WO2021072530A1 - Controlled release formulations of psilocybe-derived agents and method for their use, and methods and compositions for threating mild traumatic brain injury with post traumatic stress disorder. - Google Patents

Abstract

The current application relates to a controlled release formulation of psilocybe-derived agent, wherein psilocybe-derived agent is formulated in multiple layers to release the agent at multiple different times, locations, and dosages during dosing. The formulation is used for treating mild traumatic brain injury (mTBI) with post traumatic stress disorder (PTSD). The formulation can also be used in combination with a cannabis-derived agent.

Description

CONTROLLED RELEASE FORMULATIONS OF PSILOCYBE-DERIVED AGENTS AND

METHOD FOR THEIR USE. AND METHODS AND COMPOSITIONS FOR THREATING MILD TRAUMATIC BRAIN INJURY WITH POST TRAUMATIC STRESS DISORDER.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional patent application US 62/915,092, filed October 15, 2019, and to United States Provisional patent application US 62/924,434, file October 22, 2019, the entire contents both of which are hereby incorporated by reference.

FIELD

[0002] The present disclosure relates generally to controlled release formulations of psilocybe-derived agents and method for their use, and methods and compositions for threating mild traumatic brain injury with post traumatic stress disorder.

BACKGROUND

[0003] 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.

[0004] 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).

[0005] 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.

[0006] There has been a significant amount of research regarding the differences between Short Term Memory (STM) and Long Term Memory (LTM).

[0007] 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. [0008] 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.

[0009] 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.

[0010] 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. [0011] 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.

[0012] 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.

[0013] 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 1st day at school, the horror of 9/11 or the assassination of JFK.

[0014] 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.

[0015] 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. [0016] 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.

[0017] LTM storage and retrieval is subject to multiple theories and is still being studied.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] Psilocybin is rapidly metabolized 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-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.

[0025] 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.

[0026] 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)-1H-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.

[0027] 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.

[0028] Controlled release of varying concentrations of psilocybe-derived agents is expected to be useful in eliciting short term memories/thoughts (STMs) retention and/or recall or long term memories/thoughts (LTM) retention and/or recall.

[0029] Post-traumatic stress disorder and traumatic brain injury

[0030] Post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) often coexist because brain injuries are often sustained in traumatic experiences (Bryant, R. Dialogues Clin Neurosci. 2011 Sep; 13(3): 251-262).

[0031] TBI involves damage to the brain from an external force. Brain injuries can involve contusion, brain laceration, intracranial hematoma, contrecoup injury, shearing of nerve fibers, intracranial hypertension, hypoxia, anemia, metabolic anomalies, hydrocephalus, and subarachnoid hemorrhage (Bryant, R. Dialogues Clin Neurosci. 2011 Sep; 13(3): 251-262). Severity of TBI is typically described in terms of mild or moderate/severe with mild traumatic brain injury (MTBI) usually being defined as: (i) an external injury to the brain; (ii) confusion, disorientation, or loss of consciousness for 30 minutes or less; (iii) Glasgow Coma Scale score of 13 to 15; and (iv) post-traumatic amnesia for less than 24 hours (American Congress of Rehabilitation Medicine. Definition of mild traumatic brain injury. J Head Trauma Rehab. 1993;8:86-87; Carroll et al. J Rehab Med. 2004 36:113-125; Ruff et al. Arch Clin Neuropsychol. 2009;24:3-10).

[0032] PTSD reactions can be immediate or longer-term and are distinguished diagnostically because acute stress reactions are frequent, but often transient, as compared to the less common persistent PTSD responses. In terms of the persistent responses, PTSD is described in the American Psychiatric Association's DSM-IV as an anxiety disorder that comprises five major criteria (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association. 1994). First, one must have been exposed to or witness an event that is threatening to safety, and one must respond to this event with fear, horror, or helplessness. Second, one must report a re-experiencing symptom, which may include intrusive memories, nightmares, a sense of reliving the trauma, or psychological or physiological distress when reminded of the trauma. Third, there need to be at least three avoidance symptoms, which can include active avoidance of thoughts, feelings, or reminders of the trauma, inability to recall some aspect of the trauma, withdrawal from others, or emotional numbing. Fourth, one must suffer marked arousal, which can include insomnia, irritability, difficulty concentrating, hypervigilence, or heightened startle response. Finally, these symptoms must cause marked impairment to one's functioning, and can only be diagnosed when they are present at least 1 month after the trauma.

[0033] It was previously argued that PTSD could not develop following TBI because the impaired consciousness at the time of trauma precluded encoding of the traumatic experience, and this prevented trauma memories that are necessary for PTSD development (Sbordone RJ., Liter JC. Brain Inj. 1995;9:405-412; Price KP Law J. 1994;43:113-120). More recently, however, evidence has accumulated that PTSD can develop following mild TBI (Bryant RA., Harvey AG. Am J Psychiatry. 1998;155:625-629; Middelboe et al. Eur Psychiatry. 1992;7:183-189; Ohry et al. Brain inj. 1996;10:687-695; Hickling et al. Brain inj. 1998;12:265-274; Castro CA., Gaylord KM. J Trauma-lnj Infect Crit Care. 2008;64:S205-S206; Greenspan et al. Brain Inj. 2006;20:733-742; Harvey AG., Bryant RA. Am J Psychiatry. 2000;157:626-628; Hoge et al. N Engl J Med. 2008;358:453-463; Levin et al. J Clin Exp Neuropsychol. 2001 ;23:754-769.

[0034] Several models have been set forth to explain how PTSD can develop following TBI including fear conditioning, memory reconstruction and postamnesia resolution (Bryant, R. Dialogues Clin Neurosci. 2011 Sep; 13(3): 251-262).

[0035] The definitions of postconcussive syndrome (PCS) can vary, but generally overlap somewhat with symptoms of PTSD. For example, the International Classification of Diseases (ICD-10) stipulates that PCS is defined by headaches, dizziness, general malaise, fatigue, noise intolerance, irritability, emotional lability, depression, or anxiety, concentration or memory difficulty, sleep disturbance, reduced tolerance to alcohol, and a preoccupation with these symptoms and fear of permanent brain damage (World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. 1995 ed. Geneva, Switzerland: World Health Organization. 1995 ). The Appendix of the DSM.-IV describes PCS as fatigue, sleep disturbance, headaches, dizziness, irritability, anxiety or depression, changes in personality, and apathy (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association. 1994). These descriptions clearly overlap with common symptoms of post- traumatic stress.

[0036] 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.

[0037] 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.

[0038] These effects are the result of psilocybin’s rapid metabolism to psilocin, which then activates or partially activated 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-HT1D. In addition, psilocin indirectly increases the concentration of the neurotransmitter dopamine in the basal ganglia.

[0039] Research on cannabis has revealed hundreds of active cannabinoids and terpenes with the primary active ingredients being tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0040] Active ingredients in cannabis create a general change in perception, heightened mood, and an increase in appetite.

[0041] Downsides include a decrease in short-term memory, dry mouth, impaired motor skills, red eyes, and feelings of paranoia or anxiety.

[0042] 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.

[0043] 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® by the Swiss pharmaceutical company, Sandoz. 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 US and other countries in the 1960s (Matsushima et al., 2009) led to a ban on marketing and possession of “hallucinogenic” drugs in the US in 1965, and led Sandoz to discontinue 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. [0044] Published U.S. Application Nos. 2018/0221396 and 2019/-142851 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)-1H-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.

[0045] 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.

[0046] Administration of a psilocybe-derived agent and a cannabis-derived agent is expected to be useful in alleviating symptoms associated with mTBI with PTSB. SUMMARY

[0047] An aspect of the present invention relates to a composition comprising a psilocybe-derived agent formulated in multiple layers to release the psilocybin-derived agent at multiple different times, locations and/or dosages during dosing.

[0048] Another aspect of the present invention relates to a method for administering a composition comprising a psilocybe-derived agent via a formulation which controls release of the agent at multiple different times, locations and/or dosages during dosing.

[0049] The multilayer formulations of the present invention are expected to be useful in eliciting short term memories/thoughts (STMs) retention and/or recall or long term memories/thoughts (LTM) retention and/or recall. Such formulations are expected to be useful in inhibiting memory loss in aging individuals and individuals with Alzheimer’s disease or dementia.

[0050] An aspect of the present invention relates to a method for alleviating one or more symptoms of mTBI with PTSB. The method comprises administering to an individual suffering from mTBI with PTSB a psilocybe-derived agent and a cannabis- derived agent.

[0051] Another aspect of the present invention relates to pharmaceutical formulations and kits thereof comprising a psilocybe-derived agent and a cannabis- derived agent for use in alleviating one or more symptoms of mTBI with PTSB.

[0052] In one aspect there is provided a composition comprising psilocybin or a psilocybe-derived agent formulated in multiple layers to release the psilocybin-derived agent at multiple different times, locations and/or dosages during dosing.

[0053] In one example, the multiple layer release increasing concentrations of psilocybin or a psilocybe-derived agent.

[0054] In one example, the multiple layer release decreasing concentrations of psilocybin or a psilocybe-derived agent.

[0055] In one aspect there is provided a method for eliciting short term memories/thoughts (STMs) retention and/or recall or long term memories/thoughts (LTM) retention and/or recall in a subject comprising administering to the individual the composition of any of claims 1 through 3.

[0056] In one aspect there is provided a method for inhibiting or preventing memory loss in a subject, said method comprising administering to the individual the composition of any of claims 1 to 3. 10057] In one aspect there is provided a method for restoring memories in an individual, said method comprising administering to the subject the composition of any of claims 1 to 3.

[0058] In one example, the subject is suffering from Alzheimer’s disease, dementia or age-related memory loss.

[0059] In one example, the subject is a human.

[0060] In one aspect there is provided a use of a composition of any of claims 1 to

3, for eliciting short term memories/thoughts (STMs) retention and/or recall or long term memories/thoughts (LTM) retention and/or recall in a subject comprising.

[0061] In one aspect there is provided a use of a composition of any of claims 1 to

3, for inhibiting or preventing memory loss in a subject.

[0062] In one aspect there is provided a use of a composition of any of claims 1 to

3, for restoring memories in a subject.

[0063] In one example, the subject is suffering from Alzheimer’s disease, dementia or age-related memory loss.

[0064] In one example, the subject is a human.

[0065] In one aspect there is provided a method for alleviating one or more symptoms of mTBI with PTSD, said method comprising administering to a subject suffering from mTBI with PTSD a psilocybe-derived agent in combination with a cannabis- derived agent.

[0066] In one example, the one or more symptoms is selected from intrusive memories, nightmares, a sense of reliving the trauma, or psychological or physiological distress when reminded of the trauma, active avoidance of thoughts, feelings, or reminders of the trauma, inability to recall some aspect of the trauma, withdrawal from others, or emotional numbing, insomnia, irritability, difficulty concentrating, hypervigilence, or heightened startle response.

[0067] In one example, the the psilocybe-derived agent and cannabis-derived agent are administered simultaneously.

[0068] In one example, the psilocybe-derived agent and cannabis-derived agent are formulated in multiple layers to release the psilocybin-derived agent and the cannabis-derived agent at multiple different times, dosages and/or locations in the subject during dosing.

- IQ - [0069] 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.

[0070] In one example, the the psilocybe-derived agent is administered before the cannabis-derived agent.

[0071] In one example, the psilocybe-derived agent is administered after the cannabis-derived agent.

[0072] In one example, the psilocybe-derived agent is psilocybin.

[0073] In one example, the cannabis-derived agent is cannabidiol.

[0074] In one example, the subject is a human.

[0075] In one aspect, there is provided a use of a psilocybe-derived agent in combination with a cannabis-derived agent for alleviating one or more symptoms of mTBI with PTSD.

[0076] In one example, the one or more symptoms is selected from intrusive memories, nightmares, a sense of reliving the trauma, or psychological or physiological distress when reminded of the trauma, active avoidance of thoughts, feelings, or reminders of the trauma, inability to recall some aspect of the trauma, withdrawal from others, or emotional numbing, insomnia, irritability, difficulty concentrating, hypervigilence, or heightened startle response.

[0077] In one example, the psilocybe-derived agent and cannabis-derived agent are for simultaneous administration.

[0078] In one example, the psilocybe-derived agent and cannabis-derived agent are formulated in multiple layers to release the psilocybin-derived agent and the cannabis-derived agent at multiple different times, dosages and/or locations in the subject during dosing.

[0079] In one example, the the composition is administered to address pathological conversion of STM to LTM and promote disengagement of pathological LTM by a chemical agonist/antagonist shock.

[0080] In one example, the psilocybe-derived agent is for administration before the cannabis-derived agent.

[0081] In one example, the psilocybe-derived agent is for administration after the cannabis-derived agent.

[0082] In one example, the psilocybe-derived agent is psilocybin.

[0083] In one example, the cannabis-derived agent is cannabidiol. [0084] In one example, the said subject is a human.

BRIEF DESCRIPTION OF THE FIGURES

[0085] Embodiments of the present disclosure will now be described, by way of example only, with reference to the attached Figures.

[0086] FIG. 1 is a diagram of a nonlimiting embodiment of a time-release layered formulation of the present invention.

[0087] FIG. 2 is a diagram depicting release of the active ingredient via a time- release layered formulation of the present invention.

[0088] FIG. 3 is a diagram of a nonlimiting embodiment of a time-release layered formulation of the present invention.

[0089] FIG. 4 is a diagram depicting release of active agonist and antagonist ingredients via a time-release layered formulation of the present invention.

DETAILED DESCRIPTION

[0090] Generally, the present disclosure provides (i) compositions and methods for administration of compositions providing controlled release of varying concentrations of a psilocybe-derived agent, and (ii) provides methods and compositions for alleviating one or more symptoms of mTBI with PTSB.

[0091] Compositions and methods for administration of compositions providing controlled release of varying concentrations of a psilocybe-derived agent [0092] 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 of a psychoactive chemical such as a psilocybin-derived agent plays a major role in the effect of this agent, with different outcomes on the progression of its effects. A precise delivery system of a psilocybin-derived agent with respect to quantity, quality and timing essential for obtaining positive clinical medical outcomes with respect to eliciting short term memories/thoughts (STMs) retention and/or recall or long term memories/thoughts (LTM) retention and/or recall, is desired.

[0093] The present invention provides compositions and methods for administration of compositions providing controlled release of varying concentrations of a psilocybe-derived agent. The compositions, through measured dosages and timing of delivery, elicit physiological and/or psychological crescendos or ups combined with disease and/or timing specific, physiological and/or psychological decrescendos or downs which are expected to elicit chemical, electrical and/or biology based physiological and/or psychological clinical responses which bring about retention of short term memories/thoughts (STMs) and/or recall of long term memories/thoughts (LTM).

[0094] Clinical results are expected to be similar, the same, or superior to the advantageous outcomes scientifically established post physical (e.g., running) and/or mental(e.g., reading) exercise therapies as the compositions of the present invention provide for a passive brain exercise regiment allowing for stronger memory retention, more secure and sharper remembrance, faster recall, recollection and recognition.

[0095] Accordingly, compositions of the present invention are expected to be useful in preventing or inhibiting the progression of clinical memory loss and memory fortitude exhibited in individuals in need thereof.

[0096] In one nonlimiting embodiment, compositions of the present invention can be incorporated into an “anti aging” plan along with exercise and diet to delay decaying dysfunctional memory recall and/or aid in memory retention not only caused by disease states but also by natural physiological aging, thus acting as an “anti brain aging” agent. [0097] In one nonlimiting embodiment, compositions of the present invention are used to inhibit or prevent the progression of clinical memory loss and memory fortitude exhibited in dementia and Alzheimer’s disease.

[0098] 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.

[0099] 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)-1H-indol-4-yl] dihydrogen phosphate and 4- hydroxy-N,N,N-trimethyltryptamine].

[00100] In one nonlimiting embodiment, the crescendo/decrescendo formulations of psilocibe-derived agents are administered in continuous 12 hour cycles to confront diseases such as dementia, Alzheimer’s disease and/or age-related dysfunctional memory recall and/or retention. In one nonlimiting embodiment, the crescendo/decrescendo formulations of psilocibe-derived agents are administered in continuous 24 hour cycles to confront diseases such as dementia, Alzheimer’s disease and/or age-related dysfunctional memory recall and/or retention. As will be understood by the skilled artisan upon reading this disclosure, other time spans determined to be clinically relevant may also be used. In one nonlimiting embodiment, the first cycle may comprise an incremental increase of psilocybin-induced brain stimulation or a crescendo, followed by an incremental decrease in psilocybin-induced brain stimulation or the decrescendo.

[00101] Accordingly, one nonlimiting embodiment of the present invention relates to a crescendo multilayer capsule or tablet with increasing potency layers of psilocybin or a psilocybin-derived agent acting in accordance with a pre-set timing and/or delivery schedule which elicits an intense crescendo or increase of brain activity, especially in the hippocampus and/or frontal lobe regions as measured by brain PET scans. The hippocampus is known to be responsible for long-term declarative memories and spatial memories. With the crescendo multilayer capsule or tablet of the present invention, the hippocampus is stimulated in a steady, gradual increasing upsurge intensity collimating with a climatic point over a 12 hour or 24 hour period or any other time span determined to be clinically relevant to positive outcome realization.

[00102] Another nonlimiting embodiment of the present invention relates to a decrescendo multilayer capsule or tablet with decreasing potency layers of psilocybin or a psilocybin-derived agent acting in accordance with a pre-set timing and/or delivery schedule. In some nonlimiting embodiments, post climax of the crescendo formulation, a decrescendo capsule or tablet is administered to elicit an intense decrescendo or decrease of brain activity in the hippocampus region as measured by brain PET scan. Thus, in this nonlimiting embodiment, the hippocampus is stimulated in a steady, gradual decreasing down-surge intensity collimating with an end point of minimal or no stimulation. These crescendo and/or decrescendo cycles can be repeated indefinitely or as clinically warranted as per disease or predetermined goals, to either inhibit or prevent progression memory disease state or possibly reverse it.

[00103] A nonlimiting example of a multilayer formulation for use in the present invention is depicted in FIG. 1. In this nonlimiting embodiment, either increasing or decreasing amounts of psilocybin or a psilocybin-derived agent are included in the different layers 1 , 2 through n-1 and into the inner core n. As will be understood by the skilled artisan upon reading this disclosure, the number of layers 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 can be varied per desired outcome.

[00104] As shown in FIG. 2, the formulations of the present invention can be designed to release the increasing or decreasing amounts of psilocybin or a psilocybin- derived agent 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. 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. 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. 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. 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. As will be understood be the skilled artisan, the number of a capsular layers and the areas in which they are released in this nonlimiting embodiment is illustrative only.

[00105] Various methods for formulation of a tablet or capsule in accordance with the present invention can be used.

[00106] 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.

[00107] Methods and compositions for alleviating one or more symptoms of mTBI with PTSB

[00108] The present invention provides methods and compositions for alleviating one or more symptoms of mTBI with PTSB.

[00109] The methods and compositions involve administration of a psilocybe- derived agent in combination with a cannabis-derived agent.

[00110] 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 with a slightly lower affinity for the 5-HT2A. Psilocin further binds with low affinity to 5-HT 1 receptors, including 5-HT1A and 5-HT1D. 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.

[00111] Nonlimiting examples of psilocibe-derived agents which can be used 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)-1H-indol-4-yl] dihydrogen phosphate, [3-(2- trimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate and 4-hydroxy-N,N,N- trimethyltryptamine].

[00112] 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.

[00113] 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.

[00114] 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.

[00115] As used herein, by alleviating one or more symptoms of mTBI with PTSD is it meant to decrease severity of one or more of intrusive memories, nightmares, a sense of reliving the trauma, or psychological or physiological distress when reminded of the trauma, active avoidance of thoughts, feelings, or reminders of the trauma, inability to recall some aspect of the trauma, withdrawal from others, or emotional numbing, insomnia, irritability, difficulty concentrating, hypervigilence, or heightened startle response.

[00116] In one nonlimiting embodiment, the psilocybe-derived agent and the cannabis-derived agent are administered in combination immediately following the mTBI or within 12 to 24 hours of the mTBI. In one nonlimiting embodiment, the psilocybe- derived agent and the cannabis-derived agent are administered in combination upon the onset of symptoms of PTSD. . As will be understood by the skilled artisan upon reading this disclosure, other dosing regimens determined to be clinically relevant may also be used.

[00117] As used herein, by “in combination” it is meant to include coadministration of the psilocybe-derived agent and the cannabis-derived agent, sequential administration of the psilocybe-derived agent followed by cannabis-derived agent, or sequential administration of the cannabis-derived agent followed by the psilocybe-derived agent. [00118] In one nonlimiting embodiment, the psilocybe-derived agent and the cannabis-derived agent are coadministered in a bilayer or multilayer formulation.

[00119] In one nonlimiting embodiment, the multilayer formulations of the present invention is expected to address pathological conversion of short term memory to long term memory (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 acute traumatic events including post traumatic brain syndrome (PTBS) and chronic ailments such as post traumatic stress disorder (PTSD).

[00120] A nonlimiting example of a multilayer formulation for use in the present invention is depicted in FIG. 3. In this nonlimiting embodiment, the multilayer tablet or capsule comprises 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.

[00121] As shown in FIG. 4, the formulations of the present invention are designed to release the CBD and psilocybin 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. 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. 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. 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. 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. 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. For alleviation of specific symptoms of mTBI with 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.

[00122] Various methods for formulation of a tablet or capsule in accordance with the present invention can be used.

[00123] 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. [00124] 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.

[00125] To gain a better understanding of the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only. Therefore, they should not limit the scope of this invention in anyway.

[00126] 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.

[00127] 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.

[00128] 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 psilocybin or a psilocybe-derived agent formulated in multiple layers to release the psilocybin-derived agent at multiple different times, locations and/or dosages during dosing.

2. The composition of claim 1 , wherein the multiple layer release increasing concentrations of psilocybin or a psilocybe-derived agent.

3. The composition of claim 1 , wherein the multiple layer release decreasing concentrations of psilocybin or a psilocybe-derived agent.

4. A method for eliciting short term memories/thoughts (STMs) retention and/or recall or long term memories/thoughts (LTM) retention and/or recall in a subject comprising administering to the individual the composition of any of claims 1 through 3.

5. A method for inhibiting or preventing memory loss in a subject, said method comprising administering to the individual the composition of any of claims 1 to 3.

6. A method for restoring memories in an individual, said method comprising administering to the subject the composition of any of claims 1 to 3.

7. The method of any of claims 4 to 6, wherein the individual is suffering from Alzheimer’s disease, dementia or age-related memory loss.

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

9. Use of a composition of any of claims 1 to 3, for eliciting short term memories/thoughts (STMs) retention and/or recall or long term memories/thoughts (LTM) retention and/or recall in a subject comprising.

10. Use of a composition of any of claims 1 to 3, for inhibiting or preventing memory loss in a subject.

11. Use of a composition of any of claims 1 to 3, for restoring memories in a subject.

12. The use of any of claims 9 to 11 , wherein the subject is suffering from Alzheimer’s disease, dementia or age-related memory loss.

13. The use of any one of claims 9 to 11 , wherein the subject is a human.

14. A method for alleviating one or more symptoms of mTBI with PTSD, said method comprising administering to a subject suffering from mTBI with PTSD a psilocybe-derived agent in combination with a cannabis-derived agent.

15. The method of claim 14, wherein the one or more symptoms is selected from intrusive memories, nightmares, a sense of reliving the trauma, or psychological or physiological distress when reminded of the trauma, active avoidance of thoughts, feelings, or reminders of the trauma, inability to recall some aspect of the trauma, withdrawal from others, or emotional numbing, insomnia, irritability, difficulty concentrating, hypervigilence, or heightened startle response.

16. The method of claim 14, wherein the psilocybe-derived agent and cannabis- derived agent are administered simultaneously.

17. The method of claim 16, wherein the psilocybe-derived agent and cannabis- derived agent are formulated in multiple layers to release the psilocybin-derived agent and the cannabis-derived agent at multiple different times, dosages and/or locations in the subject during dosing.

18. The method of claim 16, 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.

19. The method of claim 14, wherein the psilocybe-derived agent is administered before the cannabis-derived agent.

20. The method of claim 14, wherein the psilocybe-derived agent is administered after the cannabis-derived agent.

21. The method of any of claims 14 through 20, wherein the psilocybe-derived agent is psilocybin.

22. The method of any of claim 14 through 21 , wherein the cannabis-derived agent is cannabidiol.

23. The method of any one claims 14 to 22, wherein said subject is a human.

24. Use of a psilocybe-derived agent in combination with a cannabis-derived agent for alleviating one or more symptoms of mTBI with PTSD.

25. The use of claim 24, wherein the one or more symptoms is selected from intrusive memories, nightmares, a sense of reliving the trauma, or psychological or physiological distress when reminded of the trauma, active avoidance of thoughts, feelings, or reminders of the trauma, inability to recall some aspect of the trauma, withdrawal from others, or emotional numbing, insomnia, irritability, difficulty concentrating, hypervigilence, or heightened startle response.

26. The use of claim 24, wherein the psilocybe-derived agent and cannabis-derived agent are for simultaneous administration.

27. The use of claim 26, wherein the psilocybe-derived agent and cannabis-derived agent are formulated in multiple layers to release the psilocybin-derived agent and the cannabis-derived agent at multiple different times, dosages and/or locations in the subject during dosing.

28. The use of claim 26, 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.

29. The use of claim 24, wherein the psilocybe-derived agent is for administration before the cannabis-derived agent.

30. The use of claim 24, wherein the psilocybe-derived agent is for administration after the cannabis-derived agent.

31. The use of any of claims 24 to 30, wherein the psilocybe-derived agent is psilocybin.

32. The use of any of claim 24 to 31 , wherein the cannabis-derived agent is cannabidiol.

33. The use of any one claims 24 to 32, wherein said subject is a human.