LSD dose identification

Abstract

To provide treatment methods for identifying and administering dose ranges of psychedelics, such as lysergic acid diethylamide (LSD), that produce specific subjective drug effects in the treatment of medical conditions.SOLUTION: Provided is a method for treating a patient by administering a psychedelic, including the steps of: administering a psychedelic at a dose selected from the group consisting of a microdose, minidose, psychedelic dose, good effect dose, ego-dissolution dose, and cardiovascular safe dose; and producing maximum positive subjective acute effects that are known to be associated with more positive long-term outcomes.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] 2. Background of the Invention 1.Technical Field The present invention relates to compositions and methods for identifying dose ranges of lysergic acid diethylamide that produce specific subjective drug effects in the treatment of medical conditions. [Background technology]

[0002] 2. Background technology Lysergic acid diethylamide (LSD) is a prototypic hallucinogen that is widely used for recreational and personal purposes (Krebs & Johansen, 2013). In addition, LSD has been used in experimental studies (Carhart-Harris et al., 2016b; Dolder et al., 2016; Liechti, 2017; Preller et al., 2017; Schmid et al., 2015) and to treat psychiatric patients (Gasser et al., 2016). al., 2014; Gasser et al., 2015). The correct dose of LSD to elicit a response is problematic.

[0003] Although LSD is widely used recreationally, because it is illegally manufactured and sold in units lacking analytical identity information, in non-prescribed amounts without clear dose uniformity, and without information on the possible presence of other psychoactive compounds, the dose required to produce the specific desired therapeutic effect cannot be ascertained from empirical prior use of LSD. Although LSD is increasingly being used in research, and researchers have reported doses used in publications, evidence of actual doses administered has been largely lacking.

[0004] Knowing the exact dose used to produce a drug effect is of crucial importance. Although the manufacture and evaluation of precise dose units is not part of this invention and has been addressed recently (Holze et al., 2019), we present this aspect because defining the dose that produces a specific effect is a prerequisite for this invention and the problem of dose determination is partly exacerbated by the use of non-prescribed doses both in reports of illicit LSD use and in research with LSD.

[0005] The LSD formulations primarily used in recent clinical studies do not have long-term stability and therefore the doses actually administered to humans were likely lower or at least unclear in these studies ( Barrett et al., 2018 , Dolder et al., 2016 , Kraehenmann et al., 2017a , Kraehenmann et al., 2017b , Preller et al., 2018 , Preller et al., 2017 , Preller et al., 2019 , Schmid et al., 2015 ). Specifically, longer-term stability data beyond the full study duration were not available for the capsule formulations used in some previous studies (Dolder et al., 2016, Dolder et al., 2017, Kraehenmann et al., 2017b, Liechti et al., 2017, Mueller et al., 2018, Mueller et al., 2017a, Mueller et al., 2017b, Preller et al., 2017, Schmid et al., 2015, Schmid&Liechti, 2018, Schmidt et al., 2017). Furthermore, iso-LSD was detected in plasma after administration of a 200 μg dose in the form of two 100 μg capsules (Steuer et al., 2017). , suggesting that this inactive decomposition product of LSD was possibly already present in the capsule at the time of its use (although its possible formation in the plasma samples cannot be completely excluded). Plasma AUCs of LSD and iso-LSD of 21 and 9.2 ng×h / ml 24 Based on values ​​(Steuer et al., 2017), on average 30% of the LSD was inactive in the capsules. This suggests that LSD may have been isomerized to iso-LSD. Therefore, the actual doses of LSD administered may have been 70 and 140 μg LSD base, respectively, rather than the indicated 100 and 200 μg. AUC ∞ Values ​​are based on the validated 96 μg LSD dose used in later studies ( Holze et al., 2019) and a similar bioavailability, which were 61% and 76% of the expected values, respectively. Finally, analytical testing of four old unused LSD capsules, performed several years after the end of the study, showed a significant reduction in LSD content (LSD remaining = 22 ± 7 μg), suggesting a lack of longer-term stability of this form of LSD and that the actual LSD dose used may have already been lower than indicated during the study period. Notably, a content reduction of 15% and even 25% in a single capsule would still be compatible with the content uniformity established during the formulation of the capsules. In summary, based on the results of various quality control measurements, analytical findings (including pharmacokinetic data (Holze et al., 2019)) and the clinical action of the various formulations (Dolder et al., 2017), the previous studies showed that the actual LSD dose was 1.5% and 2.5%. likely used approximately 60-70 (not 100) and 140-150 (not 200) μg of LSD base, corresponding to approximately 80 and 175 μg of LSD tartrate.

[0006] Another consideration is that the doses of LSD reported in previous studies were less precise or did not reflect the actual exposure of LSD in the body. This is notable in recent studies using 75 μg of hydrophobic LSD base administered intravenously in saline due to the lack of objective measures of exposure to LSD (i.e., plasma concentrations) and the unknown bioavailability of the solution (Carhart-Harris et al., 2016a, Carhart-Harris et al., 2015, Carhart-Harris et al., 2016b, Kaelen et al., 2015, Tagliazucchi et al., 2016). Clinical responses to 75 μg intravenous LSD were significantly higher than the oral 100 μg dose used in the previous studies. There was no significant difference between the 100 μg dose and the 100 μg dose (Carhart-Harris et al., 2016a, Liechti, 2017 , Liechti et al., 2017), indirectly suggesting a similar exposure comparable to oral administration of 60–70 μg LSD base.

[0007] In light of the above data, even the scientific published data regarding previously used doses of LSD are not adequate to guide the selection of a safe and efficacious dose for medical treatment.

[0008] In addition to knowing the precise LSD dose administered in a dose-finding study, to make valid claims regarding dosing, different doses must be administered within the same study, preferably to the same human subjects. For example, a previous published study reported on the effects of 100 and 200 μg doses of LSD (Dolder et al., 2016). However, different doses may be required. The data on doses of LSD were generated in different studies in different populations, which does not allow for a valid dose-response assessment. In addition, most studies tested only relatively high doses (100 or 200 μg orally), while a few others tested very low doses of LSD tartrate (6.5, 13, and 26 μg (Bershad et al., 2020; Bershad et al., 2019) or 5, 10, and 20 μg (Family et al., 2020; Yanakieva et al., 2019). et al., 2019), lack of data covering a larger dose range within the study. Summary of the Invention [Problem to be solved by the invention]

[0009] There remains a need for methods of analyzing LSD administration and accurately administering LSD in medical treatments. [Means for solving the problem]

[0010] Summary of the Invention The present invention provides a method of administering psychedelic agents to treat a patient by administering psychedelic agents in micro-, mini-, psychedelic, favorable, ego-disruptive or cardiovascular-safe doses and producing maximal positive subjective acute effects known to be associated with more positive long-term outcomes and minimizing negative acute effects.

[0011] The present invention also provides a method of determining a dose of a psychedelic agent for an individual by administering to the individual a micro-dose, a mini-dose, a psychedelic dose, a positive effect dose, an ego-disrupting dose or a cardiovascular-safe dose of a psychedelic agent, determining positive and negative acute effects in the individual, and adjusting the dose to provide more positive acute effects than negative acute effects in the individual.

[0012] The present invention provides a method of treating a psychopathological condition in an individual by administering to the individual a micro-dose of 1-20 μg of a psychedelic agent, preferably LSD, to treat the psychopathological condition.

[0013] The present invention provides a method of treatment by administering to an individual a favorable effect dose of 30-100 μg of a psychedelic agent, preferably LSD, to induce positive acute drug effects known to be associated with more positive long-term responses in psychiatric patients.

[0014] The present invention also provides a method of treatment by administering to an individual a defined ego-disruptive dose of a psychedelic agent, preferably LSD, of greater than 100 μg to provide ego-disruption.

[0015] The present invention provides a method of defining a therapeutic dose of a psychedelic agent in a clinical trial by administering a micro-dose, mini-dose, psychedelic dose, positive effect dose, ego-disrupting dose or cardiovascular-safe dose of a psychedelic agent to a healthy subject in a Phase I trial, determining the positive and negative acute effects in the individual, adjusting the dose to provide more positive acute effects than negative acute effects in the individual, and using the adjusted dose for Phase II or III trials in patients.

[0016] The present invention also provides a method of monitoring an individual for depression following treatment with LSD by measuring levels of brain-derived neurotrophic factor (BDNF) in the individual before and after LSD treatment to determine if the individual has responded to treatment if BDNF is increased.

[0017] Description of the drawings Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings. [Brief description of the drawings]

[0018] [Figure 1A]Graph of either drug effect versus time. [Figure 1B] 1 is a graph of good drug effect versus time. [Figure 1C] 1 is a graph of adverse drug effects versus time. [Figure 1D] 1 is a graph of drug preference versus time. [Figure 1E] 1 is a graph of stimulation versus time. [Figure 1F] 1 is a graph of fear versus time. [Figure 1G] A graph of ego collapse versus time. [Figure 1H] 1 is a graph of time perception versus time. [Figure 1I] 1 is a graph of concentration versus time. [Figure 2A] 1 is a graph of well-being versus time. [Figure 2B] 1 is a graph of anxiety versus time. [Figure 2C] 1 is a graph of inactivity versus time. [Figure 2D] 1 is a graph of extraversion versus time. [Figure 2E] 1 is a graph of introversion versus time. [Figure 2F] 1 is a graph of emotional arousal versus time. [Diagram 3] 1 is a comparative table of the acute effects of LSD alone, LSD plus ketanserin, and placebo. [Figure 4A] This is a graph that gives an oceanic feel. [Figure 4B] This is a graph of anxiety ego collapse. [Figure 4C] This is a graph of hallucinatory restructuring. [Diagram 5] This is the graph at the maximum percentage scale. [Figure 6A] 1 is a graph of systolic blood pressure versus time. [Figure 6B] 1 is a graph of diastolic blood pressure versus time. [Figure 6C] 1 is a graph of heart rate versus time. [Figure 6D] 1 is a graph of temperature versus time. [Figure 7]1 is a table of acute adverse drug effects. [Figure 8] 1 is a table of pharmacokinetic parameters for LSD based on compartment modeling. [Figure 9A] Graph of plasma LSD concentration-time curves at 25, 50, 100 and 200 μg. [Figure 9B] LSD effect-time curves with visual analogue scale ratings (0-100%) for "any drug effect" are shown. [Figure 9C] FIG. 1 shows the LSD effect-time curve with visual analogue scale ratings (0-100%) for "good drug effect." [Figure 9D] FIG. 1 shows the LSD effect-time curve with visual analogue scale ratings (0-100%) for "bad drug effect." [Figure 9E] FIG. 1 shows the effect-time curve of LSD with a visual analogue scale rating (0-100%) for "ego disintegration." [Figure 10] 1 is a table of subjective response characteristics. [Figure 11] 1 is a table of pharmacokinetic parameters for LSD based on noncompartmental analysis. [Figure 12] 1 is a table of pharmacokinetic parameters for OH-LSD based on non-compartmental analysis. [Figure 13] Pharmacodynamic parameter estimates are tabulated. [Figure 14] 13 is a table of drug identification after each session and after testing. [Figure 15] 1 is a graph of BDNF plasma concentration versus time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description of the Invention The present invention relates to the use of specific doses of psychedelic agents, such as LSD (lysergic acid diethylamide), to produce defined subjective drug effects that facilitate the treatment of medical conditions. Oral LSD solutions with defined long-term stability (single dose units) and high content uniformity were used to generate the data on which the present invention is based.

[0020] LSD can be used to support psychotherapy, typically in acute psychoactive doses, 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). The sexual self-perception effect is largely positive in most humans (Carhart-Harris et al., 2016a; Dolder et al., 2016; Dolder et al., 2017; Holze et al., 2019; Schmid et al., 2015). However, this may be influenced by the dose of LSD used and personality characteristics of the LSD user. There are also negative subjective effects (anxiety) of LSD in many humans, depending on the situation (environment) and other factors. The risk of acute negative psychological effects is a major problem with the use of psychedelic substances in humans. Anxiety arising from LSD-assisted psychotherapy can be a significant problem for both the patient and the treating physician. In addition to being extremely distressing for the patient, acute anxiety has been associated with unfavorable long-term outcomes in patients with depression. It has been reported that psychedelic-assisted therapy is safe and effective (Roseman et al., 2017). Furthermore, anxiety reactions during psychedelic-assisted therapy may require additional supervision, greater therapist involvement, extended sessions, and acute psychological and pharmacological interventions. Thus, the primary safety concerns are related to psychological adverse effects rather than physical adverse effects (Nichols, 2016; Nichols & Grob, 2018). Inducing an overall positive acute response to psychedelics is crucial, as studies have shown that more positive experiences are predictive of greater long-term therapeutic effects of psychedelics (Garcia-Romeu et al., 2015; Griffiths et al., 2016; Ross et al., 2016). In healthy subjects, positive acute responses to psychedelics, including LSD, have also been shown to be associated with more positive long-term effects on well-being (Griffiths et al., 2008; Schmid & Liechti, 2018).

[0021] Moderate anticipatory anxiety is common at the beginning of the onset of drug effects (Studerus et al., 2012) In a study of 16 healthy humans, significant anxiety was observed in two subjects after administration of 0.2 mg LSD. This anxiety was associated with fears of loss of thought control, out-of-body experiences, and loss of self (Schmid et al., 2015), as has also been described for psilocybin (Hasler et al., 2004). Negative drug effects (50% or more on a 0-100% scale at any time after drug administration) were identified in 9 of 16 subjects (56%) after a high dose of 0.2 mg LSD and in 3 of 24 subjects (12.5%) after a moderate dose of 0.1 mg LSD (Dolder et al., 2017). Similarly, in another study, 24 subjects after administration of 0.1 mg LSD experienced significant anxiety (50% or more on a 0-100% scale at any time after drug administration). Transient bad drug effects were reported in seven of seven subjects (29%) (Holze et al., 2019). Although these negative subjective drug effects were transient and all occurred in subjects who also reported good drug effects at other or similar time points, negative reactions are problematic. One solution to address the negative drug effects is to reduce the dose of the psychedelic agent, which would also at least partially reduce the desired drug effects. Another possibility is to give lower doses over a longer period of time, allowing a high dose to be spread out over several days / weeks.

[0022] The present invention can be used to avoid states of acute anxiety when using psychedelics in psychiatric or other medical settings, and the present invention specifically enables the identification of doses that are less likely to induce anxiety while still producing the desired positive drug effects.

[0023] In general, the present invention provides a method of administering a psychedelic agent (e.g., LSD or a salt thereof) to treat a patient by administering the psychedelic agent at a specific dose as defined below, such as a micro-dose, a mini-dose, a psychedelic dose, a good-effect dose, an ego-disrupting dose, or a cardiovascular-safe dose, and by producing a maximum positive subjective acute effect known to be associated with a more positive long-term outcome, and by minimizing negative acute effects. A specific dose of a psychedelic agent can be administered with a specific acute effect defined for the dose and a specific indication for the psychedelic agent at the specific dose. The overall objective of the present invention is to improve the positive / negative acute subjective effect response to a psychedelic agent. To this end, the method can be used for any indication of psychedelic medicine, and is typically applied to indications where a positive experience after psychedelic use predicts a long-term effect, such as psychiatric disorders including, but not limited to, depression, anxiety, and addiction.

[0024] "Positive acute effects" as used herein primarily refers to increases in subjective ratings of "good drug effects" and may also include ratings of "drug cravings", "well-being", "oceanic feeling", "solidarity experiences", "spiritual experiences", "blissful states", "insight", any "mystical type experiences" and positive experiences, "psychedelic effects", and "ego-disruptive aspects" when the experience is not accompanied by anxiety.

[0025] "Negative acute effects" as used herein refers primarily to "bad drug effects" and subjective ratings of "anxiety" and "fear", and may additionally include increased ratings of "anxious ego disruption" or descriptions of acute persecutory delusions or anxious panic states observed by others.

[0026] Doses that induce an acute psychedelic state may be effective. For LSD, doses can be high enough to produce positive effects (>25 μg LSD base), but can also be optimized to improve the positive / negative subjective effect profile of LSD (<200 μg base). Plasma concentrations of LSD increase proportionally with increasing doses. LSD produces dose-dependent subjective responses, beginning with the 25 μg dose, which produces a significant "any drug effect" compared to placebo.

[0027] To induce positive drug effects, LSD doses are 25-100 μg. Doses <25 μg are too small to produce meaningful acute positive drug effects. Increasing LSD doses achieve a ceiling effect at 100 μg doses for positive subjective effects, and there is no significant difference in terms of good drug effects between 100 and 200 μg LSD doses. Therefore, doses >100 μg are too high if primarily good subjective drug effects are to be induced. Good drug effects do not increase with doses above 100 μg. Only ego disruption and anxiety increase with doses of LSD above 100 μg. The time to onset of the LSD reaction decreases and the time to offset increases, resulting in a longer duration of action with increasing LSD doses.

[0028] A 200 μg dose of LSD produces significantly more ego disruption and more anxiety ego disruption than a 100 μg dose. A 200 μg dose of LSD induces significant anxiety (but a 100 μg dose does not). Thus, doses above 100-150 μg are useful when the goal is to induce experiences of ego disruption, but such experiences occur only at doses that are also accompanied by more anxiety compared to lower doses. Doses from 100 μg to 200 μg are subjectively identified as high doses, but cannot be confidently distinguished from one another. Doses of 100 and 200 μg LSD induce similar adverse effects in addition to anxiety.

[0029] The following more specific dosage ranges can be used in the methods of the invention:

[0030] A "micro-dose" is a dose of a psychedelic agent that produces a discernible acute subjective drug effect compared to placebo, according to (Kuypers et al., 2019). A micro-dose of LSD is 1-20 μg. Such doses have no subjective acute effects but may have therapeutic effects in humans.

[0031] A "mini-dose" is a dose of 21-29 μg of LSD or other psychedelic agent. A mini-dose of LSD represents the smallest dose that is subjectively distinguishable by an acute subjective drug effect versus placebo, and is properly identified in experimental testing as a 25 μg dose, or misused as a slightly higher dose of 50 μg LSD.

[0032] A "psychedelic dose" is a dose of LSD or other psychedelic agent greater than 30 μg.

[0033] A "good effect dose" is a dose of 30-100 μg of LSD or other psychedelic drug.

[0034] An "ego-disrupting dose" is a dose of LSD or other psychedelic drug above 100 μg. Nearly all of the good and bad effects are the same at 100 μg and 200 μg doses, except for ego-disruption and increased anxiety at higher doses. If ego-disruption is the desired outcome, using 100 μg will often be a better dose because lower doses This is because the same positive effects can be obtained at 100 μg without the negative effect of increased anxiety. In cases where ego disruption is required to treat a disease (as explained further below), a 200 μg dose is required even though anxiety may be increased.

[0035] A "cardiovascular safe dose" is simply a moderately cardiac stimulant dose of 50-200 μg of LSD or other psychedelic drugs. The adverse cardiovascular effects of LSD are absent at doses <50 μg and minimal at doses up to 200 μg. LSD only moderately but significantly increases blood pressure at doses of 50 μg and above, and heart rate at 100 and 200 μg.

[0036] The psychedelic agent used in the methods of the present invention may be, but is not limited to, LSD, psilocybin, mescaline, dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), salts thereof, tartrates thereof, analogs thereof or homologs thereof.

[0037] The compounds of the present invention are administered and prescribed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, administration schedule, the age, sex, weight of the patient, and other factors known to physicians. For purposes herein, a pharmacologic "effective amount" is determined by considerations known in the art. The amount must be effective to achieve improvement, including, but not limited to, improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators selected as appropriate measures by the skilled artisan.

[0038] In the method of the present invention, the compound of the present invention can be administered in various ways. It should be noted that it can be administered as a compound, and can be administered as an active ingredient alone or in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles. The compound can be administered orally, transdermally, subcutaneously or parenterally, including intravenous, intramuscular and intranasal administration. The patient to be treated is a warm-blooded animal, particularly a mammal, including man. Pharmaceutically acceptable carriers, diluents, adjuvants and vehicles, as well as implantation 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.

[0039] The dose may be a single dose or multiple doses or a sustained dose over several hours.

[0040] When the compound of the present invention is administered parenterally, it will generally be formulated as a unit dose injection preparation (solution, suspension, emulsion).The pharmaceutical preparation suitable for injection includes sterile aqueous solution or dispersion and sterile powder that is reconstituted into sterile injectable solution or dispersion.The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixture thereof, and vegetable oil.

[0041] Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Non-aqueous vehicles, such as Mentha 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 compositions. In addition, various additives can be added that enhance the stability, sterility, and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. In many cases, it will be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical preparations can be brought about by the use of agents that delay absorption, such as aluminum monostearate and gelatin. However, according to the present invention, any of the agents used can be used without the need for any additives. The vehicle, diluent or additive must also be compatible with the compound.

[0042] Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various other ingredients, as desired.

[0043] The pharmaceutical preparation of the present invention can be administered to a patient as an injectable formulation containing any suitable carrier, such as various vehicles, adjuvants, additives and diluents, or the compound utilized in the present invention can be administered to a patient parenterally in the form of slow 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 are included in U.S. Patent Nos. 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 known to those of skill in the art.

[0044] The present invention also provides a method for determining a dose of a psychedelic agent for an individual by administering a micro-dose, a mini-dose, a psychedelic dose, a good-acting dose, an ego-disrupting dose, or a cardiovascular-safe dose of a psychedelic agent, determining the positive and negative acute effects in the individual, and adjusting the dose to provide more positive acute effects than negative acute effects in the individual. The individual may be healthy, and the method can be used to predict doses for non-healthy individuals. The method can be used to determine long-term administration and dosing schedules. For example, one may choose to use a "good drug effect" dose initially, followed by an "ego-disrupting" dose after subjecting the subject or patient to the effects of the substance. In addition, dose-finding for clinical trials is difficult, time-consuming, and expensive. It would be much easier, cost-effective, and faster if a method were available to define the dose to be used in patients already in Phase 1 trials in healthy subjects. Evaluating acute effects in healthy subjects with a focus on positive acute effects over negative effects as definitive predictors of long-term outcomes in patients can greatly facilitate dose-finding for future Phase 2 and Phase 3 studies in patient populations. Thus, the method can be used to predict and determine doses for clinical trials.

[0045] Methods relating to the specific doses defined above are also provided.

[0046] The present invention provides a method of treating a psychopathological condition in an individual by administering a micro-dose of a psychedelic agent, preferably LSD, to the individual to treat the psychopathological condition. The psychopathological condition may be, but is not limited to, depression, anxiety, dementia, or attention deficit hyperactivity disorder. Micro-doses of LSD induce improvement of the condition with prolonged repeated administration of LSD (e.g., once a day, once every two days, once every 3-7 days) without associated acute psychedelic drug effects.

[0047] The present invention provides a method of treatment by administering to an individual a favorable dose of a psychedelic agent, preferably LSD, to induce a positive acute drug effect known to be associated with a more positive long-term response in psychiatric patients. The method can be used to treat a variety of medical conditions, including depression, anxiety, substance use disorders, other addictions, personality disorders, eating disorders, post-traumatic stress disorder, obsessive-compulsive disorder, various pain disorders, migraine headaches, cluster headaches, and palliative care.

[0048] The present invention relates to the administration of ego-disruptive doses of a psychedelic drug, preferably LSD, to an individual to induce self-regulation. Also provided is a method of treatment by providing ego-disintegration. This method is suitable for individuals who have experienced lower effective doses of LSD or other psychedelics and are aiming for a more powerful ego-disintegration experience, but are prepared for the risk of experiencing greater anxiety when dealing with this condition. Ego-disintegration as an experience can be therapeutic in some indications, namely in individuals with severe pain disorders, cancer and / or palliative care, with the goal of relief from pain or at least not experiencing somatic pain during this experience, and a sense of body presence or out-of-body. Ego-disintegration can also be a therapeutic experience during other disorders, including personality disorders (narcissistic personality disorder) or when required by psychiatric indications.

[0049] In the following examples, LSD (D-lysergic acid diethylamide base, high performance liquid chromatography purity >99%, Lipomed AG, Arlesheim, Switzerland) was administered as a single oral dose. Each dose of LSD was formulated as an orally administered solution in 1 ml of 96% ethanol according to GMP (batch BZ17-2, 25 μg and 100 μg vials) and stored free in the dark at 4° C. in argon pre-filled vials. The rigorous analytically confirmed LSD content (mean ± SD) of the 25 μg and 100 μg formulations was 98.65 ± 1.57 μg (n = 9) and 25.68 ± 0.57 μg (n = 9), respectively, after manufacture. The stability of the formulation over a longer period than the study period was established in a previous batch (batch BZ16) manufactured identically. When the solutions were stored at 4°C, a small amount of isomerization of active LSD to inactive iso-LSD occurred, resulting in iso-LSD contents (% of initial LSD content) of 0.1%, 0.1%, 1.3%, 3.2%, and 3.6% after 4, 6, 12, 18, and 24 months, respectively. No other degradation products were present. Vials stored at room temperature had higher iso-LSD contents of 0%, 3.1%, 3.4%, 6.7%, and 9.5% after 2, 4, 6, 12, and 24 months, respectively. The 100 μg LSD dose used in this study likely corresponds to an approximately 125 μg dose of LSD tartrate, including water of crystallization. This is the form of LSD with a higher potential for use when obtained illegally for recreational use (i.e., blotter form) or when used in other recent studies (Bershad et al., 2019; Yanakieva et al., 2019).

[0050] The present invention also includes data on the effects of LSD doses of 25, 50, 100 and 200 μg administered within the same study and all doses administered to the same subjects, allowing within-subject dose comparisons without adding large variability for between-subject comparisons. It was thereby possible to define LSD doses that produce specific effects in healthy subjects. Importantly, the acute effects of LSD in healthy subjects are comparable to those in patients (Liechti et al., 2017), making it possible to assume similar responses in patients and in defined medical conditions where such an acute response is desired. Therefore, dosing suggestions are made based on this data and innovation. Moreover, until now, it was not clear at which single dose of LSD would manifest subjective effects. Doses that do not produce acute subjective effects are typically referred to as "microdoses" and do not produce acute cognitive impairment but may have persistent effects on mood and cognition (Hutten et al., 2019). However, However, for larger LSD doses, dose levels for microdoses versus high psychedelic doses have not been defined, and cutoffs are unknown and debated (Kuypers et al., 2019). Therefore, the present invention also defines microdoses and cutoffs based on the use of defined doses of LSD in the supporting data.

[0051] The following conditions were observed in the examples: 1) The invention is based on the specific situation of only one patient present at the time of administration of LSD and does not include group situations where more than one person may be administered and the dose-response effects may differ. 2) The person or patient to be treated is free of acute psychological distress prior to administration of LSD. 3) The person does not have an increased risk of psychosis (schizophrenia). 4) The person is not under the acute influence of other psychoactive substances. 5) Doses cover LSD base doses and immediate release formulations. 6) LSD salt doses may need to be converted to LSD base doses (125 μg LSD tartrate is 100 μg LSD salt used as reference herein). 7) The individual is in a comfortable resting state in a controlled, quiet environment protected from loud noise, with everyone else (except for 1-3 supervisors / therapists) playing suitable music and wearing eyeshades or with their eyes closed. Psychedelic drugs can induce neuronal regeneration (Ly et al., 2018). Plasma brain-derived neurotrophic factor (BDN) F) levels are a possible biomarker for neurogenesis (Haile et al., 2014). Higher BDNF levels were associated with lower depression ratings after ayahuasca administration (de Almeida et al., 2019).

[0052] The present invention also provides a method for monitoring an individual for a depressive response after treatment with LSD by measuring the levels of BDNF in the individual before and after LSD treatment to determine if the individual responded to LSD treatment if BDNF is increased. BDNF is a growth factor found in the brain and periphery that supports the survival of existing neurons, promotes the growth and differentiation of new neurons and synapses, and is important for learning and memory. BDNF can also be found in the retina, kidney, saliva, prostate, motor neurons, and skeletal muscles. BDNF can bind to TkrB and LNGFR receptors on the cell surface and modulate other neurotransmitter receptors. Exposure to stress and the stress hormone corticosterone can decrease the expression of BDNF, which can cause atrophy of the hippocampus leading to depression. Low levels of BDNF in an individual can be associated with higher depression, and higher levels of BDNF can be associated with lower depression and response to treatment. Example 2 provides further details regarding BDNF. BDNF can be measured by taking a blood sample from an individual and performing an ELISA or other immunoassay. The administration of LSD can then be adjusted to provide fewer side effects to the individual based on the level of BDNF detected.

[0053] The present invention will be described in more detail by referring to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise specified. Therefore, the present invention should not be construed as being limited to the following examples in any way, but should be construed as embracing any variations that become evident as a result of the teachings provided herein. EXAMPLES

[0054] Example 1 This study was also presented in Holze, et al. (Holze et al., 2021). The following key findings were noted: was observed. LSD exhibited dose-dependent subjective responses starting with the 25 μg dose, which produced a significant "any drug effect" compared to placebo. Increasing doses of LSD achieved a ceiling effect at the 100 μg dose on most scales (especially those referring to positive subjective effects), with typically no significant differences between the 100 and 200 μg LSD doses. The 200 μg dose produced significantly more ego disruption on the VAS, more anxiety ego disruption on the 5D-ASC, and more subjective negative nadir effects than the 100 μg dose. The 200 μg LSD dose induced significant anxiety on the 5D-ASC and AMRS, whereas the 100 μg LSD dose did not. Thus, only ego disruption and anxiety increased at doses of LSD above 100 μg. LSD only moderately but significantly increased blood pressure at doses of 50 μg and above, and heart rate at 100 and 200 μg (Figures 3, 6A-6C). Doses of 100 and 200 μg of LSD increased adverse effects at LC compared with placebo. Plasma LSD concentrations increased proportionately with increasing dose, but the good drug effects of LSD showed a ceiling effect at 100 μg, while higher bad drug effects and greater ego disruption were reported at 200 μg compared with 100 μg. Time to onset of LSD reactions decreased and time to offset increased, resulting in a longer duration of action with increasing LSD dose. Doses from 100 μg to 200 μg were subjectively identified as high doses but were indistinguishable from each other. A dose of 25 μg of LSD was distinguishable from placebo and was indistinguishable from most participants. More properly identified or identified as 50 μg LSD.

[0055] Materials and Methods Study Design: The study used a double-blind, placebo-controlled crossover design to examine responses to 1) placebo, 2) 25 μg, 3) 50 μg, 4) 100 μg, 5) 200 μg LSD, and 6) ketanserin (40 mg) followed by 200 μg LSD in six experimental test sessions. The washout period between sessions was at least 10 days. The study was registered with ClinicalTrials.gov (NCT03321136).

[0056] Participants: 16 healthy subjects (8 males and 8 females, mean age ± SD: 29 ± 6.4 years, range: 25-52 years). Participants younger than 25 years were excluded from participating in the study. Additional exclusion criteria were: age > 65 years, pregnancy (urine pregnancy test at screening and before each study session), personal or family history (first-degree relatives) of major psychiatric disorders (assessed by Semi-structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Axis I disorders by an experienced psychiatrist), Use of medications that could interfere with the study medication (e.g., antidepressants, antipsychotics, sedatives), chronic or acute physical illness (abnormal physical examination, electrocardiogram, or hematological and chemical blood analysis), smoking (>10 cigarettes / day), lifetime prevalence (Δ 9 - tetrahydrocannabinol), illicit drug use within the past 2 months, and illicit drug use during the study period (determined by urine drug testing).

[0057] Study medication: LSD (D-lysergic acid diethylamide base, high performance liquid chromatography purity >99%, Lipomed AG, Arlesheim, Switzerland) was administered as an oral solution in units containing 100 (Holze et al., 2019) or 25 μg LSD in 1 mL of 96% ethanol. Thus, subjects received 2 mL of LSD solution and / or placebo (96% ethanol) per session: 1) placebo / placebo, 2) 25 μg LSD / placebo, 3) 25 μg LSD / 25 μg LSD, 4) 100 μg LSD / placebo, 5) 100 μg LSD / 100 μg LSD, 6) 100 μg LSD / 100 μg LSD. Ketanserin was obtained as a commercial drug (KETENSIN®, Janssen) to ensure blinding. The subjects were encapsulated in opaque capsules to determine whether they had been assigned treatment or not. The placebo consisted of identical opaque capsules filled with mannitol. Blinding to treatment was therefore ensured by a double-dummy design, with identical capsules and vials filled with mannitol and ethanol as placebos, respectively. At the end of each session and at the end of the study, participants were asked to retrospectively guess their treatment allocation.

[0058] Study Procedure: The study included screening, six 25-hour study sessions, and an end-of-study visit. Sessions were conducted in a quiet standard hospital room. Only one study subject and one investigator were present during the study sessions. Study sessions began at 7:45 AM. Subjects then underwent baseline measurements. Ketanserin (40 mg) or placebo was administered at 8:00 AM. LSD or placebo was administered at 9:00 AM. Outcome measures were repeatedly assessed over a 24-hour period. Standardized lunch and dinner were provided at 1:30 PM and 6:00 PM, respectively. Subjects were under constant supervision by the investigator until 1:00 AM. Thus, subjects were never left alone for the first 16 hours after drug administration, and the investigator was in the room next to the subject for up to 24 hours. Subjects were sent home the following day at 9:15 AM.

[0059] Subjective drug effects: Subjective effects were repeatedly assessed using a visual analog scale (VAS) 1 hour before and 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, and 24 hours after LSD administration. The VAS included “drug effects”, “good drug effects”, “bad drug effects”, “drug liking”, “drug high”, “stimulation”, “fear”, “ego disruption”, “time perception” and “concentration” (Hysek et al., 2014). The VAS is represented as a 100 mm horizontal line (0–100%) marked from “none at all” on the left to “extremely” on the right. The VAS for “concentration” and “time perception” were bi-directional (±50%). For concentration, the VAS is marked from “none at all” on the left (−50) to “normal” in the middle (0) and “extremely” on the right (+50), and for “time perception”, “slow” (−50) and “fast” (+50). To retrospectively grade the drug-induced altered wakefulness, the 5D-ASC scale (Dittrich, 1998; Studerus et al., 2010) was used 24 h after LSD administration. Mystical experiences were assessed using the German version (Liechti et al., 2017) of the 100-item State of Consciousness Questionnaire (SOCQ) (Griffiths et al., 2006) which includes 43 items and the newer 30-item MEQ (MEQ43 (Griffiths et al., 2006) and MEQ30 (Barrett et al., 2015)). The 60-item Adjunctive Mood Rating Scale (AMRS) (Janke & Debus, 2016) was administered 1 h before and 3, 6, 9, 12, and 24 h after drug administration. 1978) was applied.

[0060] Autonomic, adverse and endocrine effects: Blood pressure, heart rate and corpus tympanic temperature were measured repeatedly 1 h before and 0, 0.5, 1, 1.5, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16 and 24 h after drug administration as detailed previously (Hysek et al., 2010). Adverse effects were systematically assessed using a 66-item complaints list 1 h before and 12 and 24 h after drug administration (Zerssen, 1976). This scale is A total adverse effects score is generated to reliably measure physical and general discomfort.

[0061] Plasma drug concentrations: Blood was collected in lithium heparin tubes 1 h before and 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, and 24 h after LSD administration. Blood samples were immediately centrifuged and plasma was subsequently stored at -80 °C until analysis. Plasma concentrations of LSD and OH-LSD were determined using a validated ultra-performance liquid chromatography tandem mass spectrometry method as previously described in detail (Holze et al., 2019).

[0062] Pharmacokinetic analysis and pharmacokinetic-pharmacodynamic modeling: Pharmacokinetic parameters were estimated by a one-compartment model with first-order input, first-order elimination and no lag time in Phoenix WinNonlin 6.4 (Certara, Princeton, NJ, USA) as previously described in detail ( Holze et al., 2019 ).

[0063] Data analysis: Peak (E max and / or E min ) or peak change from baseline (ΔE max ) values ​​were determined by repeated measurements. Repeated measures analysis of variance (ANOVA) was then performed using Statistica 12 software (StatSoft, Tulsa, OK, USA) with drug as a within-subject factor. Values ​​were analyzed by VA followed by Tukey post-hoc comparisons. The criterion for significance was p<0.05.

[0064] result Subjective drug effects: Subjective effects versus time on the VAS and AMRS are shown in Figures 1A-1I and 2A-2F, respectively. LSD or placebo was administered at t=0 hours. LSD induced dose-dependent good drug effects up to the 100 μg dose. The 200 μg LSD dose further increased ego disruption compared to the 100 μg dose, but neither good drug effects nor drug preference are associated with LSD. Data are expressed as mean ± SEM % max in 16 subjects. The corresponding peak responses and statistics are presented in Figure 3. The alterations of mind and mystical type effects are shown in Figures 4A-4C and 5, respectively, with statistics shown in Figure 3. The ratings for placebo were not presented here because they were too low to be visualized. LSD exhibited dose-dependent subjective responses starting from the 25 μg dose, which produced a significant "any drug effect" compared to placebo. (P<0.05). Increasing the LSD dose achieved a ceiling effect at the 100 μg dose on most scales (especially those referring to positive subjective effects), and typically there were no significant differences between the 100 and 200 μg LSD doses (Figs. 1A-1I, 4A-4C, and 5). However, the 200 μg dose produced significantly greater ego disruption on the VAS (Figs. 1A-1I), greater anxiety ego disruption on the 5D-ASC (Figs. 4A-4C), and greater subjective negative nadir effects (Fig. 5) than the 100 μg dose (all P<0.05). Consistently, only the 200 μg LSD dose induced significant anxiety on the 5D-ASC (Figs. 4A-4C) and AMRS (Figs. 2A-2F), whereas the 100 μg dose did not (both P<0.01). Thus, only ego disruption and anxiety increased with doses of LSD above 100 μg.

[0065] Cardiovascular, autonomic, adverse and endocrine effects: Autonomic effects versus time and respective peak effects are shown in Figures 6A-6D and 3, respectively. In most cases, reported adverse effects are presented in Figure 7. LSD only moderately but significantly increased blood pressure at doses 50 μg and above and heart rate at 100 and 200 μg (Figures 6A-6D). LSD had no effect on body temperature. The 100 and 200 μg doses of LSD increased the total acute (0-12 h) adverse effect score at LC compared to placebo and all other conditions. No serious adverse events were observed.

[0066] Pharmacokinetics: Figure 8 shows the pharmacokinetic parameters of LSD. Model predicted LSD concentrations and effects versus time are shown in Figures 9A-9E. Plasma concentrations of LSD increased proportionally with increasing dose (Figures 9A-9E). Figure 9A shows plasma LSD concentration-time curves at 25, 50, 100 and 200 μg. Figures 9B-9E show LSD effect-time curves with visual analog scale ratings (0-100%) for (Figure 9B) "any drug effect", (Figure 9C) "good drug effect", (Figure 9D) "bad drug effect" and (Figure 9E) "ego disruption". LSD administration resulted in a dose-proportional increase in plasma concentrations of LSD, but the subjective good drug effect achieved a ceiling without greater positive effects at the 100 compared to the 200 μg dose. In contrast, bad drug effects and ego disruption were further increased at 200 μg compared to 100 μg LSD dose, suggesting that LSD doses above 100 μg did not produce greater good drug effects but produced more ego disruption and anxiety. Data are presented as mean ± SEM in 16 subjects after administration of 25, 50, 100 and 200 μg LSD or placebo at t = 0 h. Lines represent the mean of individual predictions based on the pharmacokinetic-pharmacodynamic model. Either and good drug effects of LSD showed a ceiling effect at 100 μg, while higher bad drug effects and greater ego disruption were reported at 200 μg compared to 100 μg (Figures 9A-9E). Time to onset of LSD reactions decreased and time to offset increased, resulting in a longer duration of action with increasing LSD dose (Figures 9A-9E and Figure 10). Pharmacokinetic parameters based on non-compartmental analysis are shown in Figure 11 and Figure 12. Parameters for the coupled PK-PD model are summarized in Figure 13.

[0067] Blinding: Data regarding retrospective identification of participants' LSD dose conditions are shown in Figure 14. In general, the 100 μg to 200 μg doses were identified as the high doses but were indistinguishable. The 25 μg dose of LSD was distinguished from placebo and was either properly identified or identified as the 50 μg LSD by most participants.

[0068] Example 2 Psychedelics can induce neural regeneration (Ly et al., 2018), and LSD can stimulate neuronal regeneration ( Enhances neuronal plasticity. Plasma brain-derived neurotrophic factor (BDNF) levels are a possible biomarker for neurogenesis (Haile et al., 2014). Higher BDNF levels were associated with lower depression ratings after ayahuasca administration (de Almeida et al., 2019). .

[0069] Plasma BDNF levels were measured at baseline and 6, 12, and 24 hours after drug administration using the Biosensis Mature BDNF Rapid ELISA Kit (Thebarton, Australia) (Akimoto et al., 2019). Levels were measured. Figure 15 shows that 200 μg LSD significantly increased BDNF plasma concentrations compared to placebo, with a peak at 6 hours. In addition, a non-significant increase in plasma BDNF was seen after lower doses of LSD or after ketanserin combined with LSD. BDNF levels are highest at the highest LSD dose of 200 μg, but lower doses such as 25 μg overlap with higher doses as well as 100 μg. In other words, lower or micro doses may have the same degree of effect as a higher psychedelic dose of 100 μg. Ketanserin blocks LSD side effects at the 5-HT2a receptor when given before LSD, but BDNF levels are elevated. BDNF effects are not eliminated by blocking the 5-HT2a receptor, which is associated with hallucinatory experiences. BDNF can be used as a possible marker for the antidepressant effects of LSD.

[0070] Ketanserin can be used with LSD to block the psychedelic response but still allow for long-term antidepressant benefit based on the maintenance of increased BDNF.

[0071] Throughout this application, various publications, including U.S. patents, are referenced by author and year as well as patent number. Full citations to the publications are listed below. The disclosures of these publications and patents are incorporated by reference in their entireties herein in order to more fully describe the state of the art to which this invention pertains.

[0072] The invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation.

[0073] Obviously, many modifications and variations of the present invention are possible in light of the above teachings and it is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

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Claims

1. 1. A method of treating a patient by administering a psychedelic agent, comprising: administering a psychedelic agent at a dose selected from the group consisting of a micro dose, a mini dose, a psychedelic dose, a positive dose, an ego-disrupting dose, and a cardiovascular-safe dose; producing a maximal positive subjective acute effect known to be associated with a more positive long-term outcome; The method includes:

2. 10. The method of claim 1, further comprising minimizing negative acute effects selected from the group consisting of adverse drug effects, anxiety, fear, increased grades of anxiety ego disruption or acute paranoia, panic states and combinations thereof.

3. 10. The method of claim 1, wherein the patient is being treated for a condition selected from the group consisting of depression, anxiety and addiction.

4. 2. The method of claim 1, wherein the positive subjective acute effect is selected from the group consisting of good drug effects, drug cravings, well-being, oceanic feeling, solidarity experience, spiritual experience, blissful state, insight, mystical type experience, positive experience psychedelic effects, ego disruption aspects and combinations thereof.

5. 2. The method of claim 1, wherein the psychedelic agent is selected from the group consisting of LSD, psilocybin, mescaline, dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), salts thereof, tartrates thereof, analogs thereof, and homologs thereof.

6. The method of claim 1, wherein the dose is a microdose of 1 to 20 μg.

7. The method of claim 1, wherein the dose is a mini-dose of 21 to 29 μg.

8. 2. The method of claim 1, wherein the dose is a psychedelic dose of greater than 30 μg.

9. 2. The method of claim 1, wherein the dose is a beneficial effect dose of 30 to 100 μg.

10. 2. The method of claim 1, wherein the dose is an apoptotic dose of greater than 100 μg.

11. 2. The method of claim 1, wherein the dose is a cardiovascular safe dose of 50-200 μg.

12. 1. A method of determining a dose of a psychedelic agent for an individual, comprising: administering to the individual a dose of a psychedelic agent selected from the group consisting of a micro dose, a mini dose, a psychedelic dose, a positive dose, an ego-disrupting dose, and a cardiovascular-safe dose; determining positive and negative acute effects in said individual; adjusting said dose to provide more positive acute effects than negative acute effects in said individual; The method includes:

13. 13. The method of claim 12, wherein the individual is healthy and the method further comprises predicting a dose for a non-healthy individual.

14. 13. The method of claim 12, further comprising determining a long-term administration and dosing schedule. 。

15. 13. The method of claim 12, wherein the psychedelic agent is selected from the group consisting of LSD, psilocybin, mescaline, dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), salts thereof, tartrates thereof, analogs thereof, and homologs thereof.

16. 13. The method of claim 12, wherein the positive acute effects are selected from the group consisting of good drug effects, drug cravings, well-being, oceanic sensations, solidarity experiences, spiritual experiences, blissful states, insights, mystical type experiences, positive experiences psychedelic effects, ego disruption aspects and combinations thereof, and the negative effects are selected from the group consisting of bad drug effects, anxiety, fear, increased grades of anxiety ego disruption or acute paranoia, panic states and combinations thereof.

17. The method of claim 12, wherein the dose is a microdose of 1 to 20 μg.

18. The method of claim 12, wherein the dose is a mini-dose of 21 to 29 μg.

19. 13. The method of claim 12, wherein the dose is a psychedelic dose of greater than 30 μg.

20. The method of claim 12, wherein the dose is a beneficial effect dose of 30 to 100 μg.

21. 13. The method of claim 12, wherein the dose is an apoptotic dose of greater than 100 μg.

22. The method of claim 12, wherein the dose is a cardiovascular safe dose of 50 to 200 μg.

23. 1. A method for defining a therapeutic dose of a psychedelic agent in a clinical trial, comprising: administering to healthy individuals in a Phase 1 study a dose of a psychedelic agent selected from the group consisting of a micro dose, a mini dose, a psychedelic dose, a positive dose, an ego-disrupting dose, and a cardiovascular-safe dose; determining positive and negative acute effects in said individual; adjusting the dose to provide more positive acute effects than negative acute effects in the individual; using said adjusted dose in a Phase 2 or Phase 3 trial in a patient. The method includes:

24. 24. The method of claim 23, wherein the psychedelic agent is selected from the group consisting of LSD, psilocybin, mescaline, dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), salts thereof, tartrates thereof, analogs thereof, and homologs thereof.

25. 24. The method of claim 23, wherein the positive acute effects are selected from the group consisting of good drug effects, drug cravings, well-being, oceanic sensations, solidarity experiences, spiritual experiences, blissful states, insights, mystical type experiences, positive experiences psychedelic effects, ego disruption aspects and combinations thereof, and the negative effects are selected from the group consisting of bad drug effects, anxiety, fear, increased grades of anxiety ego disruption or acute paranoia, panic states and combinations thereof.

26. 24. The method of claim 23, wherein the dose is a microdose of 1 to 20 μg.

27. The method of claim 23, wherein the dose is a mini-dose of 21 to 29 μg.

28. 24. The method of claim 23, wherein the dose is a psychedelic dose of greater than 30 μg.

29. 24. The method of claim 23, wherein the dose is a beneficial effect dose of 30 to 100 μg.

30. 24. The method of claim 23, wherein the dose is an apoptotic dose of greater than 100 μg.

31. 24. The method of claim 23, wherein the dose is a cardiovascular safe dose of 50-200 μg.

32. 1. A method of treating a psychiatric condition in an individual, comprising: administering to the individual a micro-dose of 1-20 μg of a psychedelic agent; Treating a psychiatric condition. The method includes:

33. 33. The method of claim 32, wherein the psychiatric condition is selected from the group consisting of depression, anxiety, dementia and attention deficit hyperactivity disorder.

34. 33. The method of claim 32, wherein the administering step is performed at a time selected from the group consisting of once daily, once every two days, and once every 3 to 7 days.

35. 33. The method of claim 32, wherein the psychedelic agent is selected from the group consisting of LSD, psilocybin, mescaline, dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), salts thereof, tartrates thereof, analogs thereof, and homologs thereof.

36. 1. A method of treatment comprising: administering to the individual a beneficial dose of a psychedelic agent of between 30 and 100 μg; Inducing positive acute drug effects known to be associated with more positive long-term responses in psychiatric patients; The method includes:

37. 37. The method of claim 36, wherein the individual has a condition selected from the group consisting of depression, anxiety, a substance use disorder, an addiction, a personality disorder, an eating disorder, post-traumatic stress disorder, obsessive-compulsive disorder, a pain disorder, migraine headache, cluster headache, and those requiring palliative care.

38. 37. The method of claim 36, wherein the psychedelic agent is selected from the group consisting of LSD, psilocybin, mescaline, dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), salts thereof, tartrates thereof, analogs thereof, and homologs thereof.

39. 37. The method of claim 36, wherein the positive acute effects are selected from the group consisting of good drug effects, drug cravings, well-being, oceanic feeling, solidarity experiences, spiritual experiences, blissful states, insight, mystical type experiences, positive experience psychedelic effects, ego disruption aspects and combinations thereof.

40. 1. A method of treatment comprising: administering to the individual a defined ego-disruptive dose of a psychedelic agent in excess of 100 μg; The process of providing ego destruction The method includes:

41. The psychedelic agents include LSD, psilocybin, mescaline, dimethyltryptamine ( 41. The method of claim 40, wherein the agonist is selected from the group consisting of 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), salts thereof, tartrates thereof, analogs thereof, and homologs thereof.

42. 41. The method of claim 40, wherein the individual has a condition selected from the group consisting of severe pain disorder, cancer, palliative care and personality disorder.

43. 41. The method of claim 40, wherein the step of providing ego disruption further comprises a step selected from the group consisting of: allowing the individual to be relieved from pain; allowing the individual to not experience somatic pain and a sense of presence in their body; and allowing the individual to feel a sense of detachment from their body.

44. 1. A method for monitoring an individual for depression following treatment with LSD, comprising: measuring the level of brain-derived neurotrophic factor (BDNF) in said individual before and after LSD treatment; determining if the individual responded to LSD treatment if BDNF is increased; The method includes:

45. 45. The method of claim 44, wherein the measuring step further comprises the steps of taking a blood sample from the individual and performing an immunoassay for BDNF.

46. 45. The method of claim 44, further comprising adjusting the dose of the LSD based on the measured level of BDNF.

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