oral LSD tartrate, “anxious ego dissolution” compared with oral LSD base ODT and oral LSD tartrate, and “anxiety” compared with all oral LSD formulations. The data are expressed as the mean ± SD percentage of maximally possible scale scores in 20 subjects. Statistics are shown in Table S4 .

All oral LSD formulations showed a similar pharmacodynamic profile when comparing time to onset, effect duration, maximal effect, and time to maximal effect. Intravenous LSD tartrate showed a significantly shorter time to onset and time to maximal effect but a comparable effect duration with the oral LSD formulations. All oral LSD formulations induced similar alterations of the state of consciousness, mystical‐type experiences, and changes in mood, reflected by similar 5D‐ASC, PES, and AMRS scores, respectively.

On the VAS, intravenously administered LSD produced significantly higher ratings of anxiety compared with all oral formulations (p < 0.01 vs. LSD base, p < 0.001 vs. RDT and tartrate). Furthermore, the intravenous formulation produced significantly greater effects on the VASs “any drug effect” (p < 0.01), “good drug effect” (p < 0.05), “stimulated” (p < 0.05), and “ego dissolution” (p < 0.05) compared with oral LSD tartrate, greater “bad drug effect” and “nausea” compared with oral base (both p < 0.05) and tartrate (p < 0.01 and p < 0.01, respectively), and greater “visual alteration” and “alteration of sense of time” (both p < 0.05) compared with oral LSD base. Intravenously administered LSD also induced significantly stronger overall alterations of the state of consciousness based on higher 5D‐ASC and 3D‐ASC total scores compared with oral LSD tartrate (both p < 0.01) and LSD base RDT (both p < 0.05) but not oral base. Intravenous LSD also produced higher ratings of the dimensions “anxious ego‐dissolution” compared with oral ODT and tartrate (both p < 0.05) and “oceanic boundlessness” compared with tartrate (p < 0.01). Intravenously administered LSD also led to higher ratings on the “anxiety” subscale (p < 0.05 vs. all oral formulations) and “experience of unity” (p < 0.05 vs. oral tartrate) and “insightfulness” (p < 0.01 vs. oral tartrate). On the MEQ30, intravenously administered LSD showed higher scores only in “ineffability” (both p < 0.05) compared with RDT and tartrate and significantly higher ratings of “transcendence of time and space” (p < 0.05) compared with RDT. Changes in mood on the AMRS did not differ significantly between the different LSD formulations.

Autonomic and adverse effects

Autonomic effects over time and corresponding statistics are shown in Figure 4 and Table S3 . Frequently reported adverse effects, assessed by the LC, and corresponding statistics are presented in Tables S3 and S8 .

Figure 4.

Acute autonomic effects induced by oral and intravenous lysergic acid diethylamide (LSD) base and tartrate formulations and placebo. LSD base and tartrate formulations similarly increased systolic and diastolic blood pressure, mean arterial pressure, and body temperature. Only intravenously administered LSD produced significantly higher maximal heart rate and rate pressure product (RPP) compared with oral LSD base and tartrate formulations and placebo. The data are expressed as the mean ± SD of maximum responses in 20 participants. The corresponding statistics are shown in Table S3 .

All LSD formulations moderately increased blood pressure. Only intravenously administered LSD increased heart rate significantly compared with placebo. Intravenously administered LSD also significantly increased heart rate compared with orally administered LSD. On the LC, LSD generally produced higher total numbers of total acute (0–12 hours) and subacute (12–24 hours) adverse effects compared with placebo, but the LSD formulations did not differ from one another. Most frequently reported acute adverse events included nausea, headache, loss of appetite, lack of concentration, inner tension, and tremor. The most frequently reported subacute adverse effects included tiredness, headache, lack of energy, feeling dull, and insomnia. A total of three flashback phenomena were reported (one participant reported two flashbacks that occurred after oral LSD base, and one participant reported one flashback that occurred after oral LSD tartrate). No long‐term incidences occurred. No serious adverse events occurred. A total of three participants dropped out of the study after the first study visit. Two participants decided to withdraw from study participation after their first study session when they both received intravenous LSD and experienced overall challenging acute drug effects, and one participant was excluded because of poor veins that hampered adequate pharmacokinetic sampling. Spontaneously reported adverse events with an onset within 48 hours after substance administration included headache (two participants, five events), nausea (one participant), and excessive tiredness (one participant).

Blinding

Participants' guesses of their assignment of the five study conditions after the study sessions and at the end of the study are shown in Table S9 . The participants could not distinguish between the different oral LSD formulations after the study session or at the end of the study, but intravenous LSD tartrate was correctly identified by 80% of the participants at the end of the session and by 95% after the study.

DISCUSSION

The present study directly compared three different oral LSD formulations to test their bioequivalence and one intravenous formulation to determine the absolute bioavailability of LSD in humans. The oral formulations included an oral ethanolic base formulation, which has frequently been used by our group and internationally in various studies in healthy volunteers and patients, ² , ⁴ , ⁷ , ¹⁸ , ¹⁹ , ³⁴ , ³⁵ , ³⁶ a watery oral LSD tartrate formulation that is the new standard, and a novel oral RDT base formulation as a potentially more practical solid form of administration. We tested bioequivalence according to regulatory standards, ²² , ³⁷ and oral bioequivalence criteria were met according to acceptance 90% CI values of 80–125% for C _max and AUC_∞ for all oral formulations and using the oral LSD base formulation as a reference. Thus, the crystal structure (base vs. tartrate) does not relevantly influence the absorption or distribution of LSD in humans. Moreover, the RDT formulation that was tested herein did not influence these parameters compared with the liquid formulations. However, an RDT may still exhibit kinetics that are different from a capsule or other solid oral formulations because some formulations may dissolve more slowly. Overall, the pharmacokinetic parameters of orally administered LSD that are reported herein are comparable to previously reported values, however values seem to be slightly more variable than in previous studies. ² , ⁴ , ⁷ , ¹⁸ , ¹⁹ , ³⁴ , ³⁵ , ³⁶ Reasons for the variability are manifold; LSD undergoes hepatic metabolism involving several cytochrome P450 isoforms, such as CYP2D6, CYP3A4, CYP1A2, and CYP2C9, ³⁸ several of which are polymorphic. In fact, we have previously shown that CYP2D6 poor metabolizers have a higher exposure to LSD due to longer half‐lives. ³⁹ Values of LSD's primary metabolite O‐H‐LSD were comparable with previously reported studies. Consistent with pharmacokinetic bioequivalence, the three oral formulations showed no difference in pharmacodynamic effects. All three oral formulations had a similar subjective pharmacodynamic profile over time, based on the VAS “any drug effect,” with comparable effect onset, offset, and maximum. In line with the variability of the pharmacokinetic parameters and given the potential influence of other factors on the acute psychedelic experience, ⁴⁰ the parameters for the acute experience (Table 2 ) also showed some variability. The oral formulations also induced similar LSD‐typical alterations of the state of consciousness, measured by the 5D‐ASC, and mystical‐type experiences, assessed by the PES and MEQ30. Consistent with the subjective drug effects, effects of the different oral formulations on vital parameters were also comparable. Oral LSD administration similarly and moderately increased heart rate, blood pressure, and body temperature.

The present study was the first to repeatedly administer the same dose of a psychedelic to the same participant outside of a therapeutic setting and without concomitant medication. There were no differences over time or order effects, thus indicating no tolerance with repeated doses of LSD when administered at a dosing interval of at least 10 days (Figure S9 ). Similarly, there were no differences in acute effects of LSD between the first and second administrations of 200 μg LSD in a study in patients with anxiety disorders. ⁴

The present study was also the first to validly determine the absolute bioavailability of LSD. The absolute oral bioavailability was 80–81%, which is slightly higher than the previously reported indirectly estimated bioavailability of ~71%. ¹⁶ Pharmacokinetic parameters of intravenous LSD administration aligned with an early preliminary study. ²⁰ Subjective drug effects after administration of the intravenous formulation peaked earlier than the oral formulations, but the effect duration was similar. Subjective effects began almost immediately after intravenous administration, but we observed a lag time between the plasma peak and subjective effect peak of ~1 hour, similar to the lag time after oral administration. The reason for this lag is unclear, and it was not observed with N,N‐dimethyltryptamine (DMT) or psilocybin. ⁴¹ , ⁴² , ⁴³ Intravenously administered LSD resulted in higher ratings on the VASs “anxiety,” “bad drug effect,” and “nausea,” higher ratings on the “anxiety” subscale of the 5D‐ASC, and higher ratings of “ineffability” on the MEQ30. This may likely be attributable to the faster onset of intravenous LSD bolus administration because effects begin rapidly, and people have less time to accommodate. Bolus intravenous DMT administration results in similar but not faster effect onsets, with relatively more negative subjective effects compared with continuous DMT infusions, which have a slower effect onset. ⁴¹ , ⁴⁴

In the present study, we tested the stability of the administered formulations. All liquid formulations were stable over the entire study duration, but the RDT showed a gradual decline in LSD base content by 18% over the study duration of 18 months. To adjust for this reduction in dose over time, we estimated individual actual doses based on the rate of decline and reported individual dose‐corrected C _max and AUC values (C _max/D and AUC/D in Table 1 ). Notably, the average administered RDT LSD dose was 81 μg, which was similar to the other formulations.

The present study has several strengths. We used a validated analytical method, sampled for 24 hours, and covered 96–98% of the total LSD AUC for each condition. We also included a rather large sample of 20 participants in this within‐subject comparison (regulatory standards suggest the inclusion of at least 12 people per condition). We also included equal numbers of male and female participants.

The present study also has limitations. We used the same catheter for intravenous drug administration and blood sampling. This procedure carries the risk of contaminating the catheter and thus may result in erroneously higher plasma concentration measurements for the first blood sample. Nonetheless, LSD tartrate dissolves homogeneously in saline. The catheters were flushed thoroughly after administration, and the data show no indication of contamination‐related errors.

In conclusion, we demonstrated that three oral LSD formulations were bioequivalent, independent of whether LSD base or tartrate salt was used. LSD's absolute oral bioavailability was ~80%. The present study is important for the correct interpretation of findings of LSD studies and future research.

FUNDING

This work was supported by the Swiss National Science Foundation (grant no.: 32003B_185111 to M.E.L. and P500PM_210867 to F.H.), the University Hospital Basel, and Mind Medicine, Inc.

CONFLICT OF INTEREST

M.E.L. is a consultant for Mind Medicine, Inc. The other authors declare no conflicts of interest. Know‐how and data that are associated with this work are owned by the University Hospital Basel and were licensed by Mind Medicine, Inc. Mind Medicine, Inc. had no role in planning or conducting the present study or the present publication.

AUTHOR CONTRIBUTIONS

F.H., C.H., and M.E.L. designed the research. D.A., F.H., D.R., and D.L. performed the research. D.A., F.H., L.M., P.V., D.R., D.L., and M.E.L. analyzed the data. D.A., F.H., and M.E.L. wrote the manuscript. C.H. contributed new reagents/tools.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT04865653.

Supporting information

Data S1