WO2021016710A1 - Controlled release formulations of multiple active pharmaceutical agents, and psilocybe-derived agents in combination with cannabis-derived agents and methods for their use - Google Patents

Abstract

Compositions and methods for controlled administration of psilocybe-derived and cannabis-derived agents are provided, and compositions for controlled oral administration of two or more active pharmaceutical agents are provided.

Description

CONTROLLED RELEASE FORMULATIONS OF MULTIPLE ACTIVE

PHARMACEUTICAL AGENTS. AND PSILOCYBE-DERIVED AGENTS IN COMBINATION WITH CANNABIS-DERIVED AGENTS AND METHODS FOR THEIR

USE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States provisional patent applications US 62/880,269, filed July 30, 2019, and US 62/880,271 , filed July 30, 2019, the contents both of which is hereby incorporated by reference in their entirety.

FIELD

[0002] The present invention relates to (i) compositions and methods for controlled release administration of psilocybe-derived agents in combination with cannabis-derived agents, and (ii) compositions for oral controlled release administration of two or more pharmaceutical agents at various times and/or locations and/or amounts in a subject.

BACKGROUND

[0003] A combination drug is a fixed-dose combination (FDC) that includes two or more active pharmaceutical ingredients (APIs) combined in a single dosage form, which is manufactured and distributed in fixed doses.

[0004] Initially, fixed-dose combination drug products were developed to target a single disease (such as with antiretroviral FDCs used against AIDS). However, FDCs may also target multiple diseases/conditions, such as Caduet (atorvastatin/amlodipine) or Exforge (amlodipine/valsartan).

[0005] Advantages of FDCs include improved medication compliance by reducing the pill burden of patients and the ability to compose combined profiles of, for example, pharmacokinetics, effects and adverse effects that may be specific for the relative dosages in a given FDC product, providing a simpler overview compared to when looking at the profiles of each single drug individually.

[0006] Memory is essential to human lives and our thinking process. Without a memory of the past, we cannot operate in the present or think about the future. Memory allows us to create new realities, something from nothing, and distinguishes us from all other animals. [0007] The term“memory” covers three important aspects of information processing and encoding. There are three main ways in which information can be encoded, namely visual (picture), acoustic (sound) and semantic (meaning).

[0008] Characteristics of memory storage include where the information is stored, how long the memory lasts for (duration), how much can be stored at any time (capacity) and what kind of information is held. The way information is stored affects the way it is retrieved.

[0009] There has been a significant amount of research regarding the differences between Short Term Memory (STM) and Long Term Memory (LTM).

[0010] Evidence suggests that the principle coding system in STM is acoustic coding. When a person is presented with a list of numbers and letters, they will try to hold them in STM by rehearsing them verbally.

[0011] The principle encoding system in LTM appears to be semantic coding by meaning. However, information in LTM can also be encoded both visually and acoustically.

[0012] It was assumed that most adults can store between 5 and 9 items in their short-term memory (Miller (1956)). Recently it was demonstrated that adults can compress information and store more data in STM. In contrast, the capacity of LTM is believed to be unlimited. Further, information can only be stored for a brief duration in STM (0-30 seconds), while LTM can last a lifetime.

[0013] Depression, obsessive compulsive disorders and the retention of traumatic experience can result from the conversion of a STM experience to a non-erasable LTM which brings about physiological, psychological and psychosomatic counteractions.

[0014] There are multiple accepted theories of the nature of conversion of STM to

LTM. One of the earliest and most influential was proposed by Tulving (1972). His theory is that there is a distinction between episodic, semantic and procedural memory.

[0015] Procedural memory is a part of the LTM and is responsible for knowing how to do things, i.e. memory of motor skills. It does not involve conscious thought and is not declarative. For example, procedural memory would involve knowledge of how to ride a bicycle.

[0016] Semantic memory is a part of the LTM responsible for storing information about the world. This includes knowledge about the meaning of words, as well as general knowledge, and involves conscious thought and is declarative. The knowledge that held in semantic memory focuses on“knowing that” something is the case (i.e. declarative). For example, semantic memory is knowing that Paris is the capital of France.

[0017] Episodic memory is a part of the LTM responsible for storing information about an event or events that an individual has experienced. Episodic memory also involves conscious thought and is declarative. An example would be a memory of the 1 st day at school, the horror of 9/11 or the assassination of JFK.

[0018] STM mechanisms for memory retrieval are relatively straight forward. The

STM is stored and retrieved sequentially. For example, if a group of participants is given a list of words to remember, and then asked to recall the fourth word on the list, participants go through the list in the order they heard it in order to retrieve the information.

[0019] No one disputes the fact that STM tends to get worse the longer the delay between learning and recall, but there is disagreement about the explanation for this effect.

[0020] One theory of trace is that there is some form of physical and/or chemical change in the nervous system. The theory of decay states that forgetting occurs as a result of the automatic decay or fading of the memory trace. The trace decay theory focuses on the time and the limited duration of STM. This theory suggests that that STM can only hold information for between 15 and 30 seconds unless it is rehearsed. After this time, the information/trace decays and fades away.

[0021] LTM storage and retrieval is subject to multiple theories and is still being studied.

[0022] It is known that LTM memory retrieval is not by simple association. LTM duration can be a few minutes up to a lifetime, theoretically. The storage capacity is believed to be unlimited, the main constraint on recall being accessibility rather than availability.

[0023] Since the era of digital information, a prevailing theory is that the brain functions like a computer, organizing information to aid in retrieval. Under this theory, information and memories are stored in electrical or chemical sequences, by size or time, in an anatomical defined area in the brain. Retrieval of information is theorized as bringing out information or memory that is already there. Applying quantum computing to LTM retention and retrieval is in the early stages.

[0024] Pathological thought or memories are theorized to be due to the inability to place memories in storage and/or a lack of conscious or subconscious control to keeping the memory suppressed. The problem with pathological LTM is that it is not only available but is undesirably accessible or even consciously or subconsciously unsurpassable.

[0025] Presently, neuroscience experiments and especially drug development efforts are concentrated on LTM retrieval, especially in the realm of forgetfulness to the pathology of Alzheimer’s disease.

[0026] A prevailing theory of LTM loss and memory retrieval failure is the theory of interference. Interference states that forgetting occurs because memories interfere with and disrupt one another. However, the interference theory, like many of the other memory theories, does not address what is LTM.

[0027] In a recent landmark snail experiment in the Journal of Neuroscience, scientists were able to selectively remove memories stored in the neuron of Aplysia, a sea slug. They demonstrated that a distinct memory stored in a connection to a single visible nerve cell can be manipulated by blocking a visible neural connection with a particular enzyme. Scientists were able to reverse long-term changes in synaptic strength at synapses known to contribute to different forms of memories.

[0028] With legalization in Canada and some states in the United States, cannabis is available more than ever before. In the internet and cannabis literature, anecdotes abound in reference to smoking or eating the substance alongside a “mushroom” experience with erratic physiological and psychological effects. The unregulated combination of cannabis-derived cannabidiol (CBD) and/or

tetrahydrocannabinol (THC) with the active ingredients in Psilocybe cubensis, psilocybin and/or psilocycin, is commonly suggested for achieving an intensified“high” or“trip”. Cannabis has been reported to“intensify the mushroom experience”, thereby acting as an agonist. However, cannabis has also been reported to“cloud” the psilocybin effect thereby acting as an antagonist.

[0029] Active ingredients in Psilocybe cubensis, psilocybin and/or psilocycin create a sympathetic arousal state characterized by euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, spiritual experiences, giddiness, joy, open and closed eye visuals common at medium to high doses, along with synesthesia (e.g. hearing colors and seeing sounds). The mind-altering effects of psilocybin typically last from two to six hours. Adverse reactions include nausea, disorientation, lethargy and depression and panic attacks with about a third of users reporting feelings of anxiety or paranoia. Additional side effects include tachycardia, dilated pupils, restlessness or arousal, increased body temperature, headache, sweating and chills.

[0030] These effects are the result of psilocybin’s rapid metabolism to psilocin, which then activates or partially activates several serotonin receptors in the brain. For example, psilocin has a high affinity for 5-HT2B and 5-HT2C receptors in the human brain, and a slightly lower affinity for the 5-HT2A receptor. Psilocin further binds with low affinity to 5-HT1 receptors, including 5-HT1A and 5-HT1 D. In addition, psilocin indirectly increases the concentration of the neurotransmitter dopamine in the basal ganglia.

[0031] Research on cannabis has revealed hundreds of active cannabinoids and terpenes with the primary active ingredients being tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0032] Active ingredients in cannabis create a general change in perception, heightened mood, and an increase in appetite.

[0033] Downsides include a decrease in short-term memory, dry mouth, impaired motor skills, red eyes, and feelings of paranoia or anxiety.

[0034] THC exerts its most prominent effects via its actions on two types of cannabinoid receptors, the CB1 receptor and the CB2 receptor. Further, THC indirectly increases dopamine release. CBD acts as an allosteric modulator of the m- and d-opioid receptors.

[0035] The benefits of psilocybin in the treatment of depression, anxiety and other disorders were first suggested in the 1960s when psilocybin was marketed in many countries, including the United States, under the trade name Indocybin®. Indocybin® provided a shorter acting alternative to lysergic acid diethylamide (LSD) which has a similar primary pharmacological mechanism of action, now known to be agonist or partial agonist effects at the 5-HT2A receptor (Nichols, 2016). While Indocybin® was used safely as an adjunct to psychotherapy, eventually the societal backlash in the United States and other countries in the 1960s (Matsushima et al., 2009) led to a ban on marketing and possession of“hallucinogenic” drugs in the United States in 1965, and led to

discontinuation of manufacturing and marketing of Indocybin® in 1966 (Belouin and Henningfield, 2018; Bonson, 2018; Novak, 1997). The 1970 placement of psilocybin,

LSD, and other“hallucinogens” in Schedule I of the CSA did not reflect an absence of therapeutic benefit, although the scientific evidence at the time was mixed.

[0036] Published U.S. Application Nos. 2018/0221396 and 2019/0142851 disclose methods and compositions comprising a psilocybin derivative selected from [3,2- dimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, 4- hydroxy-N,N-dimethyl-tryptamine, [3-(2-methylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, [3-(2-trimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate and 4- hydroxy-N,N,N-trimethyltryptamine for regulating serotonin alone or in combination with a cannabinoid and/or terpene in purposely engineered with unnaturally occurring molar ratios.

[0037] Published U.S. Patent Application No. 2019/0105313 discloses compositions comprising fungal extracts and their active ingredients including species of mushrooms and mycelia containing psilocybin and psilocin, combined with ernicines and hericenones or fungal extracts containing those active ingredients with the addition of nicotinic acid.

[0038] Controlled release of a combination of psilocybe-derived agents and cannabis-derived agents in rapid sequence is expected to be useful in eliciting short or long term traumatic experience suppression in similar fashion to electroshock therapy without memory eradication while reducing negative side effects associated with psilocibe-derived agents.

SUMMARY

[0039] An aspect of the present invention relates to a composition comprising a psilocybe-derived agent and a cannabis-derived agent. In one nonlimiting embodiment, the composition is formulated in multiple layers to release the psilocybin-derived agent and the cannabis-derived agent at multiple different times, locations and/or dosages during dosing.

[0040] Another aspect of the present invention relates to a method for administering a composition comprising a psilocybe-derived agent and a cannabis- derived agent via a formulation which controls release of each agent. In one nonlimiting embodiment, the composition is formulated in multiple layers to release psilocybin and the cannabis-derived agent at multiple different times, locations and/or dosages during dosing.

[0041] The agonist/antagonist multilayer formulations of the present invention are expected to address pathological conversion of STM to LTM and promote disengagement of pathological LTM by a chemical agonist/antagonist shock similar to insulin and/or electric shock therapy. Such formulations are expected to be useful in treating disorders related to pathological LTM such as, but not limited to, acute traumatic events including post traumatic brain syndrome (PTBS), rape, limb loss, loss of a loved one, suicide attempt and prevention, as well as chronic ailments such as post traumatic stress disorder (PTSD), nicotine or alcohol addiction, anorexia and clinical depression.

[0042] In one aspect there is described a composition comprising a psilocybe- derived agent and a cannabis-derived agent.

[0043] In one example, the composition is formulated in multiple layers to release the psilocybin-derived agent and the cannabis-derived agent at multiple different times, dosages and/or locations in a subject during dosing.

[0044] In one example, the subject is a human.

[0045] In one aspect there is provided a method for administering a composition comprising a psilocybe-derived agent and a cannabis-derived agent to a subject, said method comprising administering to the subject a composition comprising multiple layers of psilocybin-derived agent and cannabis-derived agent so that the psilocybin-derived agent and the cannabis-derived agent are released at different times, dosages and/or locations in a subject.

[0046] In one example, the composition is administered to address pathological conversion of STM to LTM and promote disengagement of pathological LTM by a chemical agonist/antagonist shock.

[0047] In one example, the subject is suffering from an acute traumatic event.

[0048] In one example, the subject is suffering from PTSD, nicotine or alcohol addiction, anorexia and/or clinical depression.

[0049] In one example, the subject is a human

[0050] In one aspect there is provided a use of a composition comprising multiple layers of psilocybin-derived agent and cannabis-derived agent so that the psilocybin- derived agent and the cannabis-derived agent are released at different times, dosages and/or locations in a subject.

[0051] In one example, the composition is for addressing pathological conversion of STM to LTM and promote disengagement of pathological LTM by a chemical agonist/antagonist shock.

[0052] In one example, the subject is suffering from an acute traumatic event.

[0053] In one example, the subject is suffering from PTSD, nicotine or alcohol addiction, anorexia and/or clinical depression.

[0054] In one aspect there is provided a use of a composition comprising multiple layers of psilocybin-derived agent and cannabis-derived agent in the manufacture of a medicament, so that the psilocybin-derived agent and the cannabis-derived agent are released at different times, dosages and/or locations in a subject.

[0055] In one example, the composition is for addressing pathological conversion of STM to LTM and promote disengagement of pathological LTM by a chemical agonist/antagonist shock.

[0056] In one example, the subject is suffering from an acute traumatic event.

[0057] In one example, the subject is suffering from PTSD, nicotine or alcohol addiction, anorexia and/or clinical depression.

[0058] In one example, the subject is a human.

[0059] In one aspect there is provided a composition comprising two or more active pharmaceutical agents formulated in multiple layers to release the two or more active pharmaceutical ingredients at multiple different set times, set dosages and/or set locations in a subject during dosing.

[0060] In one example, the composition releases one or more active

pharmaceutical ingredients in the mouth, stomach, small intestine, and large interstice.

[0061] In one example, the composition releases the active pharmaceutical ingredients over pre-set a time schedule course of ten hours or more.

[0062] In one example, the subject is a human.

BRIEF DESCRIPTION OF THE FIGURES

[0063] Embodiments of the present disclosure will now be described, by way of example only, with reference to the attached Figures.

[0064] FIG. 1 is a diagram of a nonlimiting embodiment of a time-release layered formulation of the present invention.

[0065] FIG. 2 is a diagram depicting release of active agonist and antagonist ingredients via a time-release layered formulation of the present invention.

[0066] FIG. 3A and 3B are diagrams of nonlimiting embodiments of a time and/or location release multi layers capsule of the present invention. FIG. 3A shows an embodiment for release of multiple (1 to n) active pharmaceutical ingredients at pre-set times and/or locations. FIG. 3B shows an embodiment for release of two active pharmaceutical ingredients such as an agonist and antagonist at pre-set times and/or locations. [0067] FIG. 4 is a diagram depicting release of active pharmaceutical ingredients at multiple locations via a time and/or location release layered formulation of the present invention.

DETAILED DESCRIPTION

[0068] In one aspect, there is provided compositions and methods for administration of compositions providing controlled release of a combination of a psilocybe-derived agent and a cannabis-derived agent.

[0069] When it comes to psychoactive chemicals, it is commonly believed that every person will have their own individual experience. The quantity, quality and timing of ingestion and mixing of psychoactive chemicals such as psilocybin-derived agents and cannabis-derived agents play a major role in the effects of these agents in combination, with different outcomes on the progression of their effects. A precise delivery system of both substances with respect to quantity, quality and timing is essential for obtaining positive clinical medical outcomes for numerous physical and psychological traumas where a timely recalibration of brain activity, as presently predictably achieved with electroshock therapy, is desired.

[0070] In one aspect, the present invention provides compositions and methods for administration of compositions providing controlled release of a combination of a psilocybe-derived agent and a cannabis-derived agent.

[0071] In one nonlimiting embodiment, the compositions of the present invention are designed to produce differing agonistic and antagonistic pharmacological effects in rapid sequence thereby eliciting a chemical-based result similar to insulin and/or electric shock therapy. A historical precedent for a chemical“shock” treatment for psychological ailments is insulin shock therapy which was used extensively in the 1920s through 1940s for various forms of psychiatric disorders prior to the introduction of neuroleptic drugs. While the mechanisms of action of both electric and insulin shock therapies are not clear, both are known to be effective especially in clinical depression. With the formulations of the present invention, the sudden succession of chemically induced downs and ups resulting from the combination of a psilocybe-derived agent and a cannabis-derived agent is expected to elicit short or long term traumatic experience suppression without memory eradication thus making these compositions useful in treating chronic ailments such as, but not limited to, PTSD, nicotine or alcohol addiction, anorexia and clinical depression as well as acute traumatic events such as, but not limited to, PTBS, rape, limb loss, loss of a loved one, suicide attempt and prevention. Further, inclusion of a cannabis-derived agent in these compositions is expected to reducing negative side effects associated with psilocibe-derived agents.

[0072] In a preferred embodiment, the agonist/antagonist delivery capsule is administered immediately following a traumatic event to elicit sudden lows followed by abrupt highs in ailment defined time specific sequences with pre-measured sequential psilocybin/CBD dosages eliciting multiple chemical-induced high/low shocks. It is expected that this agonist/antagonist multilayer treatment and resulting psilocybin/CBD pharmaceutically induced shock will prevent the formation of physical, hormonal, chemical, electrical or DNA/RNA bonding in conversion of STM to LTM and/or dislodge the bond from pathological LTM and allow for their conscious or sub-conscious suppression.

[0073] Psilocybin is rapidly metabolized to psilocin, which then acts on serotonin receptors in the brain. It partially activates several serotonin receptors. Psilocin has a high affinity for the 5-HT2B and 5-HT2C receptors in the human brain, and a slightly lower affinity for the 5-HT2A receptor. Psilocin further binds with low affinity to 5-HT 1 receptors, including 5-HT1 A and 5-HT 1 D. In addition, psilocin indirectly increases the concentration of the neurotransmitter dopamine in the basal ganglia. Finally, psilocin is degraded by the enzyme monoamine oxidase in the liver, lungs and gut.

[0074] Nonlimiting examples of psilocibe-derived agents which can be included in the present invention include psilocybin and psilocycin as well as 3,2- dimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, 4- hydroxy-N,N-dimethyl-tryptamine, [3-(2-methylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate, [3-(2-trimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate and 4- hydroxy-N,N,N-trimethyltryptamine].

[0075] Cannabis research has revealed hundreds of cannabinoids and terpenes that may be active in some form. However, the primary active ingredients in hemp are tetrahydrocannabinol (THC) and cannabidiol (CBD). Differences in the ratio between the two, along with a host of other suspected active compounds, allows for some discretion in modifying the mushroom experience with cannabis.

[0076] THC exerts its most prominent effects via its actions on two types of cannabinoid receptors, the CB1 receptor and the CB2 receptor. Further, THC indirectly increases dopamine release. Cannabidiol (CBD) also acts as an allosteric modulator of the m- and d-opioid receptors. Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.

[0077] Nonlimiting examples of cannabis-derived agents which can be included in the present invention are CBD and THC. In one nonlimiting embodiment, the cannabis- derived agent is CBD as this agent is expected to reduce any nausea or paranoia resulting from the psilocibe-derived agent. CBD has also been considered to reduce the jitters, balancing the effects of THC in reducing disorientation, tachycardia, and eventual drowsiness. This may be due to its activity as a serotonin receptor activator.

[0078] A nonlimiting example of a multilayer formulation for use in the present invention is depicted in FIG. 1. In this nonlimiting embodiment, the agonist/antagonist formulation is a multilayer tablet or capsule with different layers 1 , 2 through n-1 to the inner core n, of CBD and psilocybin. As will be understood by the skilled artisan upon reading this disclosure, the number of layers 1 -n, as well as the thickness of each layer, its rate of dissolution and composition can be varied per desired outcome specification. Further, pharmaceutical excipients in each layer, as well as the quantity of active agonist or antagonist can be varied per desired outcome.

[0079] As shown in FIG. 2, the formulations of the present invention are designed to release the agonist and antagonist at specific times and places in the gastrointestinal (Gl) tract. In one nonlimiting embodiment, this is accomplished by interaction with the naturally occurring pH within the Gl tract and known physiological transit time within. As shown in FIG. 2, in one nonlimiting embodiment, release starts in the mouth A where the outer layer releases over a pre-set time of, for example, 15 seconds to 3 minutes, in the mouth’s natural pH of 6.5 to 7.5. In one nonlimiting embodiment, this layer contains agonist and elicits the desired high. Next, the capsule travels down the esophagus to the upper stomach, the fundie B where layer 2 dissolves and releases the active agent over a pre-set time of, for example, 30 to 60 minutes, at the stomach fundie’s natural pH of 4.0 to 6.5. In one nonlimiting embodiment, this layer contains the antagonist and elicits the physiological low response. As the formulation of the present invention proceeds to the lower stomach C with the now exposed 3rd layer, it encounters a pH of 1.5 to 4.0 at which active agent is released for the next 1 to 3 hours. In one nonlimiting embodiment, this layer contains the agonist and again elicits the physiological high. The capsule next travels to the duodenum D where the 4th layer dissolves at a pre-set time between 30 and 60 minutes at a pH of 7.0 to 8.5. In one nonlimiting embodiment, this layer contains the antagonist and again elicits the physiological low. The fifth layer is released in the small intestine E, with a pH of 4.0 to 7.0 over a preset time of 1 to 5 hours followed by release of the inner core in the large intestine F, with a pH of 4.0 to 7.0, where the formulation can reside between 10 hours to several days. In one nonlimiting

embodiment, release in the small intestine is of the agonist and release in the large intestines is of antagonist. As will be understood be the skilled artisan, the number of agonist/antagonist capsular layers and the areas in which they are released in this nonlimiting embodiment is illustrative only and not limited to any specific pathology and/or disease state. For a specific pathological condition such as, but not limited to, depression, suicidal thought, sleep deprivation, obsessive compulsive disorders or post traumatic syndrome (PTSD), the number of layers(l-n), time of release, potency and composition of psilocybe-derived agent and a cannabis-derived agent can be varied as per experimentation and clinical validation.

[0080] Various methods for formulation of a tablet or capsule in accordance with the present invention can be used.

[0081] In one nonlimiting embodiment, an encapsulation technique is used to enclose medicines in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally. In one nonlimiting embodiment, the formulation of the present invention comprises a hard-shelled capsule containing dry, powdered ingredients, miniature pellets made by processes such as extrusion and spheronization or mini tablets. The hard-shelled capsules are typically made in two halves: a smaller-diameter body that is filled and then sealed using a larger-diameter cap. The capsule itself is typically made from aqueous solutions of gelling agents, such as animal protein (mainly gelatin) or plant polysaccharides or their derivatives (such as carrageenans and modified forms of starch and cellulose). Other ingredients can be added to the gelling agent solution including plasticizers such as glycerin or sorbitol to decrease the capsule's hardness, coloring agents, preservatives, disintegrants, lubricants and surface treatment.

[0082] In another aspect, there is provided provides compositions comprising two or more active pharmaceutical ingredients arranged in multiple layers for oral administration which release the pharmaceutical agents at various pre-determined locations, times and amounts in a subject. In one nonlimiting embodiment, the composition is formulated to release one or more active pharmaceutical agents in the mouth, stomach, small intestine and large intestine over a time course of ten hours or more. [0083] In one nonlimiting embodiment, compositions of the present invention may comprise two or more pre-determined active pharmaceutical ingredients routinely administered together to treat a single condition. Examples include, but are in no way limited to, antiretrovirals, anticancer agents, migraine treatments and psychiatric disorder medications for use in, but not limited to, memory suppression for post-traumatic stress disorder, suicidal thoughts and depression, distraction of pathological behavior patterns as drug and alcohol addiction, unconstrained mental and physical activity for obsessive compulsive disorders and/or Tourette’s syndrome and a spectrum of memory

recall/forgetfulness disorders ranging from ubiquitous memory breach, events(time and/or place) confusion up to Alzheimer’s disease.

[0084] Compositions of the present invention may also comprise two or more active pharmaceutical ingredients targeting multiple diseases/conditions which routinely appear together such as, but in no way limited to, antihypertensive agents, cholesterol lowering agents and prophylactic aspirin (ASA).

[0085] In addition, compositions of the present invention may comprise two or more (1 to n) active pharmaceutical ingredients wherein one counteracts negative side effects of the other.

[0086] Nonlimiting examples of multilayer compositions of the present invention are depicted in FIG. 3A and 3B.

[0087] In one nonlimiting embodiment, each multilayer capsule is customized as per an individual’s patient physiology and medical requirements in a specialty pharmacy or doctors office, utilizing a propriety algorithm provided via a computer or phone application or its equivalent. Customization can include capsular shell thickness, composition, time of dissolution and content in between active pharmaceutical ingredient containing capsular layers, amount and potency.

[0088] For example, a multilayer capsule as depicted in FIG. 3A can be customized for a kidney transplant patient on immuno-suppressive therapy such as cyclosporine (layer a1 of FIG. 3A), which brings about an unavoidable complication of hypertension an hour after intake, whereby a hypertensive drug is released (layer b1 of FIG. 3A). There is high likelihood of urinary tract infection within 12 hours, when the appropriate antibiotic is released (layer d of FIG. 3A) or a dormant virus such as a herpes virus can be activated, thereby an antiviral medication is released within 24 hours (layer d1 of FIG. 3A). There is also need for multivitamins (layer e1 of FIG, 3A) and protection of the stomach lining from acid reflux is paramount so an anti acid is released (layer f1 of FIG. 3A) buy which time another dose of cyclosporin is warranted (layer a2 of FIG. 3A).

[0089] Another nonlimiting example of a customized capsule is for treatment of anemia. In this nonlimiting embodiment, a blood stimulation medication such as erythropoietin may be in layer a1 of FIG. 3A with folic acid in layer b1 , iron in layer n-1 and vitamins in layer n.

[0090] Yet another nonlimiting example is a multilayer customized capsule for the treatment of Osteoporosis wherein an osteoporosis medication is in layer a1), calcium is in layer b1), vitamin D is layer d or n-1 and estrogen is in layer n), followed by timely release of a calcium supplement in another layer, i.e. b2.

[0091] In another nonlimiting embodiment, the compositions of the present invention are designed to produce differing agonistic and antagonistic pharmacological effects in rapid sequence thereby eliciting a chemical, electrical or quantum mechanics- based result similar to or even superior to the advantageous clinical outcome scientifically established post insulin and/or electric shock therapy.

[0092] In this nonlimiting embodiment, the composition is a multilayer tablet or capsule with different layers such as depicted in FIG. 3B with layers a1 ,b1 ,a2,b2through a(n-1),a(n),b(n-1),b(n) and so on to the inner core n, of active pharmaceutical ingredient a and active pharmaceutical agent b.

[0093] As will be understood by the skilled artisan upon reading this disclosure, the number of layers 1 to n, as well as the thickness of each layer, its rate and location of dissolution and composition can be varied per desired outcome specification. Further, pharmaceutical excipients in each layer, as well as the quantity and potency of the active pharmaceutical ingredients can be varied per desired outcome.

[0094] As shown in FIG. 4, the compositions of the present invention are designed to release the active pharmaceutical ingredients at specific times and places in the gastrointestinal tract. In one nonlimiting embodiment, this is accomplished by interaction with the naturally occurring pH within the Gl tract and known physiological transit time within. As shown in FIG. 4, in one nonlimiting embodiment, release starts in the mouth A where the outer layer releases over a pre-set time of, for example, 15 seconds to 3 minutes, in the mouth’s natural pH of 6.5 to 7.5. In one nonlimiting embodiment, this layer contains active pharmaceutical ingredient a1. Next, the capsule travels down the esophagus to the upper stomach, the fundie B where layer 2 dissolves and releases the active agent over a pre-set time of, for example, 30 to 60 minutes, at the stomach fundie’s natural pH of 4.0 to 6.5. In one nonlimiting embodiment, this layer contains the active pharmaceutical ingredient b1. As the formulation of the present invention proceeds to the lower stomach C with the now exposed 3rd layer, it encounters a pH of 1.5 to 4.0 at which active agent is released for the next 1 to 3 hours. In one nonlimiting embodiment, this layer contains active pharmaceutical ingredient a2. The capsule next travels to the duodenum D where the 4th layer dissolves at a pre-set time between 30 and 60 minutes at a pH of 7.0 to 8.5. In one nonlimiting embodiment, this layer contains active pharmaceutical ingredient b2. The fifth layer is released in the small intestine E, with a pH of 4.0 to 7.0 over a preset time of 1 to 5 hours followed by release of the inner core in the large intestine F, with a pH of 4.0 to 7.0, where the formulation can reside between 10 hours to several days. In one nonlimiting embodiment, release in the small intestine is of active pharmaceutical ingredient a3 and release in the large intestines is of active pharmaceutical ingredient b3.

[0095] As will be understood be the skilled artisan, the number of capsular layers and the areas in which they are released in this nonlimiting embodiment is illustrative only and not limited to any specific pathology and/or disease state. Further, the number capsular layer as well as their pre-set dissolution rates and pharmaceutical ingredients, dosages and/or potencies can be modified routinely by the skilled artisan based upon this disclosure for the specific pathology(s) or disease state(s) to be treated.

[0096] Various methods for formulation of a tablet or capsule in accordance with the present invention can be used.

[0097] In one nonlimiting embodiment, an encapsulation technique is used to enclose medicines in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally. In one nonlimiting embodiment, the formulation of the present invention comprises a hard-shelled capsule containing dry, powdered ingredients, miniature pellets made by processes such as extrusion and spheronization or mini tablets. The hard-shelled capsules are typically made in two halves: a smaller-diameter body that is filled and then sealed using a larger-diameter cap. The capsule itself is typically made from aqueous solutions of gelling agents, such as animal protein (mainly gelatin) or plant polysaccharides or their derivatives (such as carrageenans and modified forms of starch and cellulose). Other ingredients can be added to the gelling agent solution including plasticizers such as glycerin or sorbitol to decrease the capsule's hardness, coloring agents, preservatives, disintegrates, lubricants and surface treatment.

[0098] In one aspect, the subject described herein is a human. [0099] Method of the invention are conveniently practiced by providing the compounds and/or compositions used in such method in the form of a kit. Such kit preferably contains the composition. Such a kit preferably contains instructions for the use thereof.

[00100] The embodiments described herein are intended to be examples only. Alterations, modifications and variations can be effected to the particular embodiments by those of skill in the art. The scope of the claims should not be limited by the particular embodiments set forth herein, but should be construed in a manner consistent with the specification as a whole.

[00101] All publications, patents and patent applications mentioned in this Specification are indicative of the level of skill those skilled in the art to which this invention pertains and are herein incorporated by reference to the same extent as if each individual publication patent, or patent application was specifically and individually indicated to be incorporated by reference.

[00102] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modification as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising a psilocybe-derived agent and a cannabis-derived agent.

2. The composition of claim 1 formulated in multiple layers to release the psilocybin- derived agent and the cannabis-derived agent at multiple different times, dosages and/or locations in a subject during dosing.

3. The composition of claim 1 , wherein the subject is a human.

4. A method for administering a composition comprising a psilocybe-derived agent and a cannabis-derived agent to a subject, said method comprising administering to the subject a composition comprising multiple layers of psilocybin-derived agent and cannabis-derived agent so that the psilocybin-derived agent and the cannabis-derived agent are released at different times, dosages and/or locations in a subject.

5. The method of claim 4, wherein the composition is administered to address pathological conversion of STM to LTM and promote disengagement of pathological LTM by a chemical agonist/antagonist shock.

6. The method of claim 4 or 5, wherein the subject is suffering from an acute traumatic event.

7. The method of any one of claims 4 to 6, wherein the subject is suffering from PTSD, nicotine or alcohol addiction, anorexia and/or clinical depression.

8. The method of any one of claims 4 to 7, wherein the subject is a human

9. Use of a composition comprising multiple layers of psilocybin-derived agent and cannabis-derived agent so that the psilocybin-derived agent and the cannabis-derived agent are released at different times, dosages and/or locations in a subject.

10. The use of claim 9, wherein the composition is for addressing pathological conversion of STM to LTM and promote disengagement of pathological LTM by a chemical agonist/antagonist shock.

1 1. The use of claim 9 or 10, wherein the subject is suffering from an acute traumatic event.

12. The use of any one of claims 9 to 1 1 , wherein the subject is suffering from PTSD, nicotine or alcohol addiction, anorexia and/or clinical depression.

13. Use of a composition comprising multiple layers of psilocybin-derived agent and cannabis-derived agent in the manufacture of a medicament, so that the psilocybin- derived agent and the cannabis-derived agent are released at different times, dosages and/or locations in a subject.

14. The use of claim 13, wherein the composition is for addressing pathological conversion of STM to LTM and promote disengagement of pathological LTM by a chemical agonist/antagonist shock.

15. The use of claim 13 or 14, wherein the subject is suffering from an acute traumatic event.

16. The use of any one of claims 13 to 15, wherein the subject is suffering from PTSD, nicotine or alcohol addiction, anorexia and/or clinical depression.

17. The use of any one of claims 9 to 16, wherein the subject is a human.

18. A composition comprising two or more active pharmaceutical agents formulated in multiple layers to release the two or more active pharmaceutical ingredients at multiple different set times, set dosages and/or set locations in a subject during dosing.

19. The composition of claim 18, which releases one or more active pharmaceutical ingredients in the mouth, stomach, small intestine, and large interstice.

20. The composition of claim 18 or 19, which releases the active pharmaceutical ingredients over pre-set a time schedule course of ten hours or more.

21. The use of any one of claims 18 to 20, wherein the subject is a human.