Methods for gradually increasing the dosage of psychedelic drugs

Abstract

The present invention provides a method for administering psychedelic drugs in a way that avoids or reduces undesirable side effects. [Solution] A method for administering a psychedelic drug to avoid the side effects of hallucinations and perceptual disturbances, comprising: the step of administering the psychedelic drug to an individual in an escalating dosing regimen; and the step of mitigating the side effects of hallucinations and perceptual disturbances.

Description

Technical Field

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[0001] Background of the Invention 1. Technical Field The present invention relates to compositions and methods for administering psychedelic drugs.

Background Art

[0002] 2. Background Art Psychedelic drugs, including lysergic acid diethylamide (LSD), can induce changes in consciousness, positive emotions, introspection promotion, changes in the perception of the environment, body, and self, as well as synesthesia, mystical types of experiences, and experiences of ego dissolution (Carhart-Harris et al., 2016b; Dolder et al., 2016; Holze et al., 2021; Liechti, 2017; Passie et al., 2008; Schmid et al., 2015). All serotoninergic psychedelic drugs, including LSD, psilocybin, DMT, and mescaline, are non-specific serotonin agonists with agonist activity at the serotonin 5-HT2A receptor (Rickli et al., 2016), and thus can generally produce largely similar effects. Furthermore, psychedelic substances produce their acute effects in humans through activation of the serotonin 5-HT2A receptor, as specifically shown in clinical studies on LSD (Holze et al., 2021; Preller et al., 2017). LSD and other hallucinogenic drugs are partial agonists of the serotonin 5-HT2A receptor (Lopez-Gime ​​​​​​​​​​​​​​​​​nez, et al. Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathw ays. Curr Top Behav Neurosci. 2018;36:45-73;Canal CE. Serotonergic Psychedelics : Experimental Approaches for Assessing Mechanisms of Action. Handb Exp Pharmaco l. 2018;252:227-260).

[0004] The acute effects of psychedelic drugs that may contribute to their therapeutic benefits are explained in more detail below. As described, strengthening therapeutic relationships through increased openness, trust, and relationships with others. The emotion of connection or emulsion, the ability to grasp psychological problems, and the nerve regeneration process Contains stimulants (Vollenweider & Preller, 2020).

[0005] In particular, the administration of psychedelic drugs at doses considered therapeutic may cause hallucinations or paresthesia. It has the following side effects (Ungerleider, J. THOMAS. "The acute side effects from LSD.") ”The problems and prospects of LSD (1968): 61-68), (Nichols, Psychedelics, Ph. (Armacol Rev 68:264-355). Due to these side effects, direct medical supervision is required for the patient. Administering psychedelic drugs outside of the above is no longer safe, and is only possible under the supervision of a physician. Regardless, if a side effect occurs while the patient is driving or operating the machine, This could pose a significant safety risk to the individual. This is a characteristic of psychedelic drug administration. Some of these side effects are due to the administration of 5-HT2A antagonists such as ketanserin. Blocking this activity can reduce these psychoactive / hallucinogenic side effects. As evidenced by this fact, the activity of drugs at serotonin 5-HT2A receptors Therefore, it is mediated (Holze et al., 2020).

[0006] Repeated administration of psychedelic drugs (e.g., daily) may qualitatively have clinical benefits. On the other hand, the side effects of hallucinations / perceptual disturbances have been outlined by Buchborn (2016). As stated, this is due to tachyphylaxis (i.e., downregulation of the 5-HT2A receptor). (Through rations), it may disappear a few days after treatment. However, if psychedelic drugs are administered... For the first few days after administration, subjects may experience hallucinations, perceptual disturbances, and other potential risks to the patient. There is a possibility of experiencing a common adverse event related to another condition.

[0007] The Cleveland Clinic uses gradual increases to see how a person's body reacts to a drug. It states that taking time is a way to limit potential side effects. Here, drug administration is initiated at a low dose, and then this dose is increased to the maximum effective dose (target dose). Increase the dose every 2-3 weeks until the target dose is achieved or side effects occur. Caffrey, e t al. (Ther Adv Drug Saf. 2021 Jan 19; 11: 2042098620958910) found that gradual increase is the drug application. To provide treatment at the lowest possible dose while minimizing the use and side effects, It is generally described as being used for drugs with a narrow therapeutic index. This is a patient-centered approach for providing personalized medicine. Titration has been used for antibiotics, anticoagulants, anticonvulsant drugs, antidepressants, antidiabetic drugs, antipsychotics, opioids, and stimulants. SUMMARY OF THE INVENTION

[0008] There remains a need for treatment with psychedelic drugs to avoid or reduce unwanted side effects. MEANS FOR SOLVING THE PROBLEM

[0009] SUMMARY OF THE INVENTION The present invention provides a method of dosing a psychedelic drug to an individual in a titration regimen and reducing side effects of hallucinations and perceptual disturbances, thereby avoiding side effects of hallucinations and perceptual disturbances.

[0010] The present invention provides a kit for administering a psychedelic drug in a titration regimen, the kit comprising dosage forms of a pharmaceutically effective amount of the psychedelic drug divided into packages according to the dosage and time of administration in the titration regimen, and instructions for use.

[0011] The present invention also provides a method of treating an individual with a psychedelic drug by administering the psychedelic drug to an individual having a condition or disease in a titration regimen and reducing side effects of hallucinations and perceptual disturbances during treatment.

[0012] DESCRIPTION OF THE DRAWINGS Reference is made to the following detailed description when considered in conjunction with the accompanying drawings. Since similar things will become better understood, another advantage of the present invention is that it is easy to understand It is understood. [Brief explanation of the drawing]

[0013] [Figure 1] This is a graph of dose over time. [Modes for carrying out the invention]

[0014] Detailed description of the invention This invention relates to administering psychedelic drugs to an individual in a gradual increase in medication regimen, and to hallucinations. It reduces side effects such as sensory disturbances and other immediately detectable effects of psychedelic drugs. By doing so, the side effects of hallucinations and paresthesia are reduced while retaining the desired therapeutic benefits. To provide a method for avoiding the administration of psychedelic drugs.

[0015] More specifically, a dose escalation regimen involves administering an initial dose to an individual and then increasing the dose to the set amount. Between setting the dose, increasing it, and administering the increased dose to the individual, These steps should be continued throughout the period of treatment until the desired maximum dose is reached. It may include repetition. A medication regimen is generally described by the following formula. It is possible to calculate the dosage as follows: Dosage = X (starting dose) + Y (dose increase) * Z (duration).

[0016] Unlike previous uses such as repeated daily administration (for example, 100 μg of LSD daily), The starting dose may be a subsensory dose (e.g., 10 μg) and should never cause hallucinogenic side effects. However, effective doses (perceptual / hallucinatory effects when administered in the absence of an escalation regimen) may occur. (Approximately the appropriate dose) (For example, 30, 50, 100, or 200 μg as the therapeutic target dose) In regimens that will achieve g), the dose can be gradually increased over time. The starting dose may be 10 μg, which is administered (every 2, 3, 4, 5, 6, or 7 days). The dose is increased by 10 μg increments. Other starting doses may be within the ranges described below. Other examples of medication can be found in Buchborn (2016).

[0017] The period can be measured in hours, days, weeks, months, or years, or include intervals between medication administrations. The interval between dose increases may vary, and here, each dose increase period is used to maintain the desired therapeutic effect. While maintaining or enhancing the effects, avoid hallucinations, perceptions, and other detectable effects of psychedelic drugs. You will be able to do that.

[0018] The starting dose and increased dose levels are administered once daily, twice daily, or three times daily. It can be administered by a caregiver or healthcare provider, or under their supervision or supervision. It can be self-administered by the patient without assistance.

[0019] The dose increase may be a small amount, such as 10, 20, 30, or 50 μg, and the drug Differences in substances and formulations, as well as patient-specific factors, such as weight, height, body surface area, and biochemical effects. This can be obtained and determined by assay, metabolic assay, or genomic assay. .

[0020] The dosage forms used include tablets, capsules, lozenges, transdermal patches, implantable devices, and liquids. , gels, emulsions, or any solid or liquid dosage form, or any combination of dosage forms, Furthermore, any other suitable dosage form may be used, such as those further described below.

[0021] The starting dose may also be a larger loading dose, administered under the supervision of a physician. In order to maintain the therapeutic benefit while limiting the effect to only the initial dose, and also to reduce the perceived reaction The relapsed dose continues.

[0022] The psychedelic drug in this invention is not limited to, but includes lysergic acid diethylamide ( LSD), psilocybin, mescaline, 5-methoxy-N,N-dimethyltryptamine (5 -MeO-DMT), dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodine Doamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB) ), its salt, its tartrate, its analogues, or its homologues. Preferably, cy The dosage of Kederick drugs is such that it provides a meaningful effect. 0.01~1mg (10~ LSD can be used in doses of 1000 μg. Psilocybin can be used in doses of 5-50 mg. It can be administered as medication, and mescaline can be administered in doses of 50-800 mg, 5-Me O-DMT can be administered in doses of 1-20 mg, while DMT can be administered in doses of 20-100 mg. DOI can be administered at 0.1-5 mg, and DOB can be administered at 0.1- It can be administered in 5 mg doses. The effects of psychedelic drugs last for 1 to 12 hours after administration. This can continue, and during this time, the individual may be supervised by medical professionals such as psychiatrists. If a lower dose is administered, physician supervision may not be necessary.

[0023] This invention causes the serotonin 5-HT2A receptor to be downregulated (or this By reducing receptor expression, or by the hallucinogenic effects of psychedelic drugs It can achieve its clinical effects through an alternative mechanism that gradually reduces the impact.

[0024] The compounds of the present invention are based on the clinical condition of individual patients, the site and method of administration, and the administration schedule. In addition, the appropriate treatment guidelines will be established, taking into account the patient's age, sex, weight, and other factors known to the physician. Therefore, it is administered and prescribed. Therefore, for the purposes of this specification, a pharmaceutically effective amount is This is determined by the same considerations as are well known in the art. This quantity is not limited to However, it does not improve survival rates or faster recovery, or improve or eliminate symptoms, and is not possible for those skilled in the art. If it is not effective in achieving improvement, including other indicators that are selected as appropriate measures No.

[0025] In the method of the present invention, the compound of the present invention can be administered in various ways. The compound can be administered as a compound, alone or in a pharmaceutically acceptable carrier, dilute. It can be administered as a dissolving agent, an adjuvant, or an active ingredient in combination with a vehicle. It should be noted that these compounds are administered orally, transdermally, subcutaneously, or parenterally. It can be administered (including intravenous, intramuscular, and intranasal administration). Patients being treated The subjects are warm-blooded animals, especially mammals including humans. Pharmaceutically acceptable carriers, diluents, Auxiliaries, vehicles, and implantation carriers generally do not react with the active components of the present invention. This refers to inert, non-toxic solid or liquid fillers, diluents, or encapsulating materials.

[0026] Dosage may be a single dose, a repeated dose, or over a period of several hours, days, weeks, or months. It may be a sustained dose.

[0027] When the compound of the present invention is administered parenterally, it is generally administered sublingually or buccally. Tablets, dissolving films, intranasal powders, intranasal solutions, inhalation powders, inhalation solutions, transdermal patches, transdermal patches In addition to an adjuvant (containing microneedles or other penetration enhancers), or in injectable units. It will be formulated in various dosage forms (liquid, suspension, emulsion). A pharmaceutical formulation suitable for injection. This includes sterile aqueous solutions or dispersions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. It is included. The carrier is, for example, water, ethanol, polyol (e.g., glycerol, pro Pyrene glycol, liquid polyethylene glycol, etc., suitable mixtures thereof, and plants It may be a solvent or dispersion medium containing an oil.

[0028] Appropriate fluidity can be achieved, for example, by using a coating such as lecithin, in the case of dispersion. This can be maintained by maintaining the required particle size and by using surfactants. Yes, it's possible. Non-aqueous vehicles, such as cottonseed oil, sesame oil, olive oil, soybean oil, and corn oil. Oils, sunflower oil, or peanut oil, and esters, such as isopropyl myristate. It can be used as a solvent system for compound composition. Furthermore, it can be used as an antimicrobial preservative and an acid-resistant agent. Enhances the stability, sterility, and isotonicity of the composition, including chelating agents, buffers, and other additives. Various additives can be added. Prevention of microbial activity involves various antibacterial and antimicrobial agents. Antimicrobial agents, such as parabens, chlorobutanol, phenol, and sorbic acid, can reliably eliminate bacteria. This can be done. In many cases, isotonic agents, such as sugar or sodium chloride, are included. This would be desirable. Extending the absorption of injectable drug formulations is desirable for drugs that slow down absorption, for example... This can be achieved by using aluminum monostearate and gelatin. However, according to the present invention, any vehicle, diluent, or additive used is a compound And it must be compatible.

[0029] The sterile injectable solution contains the compounds used in carrying out the present invention, as desired. It is prepared by incorporating various other components into the required amount of a suitable solvent. It is possible.

[0030] The pharmacological formulation of the present invention can be used with various vehicles, auxiliaries, additives, and diluents, etc. An injectable formulation containing a suitable carrier, which can be administered to a patient; or this product The compounds used in the process are delivered as sustained-release subcutaneous tablets or targeted delivery systems, such as monoclonal tablets. Ronal antibodies, vector-based delivery, iontophoresis, polymer matrix, liposomes, It can also be administered to patients parenterally in the form of microspheres. Examples of delivery systems 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 4,475,1 96 is one example. Many other such implantable locks, delivery systems, and modules are available. This information is being disseminated to the contractors.

[0031] The present invention relates to a drug divided into packages according to the dose and timing of administration in a gradual increase in dosage regimen. A psychedelic drug in a pharmacopoeia form, including instructions for use. This kit provides a dosage escalation regimen for rickets. It includes the starting dose and each subsequent dose. The increased doses are made of different colors and / or larger sizes so that individuals can easily distinguish them. This may be the case. The increased dose may be in a single dosage form or multiple separate dosage forms (i.e.) Each dose increase is available in one dosage form (i.e., tablet, patch, etc.). The packaging indicates the period over which each dose should be taken, e.g., hourly, daily, weekly, monthly. The unit can be indicated in units of sq. or years. The packaging may indicate the exact amount required for each dose. It may be in a bubble / blister pack form that allows for dose dispensing.

[0032] The present invention also relates to a gradual increase in medication regimen in which a person with a certain condition or disease receives psychedelic drugs. By administering LICK drugs and reducing the side effects of hallucinations and paresthesia during treatment, This involves offering a method of treating individuals with psychedelic drugs.

[0033] The conditions or diseases treated by the method of the present invention are not limited to, but include, anxiety disorders (advanced stages) This includes a range of illnesses, such as anxiety in cancer, and generalized anxiety disorder, as well as depression (postpartum depression). (This includes major depressive disorder and treatment-resistant depression), headache disorders (cluster headaches and migraines) (This includes obsessive-compulsive disorder (OCD), personality disorders (including conduct disorder), Tres disorders (including adjustment disorder and post-traumatic stress disorder), drug disorders (alcohol) This includes addiction, nicotine addiction, opioid addiction, cocaine addiction, and methamphetamine addiction. ), other addictions (including gambling disorder, eating disorders, and body dysmorphic disorder), pain, nerves Degenerative disorders (dementia, Alzheimer's disease, Parkinson's disease, etc.), movement disorders (essential tremor, (e.g., tardive dyskinesia), autism spectrum disorder, eating disorders, or neurological disorders (e.g., stroke) This may include traumatic brain injury, etc.

[0034] The present invention will be described in more detail with reference to the following experimental examples. These examples are illustrative. Provided for the purpose of [specific purpose], and unless otherwise specified, it is not intended to be limited. Therefore, the present invention should by no means be construed as being limited to the following examples, rather, This interpretation includes all variations that become apparent as a result of the teachings provided herein. It should be explained. [Examples]

[0035] Example 1 The following is an example of medication to achieve LSD dose escalation. This is different from other psychedelic drugs. It can also be applied to medications. Table 1 shows the results for different number of days and different daily doses. Oral administration is indicated. The dose levels are converted to 1) the PK threshold and 2) the 5-HT2A expression threshold. This can be adjusted through other drug regimens and formulations to enable patients to perceive efficacy. Administering medication in a manner that never reaches a PK level comparable to the (increasing) threshold for the effect. This can be made to happen.

[0036] [Table 1]

[0037] Figure 1 shows how the dose increases over time up to the threshold for perceptual effect. This demonstrates that a similar effect likely exists for PK levels as well. Table 2 shows sustained-release formulations. This indicates medication using the following method.

[0038] [Table 2]

[0039] A medication kit containing multiple transdermal patches that can be applied at home or in a clinic at regular intervals. The appropriate packaging form can be used. Kit design (i.e., the size of the adhesive patch) Depending on the specific format to be determined, all differences in its characteristics, and the actual packaging design, This ensures that patients are not inadvertently exposed to hallucinogenic doses. It will no longer be revealed.

[0040] Throughout this application, various publications, including U.S. patents, are attributed to the author, year, and number. These publications are cited by patent. A complete citation of these publications is provided below. List these publications and patent disclosures as a whole to more fully represent the prior art to which the present invention belongs. For the purpose of explaining this, it is incorporated into this application by reference.

[0041] This invention is described in an illustrative manner, and the technical terms used are not limiting, but rather descriptive. It will be understood that these terms possess the characteristics of Ming dynasty terminology.

[0042] Clearly, many modifications and variations of the present invention are possible in light of the above teachings. And, within the scope of the attached claims, the present invention shall be carried out in a manner other than that specifically described herein. It will be understood that this is possible.

Claims

1. A method of administering psychedelic drugs to avoid side effects such as hallucinations and perceptual disturbances. ： The steps of administering the psychedelic drug to an individual in a gradual increase in dosage regimen; Steps to mitigate side effects such as hallucinations and perceptual disturbances A method that includes this.

2. The administration step further To administer the initial dose to the aforementioned individual; The amount is increased by the set amount over a set period of time, and the increased amount is then processed by the individual Administering to humans; Over the period during which the individual is being treated, until the desired maximum dose is reached, the increase and Repeat the administration step. The method according to claim 1, as defined above.

3. The method according to claim 2, wherein the initial dose is a dose below the perceptual dose.

4. The initial dose is 10 μg, and is increased by 10 μg at regular intervals, as described in claim 2. Method of loading.

5. The aforementioned period is selected from the group consisting of hours, days, weeks, months, and years. The method according to claim 2.

6. The aforementioned dose is increased by an amount selected from the group consisting of 10, 20, 30, and 50 μg. The method according to claim 2.

7. The administration step further involves administering a loading dose as an initial dose, and using a dose less than perceptible. The method according to claim 1, defined as administering a subsequent dose of a certain amount.

8. The aforementioned psychedelic drugs include lysergic acid diethylamide (LSD), psilocybin, and mesca. Phosphorus, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), dimethyl Tryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), its salts, its tartrate, and The method according to claim 1, selected from the group consisting of analogs and homologs thereof.

9. Pharmaceuticals A psychedelic drug comprising a moderately effective amount of the drug and instructions for use. A kit for administering a drug dosage escalation regimen.

10. The aforementioned psychedelic drugs include lysergic acid diethylamide (LSD), psilocybin, and mesca. Phosphorus, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), dimethyl Tryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), its salts, its tartrate, and The kit according to claim 9, selected from the group consisting of analogs and homologues thereof.

11. The kit according to claim 9, wherein the dosage form comprises an initial dose and an additional increased dose.

12. If the initial dose is of a different color or size than the additional increased dose, The kit described in item 11.

13. Claim 11, wherein the additional increased dose is a single dosage form or a plurality of separate dosage forms. The kit described above.

14. The kit according to claim 9, wherein the packaging indicates the period over which each dose should be taken.

15. The kit according to claim 9, wherein the packaging is a blister pack.

16. A method of treating individuals with psychedelic drugs: In a gradual increase in medication regimen, the psychedelic drug is administered to the individual who has a certain condition or disease. The step of administering; Steps to reduce the side effects of hallucinations and perceptual disturbances during treatment. A method that includes this.

17. The condition or disorder being treated is anxiety disorder, depression, headache disorder, obsessive-compulsive disorder (OCD), Personality disorders, stress disorders, drug disorders, gambling disorders, eating disorders, body dysmorphic disorders Harm, pain, neurodegenerative disorders, motor disorders, autism spectrum disorder, feeding disorders, and neurological disorders The method according to claim 16, selected from the group.

18. The administration step further To administer the initial dose to the aforementioned individual; The amount is increased by the set amount over a set period of time, and the increased amount is then processed by the individual Administering to humans; Over the period during which the individual is being treated, until the desired maximum dose is reached, the increase and Repeat the administration step. The method according to claim 16, as defined above.

19. The method according to claim 18, wherein the initial dose is a dose below the perceptual dose.

20. The initial dose is 10 μg, and is increased by 10 μg at regular intervals, according to claim 18. Method of description.

21. The aforementioned period is selected from the group consisting of hours, days, weeks, months, and years. The method according to claim 18.

22. The aforementioned dose is increased by an amount selected from the group consisting of 10, 20, 30, and 50 μg. The method according to claim 18.

23. The administration step further involves administering a loading dose as an initial dose, and using a dose less than perceptible. The method according to claim 16, defined as administering a subsequent dose of a certain amount.

24. The aforementioned psychedelic drugs include lysergic acid diethylamide (LSD), psilocybin, and mesca. Phosphorus, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), dimethyl Tryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamine (DOB), its salts, its tartrate, and The method according to claim 16, selected from the group consisting of analogs and homologs thereof.

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