Use of genotyping or phenotyping to adjust LSD dose

Abstract

Providing accurate LSD dosage information and methods for determining individualized LSD dosages. [Solution] A method for administering LSD in the treatment of a patient by evaluating the patient's genetic characteristics before use, administering LSD to the patient based on the patient's genetic characteristics, thereby producing the greatest positive subjective acute effect in the subject and / or reducing anxiety and negative effects. A method for determining a preferred dose of LSD by determining the patient's metabolic and genetic markers (e.g., by evaluating CYP2D6 activity in the patient and / or evaluating 5HTR1A_rs6295 and 5HTR2A_rs6313 genotypes), adjusting the dose of LSD based on metabolic activity and genetic profile, administering the above dose of LSD to the patient, thereby producing the greatest positive subjective acute effect in the subject and / or reducing anxiety and negative effects. A method for determining the dose of LSD based on the evaluation of the presence of a CYP2D6 inhibitor.

Description

[Technical Field]

[0001] Grant information The research presented in this application is from the Swiss National Science Foundation. This project was partially supported by grants (grant numbers 320030_170249 and 32003B_185111).

[0002] Background of the Invention 1. Technical field This invention relates to genetic testing, and the adjustment of the dosage of LSD used in humans during treatment, and This concerns methods for predicting the effects of biotechnology. [Background technology]

[0003] 2. Background technology Lysergic acid diethylamide (LSD) can be used to adjunct psychotherapy for many indications, including anxiety, depression, addiction, and personality disorders, and can also be used to treat other disorders such as cluster headaches and migraines (Hintzen & Passie, 2010; Liechti, 2017; Nichols, 2016; Passie et al., 2008). LSD is a serotonin receptor. The 5HT2A receptor is targeted. The effects of LSD include changes in thought, emotion, and perception of the surroundings, pupil dilation, increased blood pressure, and increased body temperature.

[0004] The commonly used dose for LSD support therapy / psychotherapy is 100-200 μg. In one representative study (Holze et al., 2019), a 100 μg dose produced a subjective effect in humans, which lasted for (mean ± SD) 8.5 ± 2.0 hours (range: 5.3-12.8 hours). In other studies, the effects of LSD lasted similarly for 8.2 ± 2.1 hours (range: 5-14 hours) after administration of a 100 μg dose and 11.6 ± 1.7 hours (range: 7-19.5 hours) after administration of a 200 μg dose (Dolder et al., 2017b).

[0005] The acute subjective effects of LSD are almost always positive in most people (Holze et al., 2021b; Schmid et al., 2015). However, depending on the dosage of LSD used, the setting (environment), and a set of factors including the personality traits of the person using LSD, and possibly other factors such as the specific characteristics of metabolic enzymes and the site of action of LSD (serotonin receptors) present in the individual, many people also experience negative subjective effects (anxiety) from LSD.

[0006] The risk of acute negative psychological effects is a major obstacle to the use of psychedelic substances in humans. Anxiety that occurs during LSD-assisted psychotherapy can be a significant problem for both patients and therapists. Acute anxiety is not only extremely distressing for patients but is also associated with poor long-term outcomes in patients with depression (Roseman et al., 2017). Furthermore, anxiety reactions during psychedelic-assisted therapy may require additional management, greater therapist involvement, longer sessions, and acute psychological and pharmacological interventions. Thus, the primary safety concern relates to psychological adverse effects rather than physical adverse effects (Nichols, 2016; Nichols & Grob, 2018). Several studies suggest that more positive experiences are associated with psychedelic therapy. The induction of an overall positive acute response to psychedelics is important because it has been shown to predict greater therapeutic long-term effects of psychedelics (Garcia-Romeu et al., 2014; Griffiths et al., 2016; Ross et al., 2016). Even in healthy subjects, psychedelics including LSD are important. Positive acute responses to Delix have been shown to be associated with more positive long-term effects on well-being (Griffiths et al., 2008; Schmid & Liechti, 2008). 018).

[0007] Moderate anticipatory anxiety is common at the onset of drug effects (Studerus et al., 2012). In a study involving 16 healthy individuals, significant anxiety was observed in two subjects after administration of 200 μg of LSD. This anxiety was associated with fears of loss of thought control, out-of-body experiences, and loss of self (Schmid et al., 2015), and similar findings were observed with psilocybin. This was described (Hasler et al., 2004). Adverse drug effects (at any point from drug administration) Transient adverse drug reactions (more than 50% on a 0-100% scale) were observed in 9 out of 16 subjects (56%) after high-dose administration of 200 μg of LSD, and in 3 out of 24 subjects (12.5%) after moderate-dose administration of 100 μg of LSD (Dolder et al., 2017a). Similarly, in another study, transient adverse drug effects were reported in 7 out of 24 subjects (29%) after administration of 100 μg of LSD (Holze et al., 2019a). These negative subjective drug reactions... The effect is transient and occurred in subjects who reported good drug effects at different and / or similar time points, but the negative reaction is problematic.

[0008] One solution to address negative drug effects is generally to reduce the dose of psychedelics, but this also reduces the drug's effectiveness, so dose reduction may only be necessary for some patients and not for others.

[0009] While pharmacogenetic approaches have been used for some drugs, there is currently no available information regarding the pharmacogenetics of LSD that would allow for dose adjustment of LSD. There is no prior art to guide how pharmacogenetics can be applied.

[0010] Separately, in vitro metabolic studies have shown that several cytochrome P450 (CYP) isoforms (e.g., CYP2D6, CYP1A2, CYP2C9) are involved in LSD metabolism, but in vivo data are lacking, as is the application of such studies to changes in LSD dosage.

[0011] The psychedelic effects of LSD are primarily mediated by agonism at the 5-hydroxytryptamine (5-HT)2A receptor (5HTR2A) (Holze et al., 2021b; Kraehenmann et al., 2017). However, LSD binding is also mediated at 5HTR1A, 5HTR2B, and 5H It also acts as a partial agonist for other 5-HT receptors such as TR2C (Rickli et al., 2016). [Overview of the Initiative] [Problems that the invention aims to solve]

[0012] To reduce harmful drug effects, accurate and individualized dosages of LSD are still needed. [Means for solving the problem]

[0013] Summary of the Invention The present invention provides a method for administering LSD in the treatment of a patient by evaluating the patient's genetic characteristics before LSD use, administering LSD to the patient based on the patient's genetic characteristics, thereby producing the greatest positive subjective acute effect in the subject and / or reducing anxiety and negative effects.

[0014] The present invention determines a patient's metabolic and genetic markers (for example, by evaluating CYP2D6 activity in the patient and / or evaluating the 5HTR1A rs6295 and 5HTR2A rs6313 genotypes), adjusts the dose of LSD based on metabolic activity and genetic profile, administers the above dose of LSD to the patient, and provides the subject with the greatest positive subjective effect. Provided is a method for determining a preferred dose of LSD by producing an acute effect and / or reducing anxiety and negative effects.

[0015] The present invention also provides a method for evaluating a concomitant drug that may have the potential for CYP2D6 inhibition in a patient, evaluating CYP2D6 activity in the patient, administering LSD to the patient to produce the maximum positive subjective acute effect in the patient, and / or reducing anxiety and negative effects, and determining the dose of LSD based on the evaluation of the presence of a CYP2D6 inhibitor.

[0016] Description of the Drawings The advantages of the present invention will be better understood when considered in connection with the accompanying drawings and by reference to the following detailed description, and these advantages will be readily understood.

Brief Description of the Drawings

[0017] [Figure 1] Graph of modeled LSD plasma concentration-time curve over 24 hours after administration of LSD to subjects having genetically determined non-functional (red) or functional (blue) CYP2D6 enzymes. [Figure 2] Graph showing a linear regression model of the participant's body weight (kg) against LSD plasma exposure, expressed as the area under the infinite curve (AUC∞) (z-score). [Figure 3] Table showing the effect of CYP2D6 on the pharmacokinetics of LSD. [Figure 4] Table showing the effect of CYP2D6 on the pharmacokinetics of the major LSD metabolite O-H-LSD. [Figure 5] Table showing the effect of CYP2D6 on the subjective and autonomic effects of LSD. [Figure 6] Table showing the effect of CYP2D6 on the acute changes in mood induced by LSD. [Figure 7] Table showing the effect of the HTR1B rs6296 genotype on the effect of LSD. [Figure 8]The table shows the effect of the HTR1A rs6295 genotype on the effects of LSD. [Figure 9] The table shows the effect of HTR2A rs6313 on the effect of LSD. [Figure 10] An example table of the target population is shown below. [Figure 11] A table showing the allele frequencies and classifications of CYP2D6 is provided. [Figure 12] The table shows the allele frequencies and activity scores of the CYP2C19 genotype. [Figure 13] The table shows the single nucleotide polymorphism frequencies within the tested genotypes. [Figure 14] A table showing the subjective effects of LSD is provided. [Figure 15] A table showing the effects of LSD on the autonomic nervous system is shown. [Figure 16] A table showing the emotional changes induced by LSD is provided. [Figure 17] The table shows the effect of the CYP2D6 activity score on LSD pharmacokinetics. [Figure 18] The table shows the effect of the CYP2C19 activity score on LSD pharmacokinetics. [Figure 19] The table shows the effect of CYP1A2 genotype on the pharmacokinetics of LSD. [Figure 20] The table shows the effect of the CYP2C19 genotype on the pharmacokinetics of LSD. [Figure 21] The table below shows the pharmacokinetics of LSD according to CYP2B6 rs3745274. [Figure 22] A table showing the CYP1A2 rs762551 genotype related to the pharmacokinetics of LSD is provided. [Modes for carrying out the invention]

[0018] Detailed description of the invention This invention provides a method for better determining the dose of LSD to a patient (human) before administration using pharmacogenetics. The method described herein provides personalized treatment for LSD patients. ru.

[0019] More specifically, the present invention provides a method for determining the dosage of LSD in a patient's treatment by evaluating the patient's genetic characteristics before LSD use, and administering LSD to the patient at a dose based on the patient's genetic characteristics, use for therapist training, or any other legally regulated setting in a healthy subject, to produce the greatest positive subjective acute effect in the subject. This method can also be used to mitigate the anxiety and negative effects of LSD.

[0020] A further objective of the present invention is to maximize the effectiveness of LSD administration, or at least maintain safety and minimize adverse effects, while enabling effective treatment of diverse patient populations.

[0021] While LSD is mentioned throughout this application, it should be understood that its analogues, derivatives, or salts thereof may also be used. The present invention enables dose optimization of LSD analogues when the LSD analogue is partially metabolized by LSD-like CYP2D6.

[0022] After evaluating a patient's genetic characteristics, these can be used to adjust the dose for patients with genetic profiles that predict a greater or more adverse response to LSD. Specifically, the dose of LSD can be adjusted by determining a decrease in the activity of enzymes involved in LSD metabolism or genetic alterations in the pharmacological targets of LSD. Preferably, LSD is administered in a therapeutic setting or in a legally regulated setting (but not limited to clinical trials) involving healthy subjects.

[0023] This invention uses psychometric, pharmacokinetic, and genetic data from large samples of controlled LSD administration to humans to determine the pharmacogenetics of both the major metabolic enzymes and target receptors of LSD in relation to the acute effects of LSD, thereby providing novel data and specific instructions for adjusting LSD doses based on genetic characteristics.

[0024] In addition to the methods used herein, other variables, including age, personality, treatment status, and a person's past psychedelic experiences, may also be useful in determining an appropriate dose of LSD, but these are not part of the present invention.

[0025] This invention investigates the effects of genetic polymorphisms in CYP genes on the pharmacokinetics and acute effects of LSD in healthy subjects, using data from clinical trials. The above trials were published after the provisional patent application (Vizeli et al., 2021). LSD is associated with 5HTR2A and 1A / Because CYP receptors strongly bind to B receptors and their psychedelic effects depend on the activation of 5HTR2A, these receptor genes can be mitigated by genetic mutations. Therefore, to derive the data necessary for the present invention, common CYP gene variants (CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2B6) and serotonin receptors (5HTR1A, 5HTR1B, and 5HTR2A) were identified in 81 healthy subjects pooled from four randomized, placebo-controlled, double-blind Phase 1 trials.

[0026] The above study demonstrated that genetically determined CYP2D6 functionality significantly influences the pharmacokinetics of LSD. Individuals without a functional CYP2D6 allele (low-activity metabolizers) had longer LSD half-lives and approximately 75% higher plasma concentrations of the parent drug and its major metabolite, 2-oxo-3-hydroxyLSD (OH-LSD), compared to individuals who were carriers of the functional CYP2D6 allele. Non-functional CYP2D6 metabolizers also exhibited greater emotional changes and longer-lasting subjective effects in response to LSD compared to functional CYP2D6 metabolizers. The duration of action was also indicated. No effect of LSD on pharmacokinetics or acute effects was observed with other CYPs.

[0027] Variants in the target receptors of LSD also weakly mitigated the acute effects of LSD on the 5D-ASC scale. Specifically, carriers of two HTR2A rs6313 A alleles showed lower emotional changes (total 5D-ASC score and ego annihilation anxiety) than carriers of the G allele. Homozygous carriers of the HTR1A rs6295 G allele reported lower total 5D-ASC, hallucinatory restructuring, and blissful state ratings compared to carriers of the C allele.

[0028] In summary, this invention demonstrates that genetic polymorphisms influence the effects of LSD in humans. Specifically, CYP2D6 genetic polymorphisms significantly affected the pharmacokinetics and subjective effects of LSD. Therefore, this can be used to determine the dosage of LSD based on the genetic testing and interpretation of findings developed using this invention.

[0029] The dose of LSD may be 50% of the dose for patients with non-functional CYP2D6 compared to individuals with functional CYP2D6 (i.e., 100 μg compared to 200 μg).

[0030] Accordingly, the present invention provides a method for determining a preferred dose of LSD by determining metabolic and genetic markers in a patient (e.g., by evaluating CYP2D6 activity and / or evaluating 5HTR1A rs6295 and 5HTR2A rs6313 genotypes), adjusting the dose of LSD based on the metabolic activity and genetic characteristics of the pharmacologically targeted receptor determined genetically or otherwise (i.e., CYP2D6 activity and / or 5HTR1A rs6295 and 5HTR2A rs6313 genotypes), and administering the above dose of LSD to the patient. Metabolic activity may relate to enzymatic digestion. Pharmacological activity may relate to activation or binding to the receptor (major sites of action such as 5-HT1 and 5-HT2). The genotype of the gene encoding the receptor may increase or decrease binding, psychedelic effects, actual efficacy, etc. By understanding these pharmacogenetic effects, the dose can be adjusted to appropriately tailor its effects to individual patients or well-defined patient groups sharing a genetic signature.

[0031] The present invention also provides a method for determining the dose of LSD based on an assessment of the presence of a CYP2D6 inhibitor by evaluating concomitant medications that may inhibit CYP2D6 in a patient and assessing CYP2D6 activity in the patient, and for administering LSD to the patient to produce the greatest positive subjective acute effect and / or reduce anxiety and negative effects. Some patients are treated with serotonin reuptake inhibitors that can act as CYP2D6 inhibitors, such as fluoxetine or paroxetine. Such individuals may also have reduced CYP2D6 activity due to genetics. Therefore, the CYP2D6 inhibitor can be discontinued (up to two weeks) before initiating LSD treatment to allow the enzyme to regenerate, or the dose of LSD can be adjusted to decrease in the presence of the CYP2D6 inhibitor.

[0032] This invention further demonstrates that common mutations in the 5-HT receptor gene also affect acute emotional changes induced by LSD. This pharmacogenetic effect can be considered in LSD research and LSD-supported psychotherapy using the current data and instructions for use.

[0033] The compounds of the present invention are administered and the dosage determined in accordance with appropriate medical practice, taking into consideration the individual patient's clinical condition, administration site and method, administration schedule, patient's age, sex, weight, and other factors well known to healthcare professionals. Thus, the pharmaceutically effective amount for the purposes of this specification is determined by considerations well known in the art. The quantity must be effective in achieving improvement, and such improvement includes, but is not limited to, improved survival rates or faster recovery, or improvement or elimination of symptoms, as well as other indicators as selected by those skilled in the art as appropriate means.

[0034] In the method of the present invention, the compound of the present invention can be administered by various methods. It should be noted that the compound can be administered as an active ingredient, either alone or in combination with pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles. The compound can be administered parenterally, including orally, sublingually, subcutaneously, transdermally, or intravenously, intramuscularly, and intranasally, as well as by infusion techniques. Implants of the compound are also useful. Patients receiving treatment are warm-blooded animals, particularly mammals, including humans. Pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles, as well as implant carriers, generally refer to inert, non-toxic solid or liquid fillers, diluents, or encapsulating materials that do not react with the active ingredient of the present invention.

[0035] The dosage may be a single dose or multiple doses over several days. The duration of treatment is generally proportional to the disease process, the duration of drug effectiveness, and the species of the patient receiving treatment.

[0036] When the compounds of the present invention are administered parenterally, they are generally formulated in unit-dose injection form (solution, suspension, emulsion). Suitable pharmaceutical formulations for injection include sterile aqueous solutions or dispersions, and sterile powders for reformulation in sterile injection solutions or dispersions. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils.

[0037] Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersion, and further by the use of surfactants. Non-aqueous vehicles, such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters such as isopropyl myristate, can also be used as solvent systems for the compound composition. Furthermore, various additives can be added to enhance the stability, sterility, and isotonicity of the composition, including antimicrobial preservatives, antioxidants, chelating agents, and buffers. Inhibition of microbial action can be ensured by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. In many cases, it would be desirable to include isotonic agents, such as sugars and sodium chloride. Long-term absorption of injectable pharmaceutical forms can be achieved by the use of absorption-delaying agents, such as aluminum monostearate and gelatin. However, according to the present invention, any vehicle, diluent, or additive used must be compatible with the compound.

[0038] A sterile injection solution can be prepared by incorporating the compounds used in carrying out the present invention, together with various other components as desired, in the required amount of a suitable solvent.

[0039] The pharmacological formulations of the present invention can be administered to patients as injectable formulations containing any suitable carrier such as various vehicles, adjuvants, excipients, and diluents; or the compounds used in the present invention can be administered parenterally to patients in the form of sustained-release subcutaneous implants or targeted delivery systems, such as monoclonal antibodies, vector delivery, iontophoresis, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include: 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4 ,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0040] The present invention will be described in more detail by reference to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to limit the invention unless otherwise explicitly stated. Thus, the present invention should not be construed as being limited in any way to the following examples, but rather as encompassing any and all variations that become apparent as a result of the teachings provided herein. [Examples]

[0041] Example 1 This invention was developed based on data from a pooled analysis of clinical trials, which were published after the filing of a provisional patent application (Vizeli et al., 2021).

[0042] Background of the Exam Despite its widespread use, the metabolism of LSD is not well understood. Two recent in vitro studies have revealed the involvement of cytochrome P450 enzymes (CYP) in LSD metabolism (Luethi et al., 2019; Wagmann et al., 2019). In one study using CYP2, it was revealed that CYP2D6, 3A4, and 2E1 contribute to the N-demethylation of LSD to 6-nor-LSD (nor-LSD), while CYP2C9, CYP1A2, CYP2E1, and CYP3A4 are involved in the formation of the major metabolite 2-oxo-3-hydroxy-LSD (OH-LSD) (Luethi et al., 2019). Another study using the human liver S9 fraction revealed that CYP2C19 and 3A4 are involved in the formation of nor-LSD, while CYP1A2 and CYP3A4 contribute to the hydroxylation of LSD (Wagmann et al., 2019).

[0043] Some CYPs (i.e., CYP2D6, CYP1A2, CYP2C9, CYP2C19) have common functional genetic polymorphisms that result in different phenotypes (Gaedigk, 2013; Hicks et al., 2015; Hicks et al., 2013; Preissner et al., 2013; Sachse et al., 1997; Sachse et al., 1999). In most cases, CYP2D6 has different base genotypes. Several phenotypes are observed, ranging from low-activity metabolizers (PM, 5-10% in Caucasians) to very high-activity rapid metabolizers (UM, 3-5%) (Sachse et al., 1997). LSD metabolism involves CYP, especially C The YP2D6 gene variant (Luethi et al., 2019) affects the pharmacokinetics of LSD, and furthermore, individual It may affect the acute effects of LSD in the body, which are closely related to the plasma concentration-time curve (Holze et al., 2019; Holze et al., 2021a; Holze et al., 2021b). The CYP2D6 genotype has also been previously shown to affect the pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) (Schmid et al., 2016; Vizeli et al., 2017), a substance also used in substance-supported psychotherapy (Schmid et al., 2021).

[0044] As part of this invention, this analysis investigated the influence of significant genetic polymorphisms of key CYP enzymes (CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2B6) on the pharmacokinetic parameters of LSD and its acute subjective effects.

[0045] Stronger and more positive acute effects are thought to predict long-term treatment outcomes in patients treated with psychedelic-assisted therapy (Griffiths et al., 2016; Roseman et al., 2017; Ross et al., 2016) and even positive long-term effects in healthy subjects (Griffiths et al., 2008; Schmid & Liechti, 2018), thus predicting the quality of subjective effects of psychedelics. And the degree of this is of particular note.

[0046] LSD includes several subtypes, including 5HTR1A, 5HTR2B, and 5HTR2C. It binds very strongly to the 5-HT receptor and acts as a partial agonist there (Eshleman). et al., 2018; Kim et al., 2020; Rickli et al., 2016; Wacker et al., 2017). death However, the various psychedelic effects of LSD are thought to be primarily mediated by agonism in 5HTR2A (Holze et al., 2021b; Kraehenmann et al., 2017; Preller et al., 2017). Mutations in genes encoding major targets of the 5-HT system are associated with LSD. This may mitigate the acute effects of D.

[0047] To date, there is no data on the pharmacological genetics of LSD or other psychedelics.

[0048] However, the single nucleotide polymorphism (SNP) HTR2A rs6313 had a weak influence on MDMA effects such as "favorable drug effects," "drug preference," or "familiarity with others" (Vizeli et al., 2019).

[0049] Furthermore, the C allele of the rs6313 SNP was associated with lower expression, which was found to be linked to suicide, a reduced ability to adopt others' perspectives, increased anxiety when observing pain, and communication problems (Ghasemi et al., 2018; Gong et al.). 2015; Polesskaya et al., 2006).

[0050] Furthermore, the rs6295 SNP in the HTR1A gene encoding 5HTR1A may play a certain role in substance use disorders (Huang et al., 2004). Female homozygous carriers of the G allele of rs6295 with major depressive disorder benefited more from treatment with 5-HT reuptake inhibitors compared to carriers of the C allele (Houston et al., 2012).

[0051] The rs6296 SNP of HTR1B, which encodes the 5HTR1B receptor, was found to influence aggressive behavior in childhood. Individuals homozygous for the C allele were more aggressive than those with the G allele (Hakulinen et al., 2013). The 5-HT receptor is one of the most studied pharmacological targets for psychotropic drugs. However, this is the first information regarding the pharmacogenetics of a classic serotonergic psychedelic substance in humans.

[0052] The following studies investigated whether genetic polymorphisms in major metabolic enzymes involved in LSD degradation, including CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP2B6, or in major LSD targets, including HTR1A, HTR1B, and HTR2A, mitigate the pharmacokinetics of the acute effects of LSD in healthy subjects.

[0053] While LSD was used to develop this invention, LSD analogs or derivatives may also be used if CYP2D6 contributes to metabolism in a similar way to LSD.

[0054] Furthermore, since all psychedelics act primarily via 5-HT1 / 2 receptors, HTR1A, HTR1B, and HTR2A genetics can similarly be used for the pharmacological administration of other psychedelics such as psilocybin, mescaline, and dimethyltryptamine (DMT).

[0055] method Test design This was a pooled analysis of four phase 1 trials conducted in the same laboratory, each using a randomized, double-blind, placebo-controlled, crossover design (Dolder et al., 2017b; Holze et al., 2021b; Holze et al., 2020; Schmid et al., 2015).

[0056] All trials were registered on ClinicalTrials.gov (Trial 1: NCT01878942, Trial 2: NCT02308969, Trial 3: NCT03019822, and Trial 4: NCT03321136). A total of 84 healthy subjects were included in the trials. Trial 1 (Schmid Study 4 (Holze et al., 2021b) included 16 participants each, Study 2 included 24 participants (Dolder et al., 2017b), and Study 3 included 29 participants (Holze et al., 2020).

[0057] In Study 1, each subject received a single dose of either 200 μg of LSD or placebo. In Studies 2 and 3, each subject received a single dose of either 100 μg of LSD or placebo. In Study 4, each subject received 25, 50, 100, and 200 μg of LSD, as well as 200 μg of LSD + 40 mg of ketanserine (5-HT10). 2A The antagonist was administered. In this pooled analysis, the mean data from the four LSD doses used for the same subjects in Study 4 were used. The 200 μg LSD + 40 mg ketanserine condition was used for pharmacokinetic analysis but not for analysis of the effect of LSD.

[0058] All trials were approved by the local ethics committee and conducted in accordance with the Declaration of Helsinki. The use of LSD was approved by the Swiss Federal Public Health Center in Bern, Switzerland. To the Swiss Federal Office for Public Health (Bundesamt fuer Gesundheit) Therefore, it was approved. Written informed consent was obtained from all participants. All subjects were compensated for their participation.

[0059] The washout period between doses was 7 days for trials 1 and 2, and 10 days for trials 3 and 4. Test sessions were conducted in a quiet hospital test ward, with only one subject participating per session. Subjects were under constant supervision while experiencing acute drug effects. Participants lay comfortably in hospital beds, mostly listening to music and not engaging in physical activity. LSD was administered in the morning after a standardized small breakfast. A detailed overview of the included trials is shown in Figure 10 (Table S1).

[0060] subject A total of 85 healthy subjects of European descent, aged 25-60 (mean ± SD = 30 ± 8 years), were recruited, mostly from the University of Basel campus, to participate in the trial. Participants were included. One participant dropped out before the final LSD session, one participant stopped participating before the first test session, and two participants did not consent to genotyping. As a result, a final dataset for analysis was obtained for 81 subjects (41 women). The mean ± SD weight of the subjects was 70 ± 12 kg (range: 50-98 kg). Participants under 25 years of age were excluded from the study due to a higher incidence of psychotic disorders and the association of younger age with a more anxious response to hallucinogens (Studerus et al., 2012). Exclusion criteria included a history of mental disorders, physical illness, smoking (>10 cigarettes / day), and 10 sessions. The above included a lifetime history of illegal drug use (excluding past cannabis use), illegal drug use within the past two months, and illegal drug use during the study (determined by a urine test conducted before the study session). Of the 22 subjects, 16 had previously used lysergic acid diethylamide (1-3 times), 5 had previously used psilocybin (1-3 times), and 1 had previously used dimethyltryptamine (4 times), mescaline (1 time), and salvia divinorum (3 times).

[0061] Investigational drug LSD-based (Lipomed AG Arlesheim, Switzerland) was found in trials 1 and 2 to be gelatinous. As capsules (Dolder et al., 2017b; Schmid et al., 2015), or in studies 3 and 4 As a drinking solution in 96% ethanol (Holze et al., 2021b; Holze et al., 2020) It was prepared for oral ingestion.

[0062] Table S1 shows the doses used in each trial. Data on content uniformity and long-term stability are available for the doses used in trials 3-4 (Holze et al., 2019; Holze et al., 2021b; Holze et al., 2020), and the exact actual average dose based on administered LSD is shown in the figure. This is shown in 10 (Table S1).

[0063] The planned mean doses used in trials 1 and 2 were later found to be lower, and the actual doses used were estimated based on a comparison of the area under the curve (AUC) values ​​from trials 1 and 2 with those from trials 3 and 4 (Holze et al., 2019). Doses were not adjusted for weight or sex.

[0064] Pharmacokinetic analysis Pharmacokinetic parameters were calculated using non-compartmental analysis of Phoenix WinNonlin 6.4 (Certara, Princeton, NJ, USA). max The values ​​were obtained directly from the observational data. AUC and AUEC values ​​were calculated using the linear log trapezoidal method. The AUC value is the last measured concentration (AUC) in all tests. 10 It was calculated up to ) and extrapolated to infinity (AUC∞). Furthermore, Phoenix WinNonlin 6.4 has a primary input, a primary erase, and ragta Using an immunoassay-free 1-compartment model, the pharmacokinetics of LSD were compared in functional and non-functional CYP2D6 groups, illustrating the time-course LSD concentrations after 100 μg LSD-based administration (Figure 1). This analysis included data from all 81 subjects. For Study 4, only the 100 μg dose was included. Subjective response onset, offset, and duration were measured using a VAS (Visual Analog Scale) with a threshold of 10% of the individual maximum response, using Phoenix WinNonlin. "The effect of any drug" was determined using a time curve.

[0065] Physiological effects Blood pressure, heart rate, and body temperature were repeatedly assessed before LSD or placebo administration and at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 10 hours after administration. Systolic and diastolic blood pressure and heart rate were measured using an automated oscillometric device (OMRON Healthcare Europe NA, Hoofddorp, Netherlands). Measurements were performed at 1-minute intervals, with two repetitions after at least a 5-minute rest period. Mean values ​​were calculated for analysis. Mean arterial pressure (MAP) was calculated as diastolic blood pressure + (systolic blood pressure - diastolic blood pressure) / 3. The double product (RPP) was calculated as systolic blood pressure × heart rate. Core (tympanic membrane) temperature was measured using a Genius two-ear thermometer (Tyco Healthcare Group LP, Watertown, NY, USA).

[0066] Subjective effects The Visual Analog Scale (VAS, Figure 14, Table S5) was presented as a 100mm horizontal line (0-100%) ranging from "not at all" on the left to "extremely" on the right. Subjective effects such as "friendliness," "talkativeness," "frankness," "concentration," "thinking speed," and "trustworthiness" were bidirectional (±50mm). The VAS was applied before LSD or placebo administration and at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 10 hours after administration.

[0067] 5-dimensional altered states of consciousness (5D-ASC) scale (Dittrich, 1998; Studerus et al.) The peak drug response was retrospectively evaluated by administering the drug at the end of the acute drug effect (2010). Consciousness The main subscales representing the changes are oceanic infinity (OB), ego annihilation anxiety (AED), and hallucinatory restructuring (VR) (Figure 16).

[0068] Genotyping Genomic DNA was extracted from whole blood using the QIAamp DNA Blood Mini Kit (Qiagen, Hombrechtikon, Switzerland) and the automated QIAcube system. SNP genotyping The assay was performed using a commercially available TaqMan SNP genotyping assay (LuBio Science, Lucerne, Switzerland). The following SNPs and their respective alleles were assayed. ta: HTR1A rs6295 (Assay: C_11904666_10), HTR1B rs9296 (Assay: C_2523534_20), HTR2A; rs6313 (Assay: C_3042197_1_), CYP1A2*1F; rs762551 (Assay: C_8881221_40), CYP2B6; rs3745274 (Assay: C_7817765_60), CYP2C9*2 (rs1799853, Assay: C_25625805_10), CYP2C9*3 (rs1057910, Assay: C_27104892_10), CYP2C19*2 rs4244285 (Assay: C_25986767_70), CYP2C19*4 (rs28399504, Assay: C_30634136_10), CYP2C19*17 (rs12248560, Assay: C_469857_10), CYP2D6*3 (rs35742686, Assay: C_32407232_50), CYP2D6*4 (rs3892097, Assay: C_27102431_D0, and rs1065852, Assay: C_11484460_40), CYP2D6*6 (rs5030655, A Assay: C_32407243_20), CYP2D6*9 (rs5030656, assay: C_32407229_60), CYP2D6*10 (rs1065852), CYP2D6*17 (rs28371706, assay: C_2222771_A0, and rs16947, assay: C_27102425_10), CYP2D6*29 (rs59421388, assay: C_3486113_20), and CYP2D6*41 (rs28371725, assay: C_34816116_20, and rs16947). CYP2D6 gene deletion (alele*5) and duplication / proliferation (alele*xN) were determined using the TaqMan copy number assay (Hs04502391_cn). CYP2D6 activity scores were assigned according to established guidelines (Caudle et al., 2020; Crews et al., 2012; Gaedigk et al., 2008; Hicks et al., 2015; Hicks et al., 2013). Pharmacokinetics and pharmacodynamics of LSD. To confirm the clear effect of CYP2D6 function on the therapeutic effect, subjects were classified into non-functional CYP2D6 (PM, activity score = 0) and functional CYP2D6 (activity score > 0). CYP2C9 activity scores were generated using the relative metabolic activity of warfarin (Gage et al., 2008; Hashimoto et al., 1996). Genetically determined CYP 1A2 activity inducibility was combined with the subjects' smoking status (>5 cigarettes per day = smoker; rs762551 AA = inducible) (Sachse et al., 1999; Vizeli et al., 2017). Predicted CYP2C19 active metabolizers (IM) included CYP2C19*1 / *2 and CYP2C19*2 / *17, normally active metabolizers (EM) included CYP2C19*1 / *1, and UM included both CYP2C19*17 / *17 and CYP2C19*1 / *17 (Hicks et al., 2013). No CYP2C19PM was detected in the samples. In the case of CYP2B6, the decreased activity SNP rs3745274 (516G>T, CYP2B6*6 or CYP2B6*9, assay: C_7817765_60) was identified. The allele frequencies for the classification of CYP2D6 and CYP2C9 are shown in Figures 11 and 12 (Tables S2 and S3), respectively. All tested SNP frequencies are equivalent to those in the Allele Frequency Aggregator (ALFA) Project data bank and are listed in Figure 13 (Table S4) (L. Phan, 2020).

[0069] statistical analysis All data was analyzed using the R language and environment for statistical calculations (R Core Team, (2019). To investigate the influence of genotype, the pharmacokinetics of LSD (ΔLSD-placebo) were studied. Lameters or effects were compared using one-way analysis of variance (ANOVA) with genotype as an intergroup factor. Because the actual values ​​may be biased due to the possible uneven distribution of genotypes across trials, the data are presented as actual values ​​and z-scores for each trial.

[0070] Since no correlation was found between sex or weight and drug exposure, statistics were not adjusted for sex or weight (LSD AUC∞) (Figure 2, S1). As shown in Figure 2, isolated individuals were identified as non-functional CYP2D6. To minimize the impact of outliers and associated non-normalized data distributions on parametric statistics, non-parametric statistics (Wilcoxon signed-rank test and Kruskal-Wallis test) were used to confirm the effects of CYP2D6 on the pharmacokinetics and effects of LSD. LSD AUC∞ values ​​were z-normalized for each trial. The color of the dots indicates male (dark blue) or female (red) participants. Filled dots indicate non-functional CYP2D6 genotype. Sex or weight did not have a relevant effect on plasma LSD concentration.

[0071] The significance level was set at p<0.05. For pharmacokinetic analyses, p-values ​​were not corrected for numerous studies because a hypothesis regarding the influence of specific enzyme (i.e., CYP2D6) activity was a priori formulated. For the analysis of serotonin receptor SNPs (rs6295, rs6296, and rs6313), primary analyses were performed using an additive genotyping model of the SNPs. Recessive or dominant model analyses were performed, but results are reported only if the additive model is significant. In serotonin receptor genotyping analyses, differences in LSD plasma concentrations that may arise due to differences in metabolic enzymes were explained by including the LSD AUC∞z score as a covariate.

[0072] result Compared to placebo, LSD produced significant acute subjective effects across all scales, moderately increasing blood pressure, heart rate, and body temperature (Figure 14, Table S5). Differences in sex or weight did not correlate with altering the pharmacokinetics of LSD (Figure 2).

[0073] Influence of CYP genotype on the pharmacokinetics and acute effects of LSD CYP2D6 function significantly affected the pharmacokinetics and acute effects of LSD (Figs. 3 - 5, Tables 1a - c, and Fig. 1). Specifically, subjects genetically classified as CYP2D6 PM (non-functional) had significantly greater AUC∞ and AUC 10 values, statistically proven by the 10 value (Fig. 3, Table 1a), indicating higher exposure to LSD in plasma (Fig. 1). In Fig. 1, the shaded area indicates the standard error of the mean. CYP2D6 non-functional (N = 7) and functional (N = 74) subjects received doses (mean ± SD) of 100 ± 30 μg of LSD and 98 ± 35 μg of LSD, respectively. Both the half-life and AUC values were significantly increased in non-functional subjects compared to functional CYP2D6 enzymes. Additionally, CYP2D6 PM had a longer 1 / 2 value, consistent with reduced metabolism, compared to functional CYP2D6 subjects (Fig. 3, Table 1a), although the C max of LSD was not significantly affected. Furthermore, in parallel with the effect on LSD concentration, the O-H-LSD AUC∞ value was greater in CYP2D6 PM compared to functional CYP2D6 subjects (Fig. 4, Table 1b), indicating that the conversion to O-H-LSD is independent of CYP2D6. Compartment modeling for a 100 μg dose of LSD showed LSD AUC∞ and max values for CYP2D6 PM vs. functional subjects of 24169 ± 13112 vs. 13819 ± 6281 pg / mL*h ( 1,79 F = 13.8; p < 0.001) and 2369 ± 891 vs. 2061 ± 999 pg / mL ( 1,79 F = 0.62; p = 0.43), respectively (Fig. 1). Analysis across all CYP2D6 genotype activity score groups showed that lower CYP2D6 activity was also associated with significantly higher exposure to LSD (Fig. 17, Table S6).

[0074] Consistent with the effect on the pharmacokinetics of LSD (Fig. 1), CYP2D6 PM showed a substantially longer duration of the acute subjective response to LSD (Fig. 5, Table 1c) and significantly greater mood changes compared to functional CYP2D6 subjects (Fig. 6, Table 1d). Specifically The 5D-ASC total score, AED subscale (including out-of-body experiences, control and cognitive impairment, and anxiety), and VR subscale (including changes in the meaning of complex and elementary images and perceptual representations) were significantly increased in PM subjects compared to functional CYP2D6 subjects (Figure 6, Table 1d). CYP2D6 genotype did not have any effect related to autonomic nervous system responses to LSD (Figure 5, Table 1c).

[0075] In contrast to CYP2D6, gene polymorphisms of other CYP enzymes, including CYP1A2, CYP2B6, CYP2C19, and CYP2C9, did not have any relevant effects on the pharmacokinetics or subjective or autonomic effects of LSD (Figures 17-22, Tables S7a-b and S8a-c).

[0076] The influence of 5-HT receptor genotype on response to LSD Figures 7-9 (Tables 2a-c) show the effects of 5-HT receptor gene polymorphisms (HTR1A, HTR1B, and HTR2A) on acute subjective and autonomic responses to LSD. 5-HT receptor gene polymorphisms showed a small effect on 5D-ASC, i.e., HTR2A rs6313 and HTR1A rs6295. Carriers of the two HTR2A rs6313 A alleles were G allele carriers (F 1,78 =5.16, p<0.05) The 5D-ASC overall score (F 1,78 (=5.88, p<0.05) and the AED subscale evaluation was lower. Homozygous carriers of the HTR1A rs6295 G allele were evaluated lower than carriers of the C allele in the 5D-ASC overall score and VR subscale (F1 each). 1,78 =6.87, p<0.05 and F 1,78 (=7.75, p<0.01). Vital parameters were not affected by any of the genotypes tested here.

[0077] Interpretation of test results This is the first analysis to investigate the effects of genetic polymorphisms on the pharmacokinetics and acute effects of LSD in humans.

[0078] The main finding was that CYP2D6 gene polymorphisms significantly affect the pharmacokinetics of LSD, and subsequently, its subjective effects. This suggests that CYP2D6 gene testing can be used to predict the ideal dose of LSD for an individual, while also reducing associated side effects such as overdose and anxiety.

[0079] In addition, common mutations in the 5-HT receptor gene also weakly affect the acute emotional changes induced by LSD, allowing for further, or individual, determination of the ideal dose of LSD for each individual. However, the effect and extent of this mitigation are weaker than those of the CYP2D6 gene.

[0080] LSD is almost completely metabolized in the human body, with only a very small amount of the parent drug (about 1%) being excreted in the urine (Dolder et al., 2015). In vitro studies using human liver microsomes and human liver S9 fraction The study demonstrated the role of CYP enzymes in LSD metabolism (Luethi et al., 2019; Wagmann et al., 2019). Specifically, CYP2D6 is involved in N-desorption from LSD to norLSD. It is involved in methylation (Luethi et al., 2019). This study investigated whether CYP2D6 is involved in human This provides new in vivo evidence that genetic polymorphisms are involved in LSD metabolism, particularly influencing both the metabolic and acute response to LSD in humans. Human plasma norLSD concentrations are mostly too low to measure, even with highly sensitive methods (Steuer et al., 2017). However, LSD and acute responses in individuals with non-functional CYP2D6 genotypes... Increases were observed in both normal LSD and OH-LSD plasma concentrations, consistent with the role of CYP2D6 in normal LSD formation, but not in OH-LSD. Therefore, while CYP2D6 plays an important role in LSD degradation, it does not play a significant role in the formation of its major metabolite, OH-LSD. That's not the case.

[0081] The role of CYP2D6 can be further investigated in drug interaction studies using LSD with and without selective CYP2D6 inhibition. It is also noteworthy that LSD can be used as a therapeutic agent for patients with mental disorders and can be used with serotonin reuptake inhibitor therapy, which also acts as a CYP2D6 inhibitor (mainly fluoxetine and paroxetine). Accordingly, the present invention can be further refined by adding information regarding the co-use of drugs having CYP2D6 inhibitory or induced potentials, either within the algorithm to which the present invention is applied or by those skilled in the art.

[0082] Regarding other CYP enzymes, CYP2C19 was involved in norLSD formation in vitro (Wagmann et al., 2019). However, in this study, no influence of its genotype on the pharmacokinetics of LSD was observed, and dose adjustment of LSD does not appear to be necessary.

[0083] Furthermore, it has been reported that CYP2C9 and CYP1A2 contribute to the hydroxylation of LSD to OH-LSD (Luethi et al., 2019; Wagmann et al., 2019). P2C9 also catalyzes N-deethylation to lysergic acid monoethylamide (LAE) (Wagmann et al., 2019). However, the effect of CYP2C9 genotype on the pharmacokinetics of LSD was not observed in humans in this study. Regarding CYP1A2, no common loss-of-function polymorphisms have been identified to date. However, CYP1A2 is more inducible by tobacco smoking in subjects with the common SNP rs762551 A / A genotype compared to the C / A and C / C genotypes (Sachse et al., 1999). Therefore, CYP1A2 The activity-inducing properties were combined with the subjects' smoking status (>5 cigarettes per day = smoker). In a similar pharmacogenetic study using MDMA, higher MDA levels (trace metabolites of MDMA) were observed in subjects who smoked 6-10 cigarettes per day and had the CYP1A2 inducible genotype compared to subjects who smoked less and / or had non-inducible polymorphisms (Vizeli et al., 2017). In this study, the CYP1A2 genotype / smoking status was combined. No effect was observed on the pharmacokinetics of LSD. However, only five subjects enrolled in this study met both requirements: being a smoker and possessing the inducible CYP1A2 genotype. Thus, these data indicate that dose adjustment of LSD based on CYP1A2 genotype is not appropriate.

[0084] The pharmacogenetic effects of metabolic enzymes on LSD appear to be quite similar to those on MDMA. For both LSD and MDMA, which are psychoactive substances, only CYP2D6 polymorphisms seem to substantially influence pharmacokinetics and subjective effects (Vizeli et al., 2017). However, because MDMA inhibits CYP2D6 and its own metabolism (i.e., autoinhibition), the effect of CYP2D6 genotype alteration is limited and only evident during the onset of MDMA effects in the first two hours after administration (Schmid et al., 2016).

[0085] In contrast, with LSD, the relaxation of the CYP2D6 genotype appears to be more significant in the later stages of elimination rather than in absorption and the initial effect peak, increasing the AUC and half-life of LSD and the duration of its effects. CYP2D6 PMs showed approximately 75% higher total drug exposure (larger AUC values) than individuals with functional CYP2D6 enzymes. There was only a non-significantly higher mean peak concentration of approximately 15%. Therefore, total drug exposure, as reflected by AUC∞, was determined primarily by the decrease in post-peak elimination. This pattern can also be observed in the subjective effects of LSD. While there was no difference in peak effects on VAS between different CYP genotypes, the 5D-ASC assessment, which reflects subjective changes in mental state throughout the day, showed clear differences depending on the functionality of CYP2D6. The non-functional CYP2D6 group reported an overall increased change in states of consciousness, particularly high ratings for out-of-body experiences, control and cognitive impairment, anxiety, complex imagery, elementary imagery, and changes in perceptual meaning.

[0086] Because the genetic influence on acute subjective responses to LSD is clinically relevant, the present invention is substantially useful and effective in adjusting the dose and partially addressing the problem of overdose in vulnerable subjects.

[0087] Several studies involving healthy subjects and patients have revealed a correlation between the degree and quality of acute subjective experience and the long-term effects of psychedelics, including LSD (Griffiths et al., 2008; Griffiths et al., 2016; Roseman et al., 2017; Ross et al., 2016; Schmid & Liechti, 2018). Typically, greater substance-induced out-of-body experiences and more mystical effects are associated with these. The effects of Ip may be associated with more beneficial long-term effects. Specifically, regarding the 5D-ASC rating scale used in this analysis, a higher acute psilocybin-induced obesity score and a lower AED score were associated with a better treatment outcome at 5 weeks in depressed patients, but the VR score did not show a significant effect (Roseman et al., 2017).

[0088] Regarding acute responses to LSD (200 μg), the same predictive pattern was observed in patients with anxiety disorders 2-5 weeks after LSD administration: positive OB, negative AED, and no association between beneficial effects on depression, anxiety, and overall psychological distress and VR scores (Liechti personal communication).

[0089] Given that CYP2D6 PMs showed higher LSD-induced scores, primarily with AEDs and VR, but not with OB scores, these subjects are likely to have had a more challenging acute experience overall, particularly with more acute anxiety and possibly reduced therapeutic efficacy.

[0090] The present invention, including genotyping, is expected to be particularly useful in patients receiving LSD-assisted therapy. Based on current findings, CYP2D6 PM is expected to benefit from approximately 50% lower doses than those used in functional CYP2D6 individuals. This direct result based on current data and approaches is consistent with the observation that higher doses of LSD, such as 200 μg compared to 100 μg, did not result in higher OB ratings but increased AED use and anxiety for 5D-ASC (Holze et al., 2021b).

[0091] As this invention is further developed, it may require some modifications in its implementation. Despite being developed using the largest available sample of healthy human subjects who received LSD in a placebo-controlled trial, the sample size is still relatively small. While the sample size was sufficient to detect the effects of functionally very different genotypes (i.e., CYP2D6), the samples used to develop this invention may have been too small to detect smaller mitigation effects.

[0092] Furthermore, while CYP3A4 may play a specific role in LSD metabolism, polymorphisms are rare (Werk & Cascorbi, 2014). Therefore, CYP3A4 genotyping is useful. However, phenotyping may be used and added as a modification or extension of the present invention.

[0093] The present invention is also useful when considering drug interactions between concomitant drugs and LSD. Before using LSD, the CYP2D6 inhibitor should be discontinued to allow sufficient time (up to two weeks) for the enzyme to regenerate. Alternatively, in the presence of a CYP2D6 inhibitor, the dose of LSD should be reduced by 50% based on the findings of this invention.

[0094] In conclusion, this is the first study to investigate the effects of genetic polymorphisms on the pharmacokinetics and acute effects of LSD in humans. Genetic polymorphisms in CYP2D6 significantly affected pharmacokinetics and subsequently significantly affected the subjective effects of LSD. Other CYPs showed significant effects on LSD No effects on pharmacokinetics or responses were observed. Furthermore, common mutations in the 5-HT receptor gene weakly mitigated the subjective effects of LSD.

[0095] Throughout this application, various publications, including U.S. patents, are referenced by author and year, and patents are referenced by number. A complete citation of these publications is listed below. The disclosures of the above publications and patents are incorporated into this application by reference in their entirety to better illustrate the current art to which the present invention relates.

[0096] The present invention is described in an illustrative manner, and it should be understood that the terms used are intended to be descriptive rather than limiting.

[0097] Clearly, in light of the above teachings, many modifications and variations of the present invention are possible. Therefore, it should be understood that the present invention may be carried out in ways other than those specifically described, within the scope of the appended claims.

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Claims

1. A method of administering LSD to a patient in treatment, as follows: A step of evaluating the patient's genetic characteristics before using a composition selected from the group consisting of LSD, its analogues, its derivatives, and salts thereof; A step of administering the composition to the patient based on the patient's genetic characteristics; and A step to produce the greatest positive subjective acute effect in the patient and / or reduce anxiety and negative effects. A method that includes this.

2. The method according to claim 1, wherein the evaluation step is further defined as identifying gene variants of CYP and serotonin receptors.

3. The method according to claim 1, wherein the evaluation step is further defined as identifying polymorphisms of CYP26D.

4. The method according to claim 3, wherein the administration step is further defined as administering a 50% dose to a patient having non-functional CYP2D6 compared to a dose to a functional CYP2D6 individual.

5. The method according to claim 1, wherein the evaluation step is further defined as identifying the 5HTR1A rs6295 and 5HTR2A rs6313 genotypes.

6. A method for determining a preferred dose of LSD, A step of determining the patient's metabolic and / or genetic markers; A step of adjusting the dose of a composition selected from the group consisting of LSD, its analogues, its derivatives, and its salts, based on the aforementioned metabolism and gene activity (pharmacogenetics); The step of administering the aforementioned dose of the composition to the patient; and, A step to produce the greatest positive subjective acute effect in the patient and / or reduce anxiety and negative effects. A method that includes this.

7. The method according to claim 6, wherein the determination step is further defined as evaluating CYP2D6 activity in a patient and / or evaluating 5HTR1A rs6295 and 5HTR2A rs6313 genotypes.

8. The method according to claim 7, wherein if CYP26D activity is low or absent, the adjustment step is further defined as adjusting the dose to 50% of the dose for functional CYP26D.

9. The method according to claim 6, wherein the metabolic activity is related to enzymatic digestion.

10. The method according to claim 6, wherein the pharmacological activity is related to activity toward or binding toward receptors.

11. A method for determining the dose of LSD based on an assessment of the presence of a CYP2D6 inhibitor, A step to evaluate concomitant medications that may inhibit CYP2D6 in the patient; A step to evaluate CYP2D6 activity in a patient; The step of administering to the patient a composition selected from the group consisting of LSD, its analogues, its derivatives, and its salts; and A step to produce the greatest positive subjective acute effect in the patient and / or reduce anxiety and negative effects. A method that includes this.

12. The method according to claim 11, wherein the concomitant drug is a serotonin reuptake inhibitor.

13. The method according to claim 12, further comprising the step of discontinuing treatment with a serotonin reuptake inhibitor before the administration step.

14. The method according to claim 13, wherein the cessation step is performed up to two weeks before the administration step.

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