Electroencephalography-guided dosing of psychedelics

Abstract

The present invention relates to a method for identifying an optimal dose of psilocybin, psilocin or combination thereof for a subject, the method comprising administering a dose of psilocybin or psilocin to the subject; measuring theta, medium gamma and high gamma bands of the subject using an electroencephalograph (EEG); determining the density of posterior theta and frontal high gamma network using the EEG, and determining coupling status of theta phase and gamma amplitudes using the EEG wherein the optimal dose causes a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes.

Description

ELECTROENCEPHALOGRAPHY-GUIDED DOSING OF PSYCHEDELICSTECHNICAL FIELD

[0001] The present invention relates to the use of EEG to guide dosing of psychedelic drugs such as psilocybin and psilocin. In particular, the invention relates to the EEG to guide administration of psilocybin or psilocin drugs to subjects as part of psilocybin / psilocin-assisted psychotherapy.CROSS REFERENCE TO RELATED APPLICTION

[0002] This application claims priority to US provisional patent application number 63 / 571 ,179 filed on 28 March 2024, the entire contents of which are incorporated by reference in their entiretyBACKGROUND OF THE INVENTION

[0003] In humans, psilocybin produces an altered state of consciousness, associated with complex changes in brain network activity including increased posterior connectivity and decreased frontal connectivity, increased spatiotemporal complexity, decreased network segregation and decreased spectral power and connectivity in low (<40 Hz) frequencies.

[0004] Functional connectivity changes have also been shown to correlate with psychedelic-induced subjective experiences, suggesting network dynamics may be an important component of the mechanisms underpinning the action of psychedelic drugs, including psilocybin.

[0005] Recent electrophysiological studies in rodents suggest that the emergence of high gamma (>110 Hz) amplitude and connectivity, observed during administration of lysergic acid diethylamide (LSD), ketamine, and phencyclidine, may be an important common marker of psychedelics. However, this high gamma emergence phenomenon has not been documented during psilocybin administration and previous studies using psilocin or intracranial recordings after systemic delivery of psilocybin lacked the spatial resolution to allow corticocortical network analysis. Relatedly, gamma amplitude is known to be modulated according to the phase of theta band (4-10 Hz) oscillations, and it has been demonstrated that the relationship between these two frequency bands changes with cognitive demands and state of arousal.

[0006] Psilocybin and psilocin are useful in the treatment of a range of disorders, particularly psychiatric disorders orthose with a psychiatric component. Psilocybin is particularly useful when used in combination with psychotherapy. However, establishing appropriate doses or dose-response relationships for psilocybin or psilocin comes with several challenges. In particular, the response measure must be accurately acquired across participants, which is challenging for psychological effects that depend on introspection.

[0007] The use of psilocybin and psilocin as therapeutics has grown significantly in recent years. Despite increasing access, there remains a lack of practical guidance as to the appropriate dose. This is particularly concerning given the medical complexity and vulnerable nature of patients for whom psilocybin-assisted psychotherapy is useful.

[0008] For at least the reasons above, there is a need for methods to determine an appropriate dose of psilocybin and psilocin which is the active metabolite of psilocybin.SUMMARY

[0009] According to a first aspect there is provided a method of identifying an optimal dose of psilocybin, psilocin or combination thereof for a subject, the method comprising a. administering a dose of psilocybin or psilocin to the subject; b. measuring theta, medium gamma and high gamma bands of the subject using an electroencephalograph (EEG) c. determining the density of posterior theta and frontal high gamma network using the EEG, and determining coupling status of theta phase and gamma amplitudes using the EEG wherein the optimal dose causes a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes.

[0010] According to second aspect there is provided a method of inducing a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes in the brain of a subject, the method comprising a. administering a dose of psilocybin, psilocin or a combination thereof to the subject; b. measuring theta, medium gamma and high gamma bands of the subject using an electroencephalograph (EEG) c. determining the density of posterior theta and frontal high gamma network using the EEG, and determining coupling status of theta phase and gamma amplitudes using the EEG. wherein an optimal dose of psilocybin, psilocin or a combination thereof induces the high-density posterior theta network, the high-density frontal high gamma network, and the decoupling of theta phase from gamma amplitudes.

[0011] The decoupling of theta phase from gamma amplitudes may be substantially cortex-wide, and may be complete or partial.

[0012] The psilocybin, psilocin or combination thereof may administered by intravenous infusion.

[0013] If the dose of psilocybin, psilocin or combination thereof is the optimal dose, the method may further comprises administering additional psilocybin, psilocin or combination thereof to maintain in the subject a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes.

[0014] Administering additional psilocybin, psilocin or a combination thereof may comprise reducing the infusion rate, reducing the concentration of the psilocybin or psilocin in the infusion, or both.

[0015] If the dose of psilocybin or psilocin is not the optimal dose, the method further comprises administering an additional dose of psilocybin, psilocin or a combination thereof and repeating steps b and c.

[0016] However, if the brain network state is dominated by the high gamma network then the administration of the psilocybin, psilocin or a combination thereof is stopped or reduced.

[0017] If the posterior theta density is decreased compared to density observed at an optimal dose then the administration of psilocybin, psilocin or a combination thereof is stopped or reduced.

[0018] If the frontoparietal medium gamma connectivity is weakened compared to that observed at an optimal dose, then the administration of the psilocybin, psilocin or a combination thereof is stopped or reduced.

[0019] In one embodiment the density of the posterior theta network and / or the frontal high gamma network are characterized by a node degree that is significantly increased (for example p<0.05) compared to the node degree before administration of the dose of psilocin, psilocybin or combination thereof.

[0020] In one embodiment the optimal dose causes an increased frontal and / or posterior node degree compared to a subject that has not been administered psilocin, psilocybin or combination thereof.

[0021] In one embodiment the optimal dose causes an increase in local- and / or long-range frontoparietal synchronization compared to a subject that has not been administered psilocin, psilocybin or combination thereof.

[0022] In one embodiment the theta bands are measured at a frequency of 4-10Hz.

[0023] In one embodiment the medium gamma bands are measured at a frequency of 70-110 Hz.

[0024] In one embodiment the high gamma bands are measured at a frequency of 110-150 Hz.

[0025] In one embodiment the administration of the additional psilocybin, psilocin or combination thereof is administered by intravenous infusion.BRIEF DESCRIPTION OF THE FIGURES

[0026] Figure 1 is a schematic showing the experimental design and timeline. Each rat (n=12, 6 male, 6 female) received 0.9% saline and three doses of psilocybin (0.1 mg / kg, 1 mg / kg, and 10 mg / kg) as a continuous infusion over the course of an hour. Each infusion session was separated by 5-7 days and was conducted in a counter-balanced manner. On the right-side of the experiment timeline is shown an image of the rat cranium indicating the EEG, ground, and reference electrode location.

[0027] Figure 2 shows psilocybin altered global peak oscillatory frequencies and amplitudes in a dosedependent manner. (A-C) Global spectrograms averaged across rats (n=12, 6 male, 6 female) depicting the difference between each dose (0.1 mg / kg, 1 mg / kg, and 10 mg / kg) and saline. Psilocybin / saline infusion started at time=0 and stopped at time=60 minutes. Lighter shades (Warm colors in the original) indicate higher spectral power while darker shades in 2C (cool colors in the original) indicate lower spectral power relative to saline. (D) Representative global power spectrum averaged over minutes -10 to 0 (left) and 10-20 (right) of 10 mg / kg psilocybin dose. The FOOOF algorithm was used to model and remove the 1 / f component from the original power spectrum to quantify band-specific peak frequencies and amplitudes. Displayed here are the original power spectrum (#), the aperiodic component (*), and the oscillatory component (A). For visualization the original and aperiodic spectra are log-transformed (left y-axis) and the oscillatory spectra are on a linear scale (right y-axis). (E-J) Changes in peak frequency and amplitude in the theta, medium gamma, and high gamma bands. The 1 mg / kg of psilocybin slowed theta peak frequency and increased medium gamma peak frequency. The 10 mg / kg psilocybin dose caused a significant decrease in theta peak frequency. The 10 mg / kg dose initially increased medium gamma peak frequency, but towards the end of infusion the peak frequency slowed relative to saline. The 1 mg / kg and 10 mg / kg doses of psilocybin decreased theta amplitude and increased medium and high gamma amplitudes relative to saline. The data are provided as mean ± standard error of the mean. *p<0.05, FDR- corrected post-hoc comparisons.

[0028] Figure 3 shows the effect of psilocybin on rat movement. 3D gyroscope activity averaged in 10- minute bins plotted as mean ± standard error of the mean. The 1 mg / kg dose briefly increased rat head movements, whereas the 10 mg / kg dose resulted in a quiescent state with minimal movement, thereby dissociating the increased gamma power from movement. *p<0.05, FDR-corrected post-hoc comparisons between saline and psilocybin doses.

[0029] Figure 4 shows intravenous psilocybin dose-dependently disrupts theta-gamma coupling. Following psilocybin infusion, both the 1 mg / kg and 10 mg / kg doses resulted in decoupling of theta phase from medium (A) and high (B) gamma amplitudes in a dose-dependent fashion. PAC was not altered by the 0.1 mg / kg dose. Each grid represents a 10-minute average of PAC values across all rats (n=12).Each square indicates an electrode in the layout described in Figure 1 . White and black asterisks: p<0.05, FDR-corrected post-hoc comparisons.

[0030] Figure 5 shows intravenous psilocybin induces broad reorganization of theta and gamma cortical connectivity patterns. wPLI connectivity differences between psilocybin and saline averaged across rats (n=12) and over 10-minute bins. Red lines indicate increased wPLI relative to saline, lines (blue in the original) indicate decreased wPLI. Dots indicate electrode location corresponding to the electrode map shown in Figure 1. Dot size indicates node degree magnitude. There is significantly increased node degree relative to saline. Only connections that were significantly different (p<0.05) from saline following FDR-correction are displayed. Beginning halfway through infusion, the 1 mg / kg psilocybin dose caused sparse increases in frontoparietal theta connectivity (A), increased medium gamma frontal connectivity, but decreased posterior connectivity (B), and caused broad frontoparietal increases in high gamma connectivity (C). The 10 mg / kg psilocybin dose had a similar effect on cortical connectivity, but was amplified in a dose-dependent fashion, in particular causing large increases in theta posterior connectivity (A), increasing, then decreasing medium gamma frontoparietal connectivity (B), and increasing frontoparietal high gamma connectivity (C).

[0031] Figure 6 shows projected psilocin I psilocybin dosing comparisons in humans.

[0032] Figure 7 shows initial pharmacokinetic modelling in humans for intravenous psilocin administration assuming a 20 minute loading dose and 120 minute maintenance dose.DEFINITIONS

[0033] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a statedelement, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The term "consisting of means "consisting only of, that is, including and limited to the stated element(s), integer(s) or step(s), and excluding any other element(s), integer(s) or step(s). The term "consisting essentially of means the inclusion of the stated element(s), integer(s) or step(s), but other element(s), integer(s) or step(s) that do not materially alter or contribute to the working of the invention may also be included.

[0034] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this specification.

[0035] Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements of the technology recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements.

[0036] In the context of the present specification the terms "a" and "an" are used to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, reference to "an element" means one element, or more than one element.

[0037] In the context of the present specification the term "about" means that reference to a figure or value is not to be taken as an absolute figure or value but includes margins of variation above or below the figure or value in line with what a skilled person would understand according to the art, including within typical margins of error or instrument limitation. In other words, use of the term "about" is understood to refer to a range or approximation that a person or skilled in the art would consider to be equivalent to a recited value in the context of achieving the same function or result.

[0038] The terms "treating", "treatment" and "therapy" are used herein to refer to curative therapy, prophylactic therapy, palliative therapy and preventative therapy. Thus, in the context of the present disclosure the term "treating" encompasses curing, ameliorating ortempering the severity of a medical condition or one or more of its associated symptoms.

[0039] "Subject" includes any human or non-human mammal. Thus, in addition to being useful for human treatment, the compounds of the present invention may also be useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs. In preferred embodiments the subject is a human.

[0040] In the context of this specification the term "administering" and variations of that term including "administer" and "administration", includes contacting, applying, delivering or providing a psilocin or psilocybin to a subject by any appropriate means.DETAILED DESCRIPTION

[0041] The invention will be described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modification may be made while remaining within the spirit and scope of the invention.

[0042] Despite increasing access, there remains a lack of practical guidance as to the appropriate dose of psilocybin or psilocin. This is particularly concerning given the medical complexity and vulnerable nature of patients for whom psilocybin-assisted psychotherapy is useful. To date the optimal blood levels required to achieve optimal efficacy and safety have not been identified. Use of real time EEG will assist in establishing this important correlation.

[0043] Due to psilocybin’s large therapeutic index (1 :1000) and a typically unattainable lethal dose, it has a favourable safety profile relative to other psychedelics (such as MDMA, DMT, etc.). Psilocybin has lower occurrence of seizures, hospital admissions and other serious adverse effects, and lacks addictive or reinforcing properties. The primary risk for psilocybin is psychological safety, not physiological safety as it is for most classic drugs (e.g., opioids, sedatives, stimulants). Unpleasant acute psychological experiences under psychedelics are not rare, even in research environments. For example, one study (Griffiths et al Psychopharmacology 187(3), 268-283 (2006)) reported an approximately 40% prevalence of moderate to severe anxiety, panic or distress with high dose psilocybin in healthy volunteers.Colloquially, these experiences are referred to as ‘bad trips’ but more formally, they are defined and measured as ‘challenging experiences’. The ability to avoid blood levels associated with these adverse events is also a benefit to the patient.

[0044] It has been found that there is a dose-response relationship for the use of psilocybin combined with psychotherapeutic support, with a curve that reaches a plateau (Perez et al, European Neuropsychopharmacology 76, 61-76, (2023). The optimal therapeutic dose, beyond which no further therapeutic gain is observed, depends on the specific patient population and confounding factors such as age and previous psychedelic experience, first pass metabolism and efficiency of converting psilocybin to psilocin.

[0045] Considering the increased use of psychedelics such as psilocybin, and the crucial aspect of the dose-relationship concerning efficacy and potential side-effects, there is a need to determine the optimal effective doses of psilocybin and psilocin for an individual subject.

[0046] The invention described herein is based on the inventor's finding that there are two distinct brain states for lower and higher doses of psilocybin which may be enabled by psilocybin-associated loss of local PAC-based modulation of theta and gamma band temporal dynamics. In this regard, while a subject may be administered psilocybin, this is rapidly converted to the active metabolite psilocin, which can cross the blood-brain barrier and cause the characteristic EEG changes observed by the inventors. The present inventors have demonstrated that the EEG changes in a dose-dependent manner thus it can be concluded that the changes are induced by administered psychedelic and that a preferred EEG pattern can be obtained by varying the dose, for example the preferred EEG patter may indicate a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes in the brain of a subject..

[0047] The inventor's observation of two distinct brain states for lower and higher doses of psilocybin supports the use of EEG as a real time means to identify optimal dosing to achieve optimal changes in EEG patterns and increase the likelihood of optimal long-term therapeutic benefit.

[0048] The invention provides a means to minimize the potential for adverse effects by identifying an optimal dose of psilocybin or psilocin for an individual subject by non-invasive monitoring or brain activityand is based on the observation by the inventors that psilocybin has a non-linear effect on brain network dynamics. In particular lower doses increase network density and decouple theta phase from gamma frequency while higher doses of psilocybin produce a brain state distinct from lower doses.

[0049] The methods allow real time monitoring for a subject and observation of an EEG 'signature' or 'biomarker' that corresponds not only with the psychedelic state but also the optimal psychedelic state provided by the optimal dose of psilocybin or psilocin that translates to therapeutic benefit.

[0050] In this context, an optimal dose refers to the amount of psilocybin or psilocin administered to a patient that causes enhanced neuroplasticity, that allows the subject to benefit from additional therapy such as psychotherapy while minimising the risk of psychological damage, self-perceived ‘negative’ psychological responses or other adverse effects.

[0051] In general, the methods described herein involve identifying an optimal dose of psilocybin or psilocin for an individual subject. After, or at the same time as administering a dose of psilocybin or psilocin to the subject, preferably by IV infusion, an electroencephalograph is used to measure the theta, medium gamma and high gamma bands of the subject. This measuring may be intermittent or continuous. In some embodiments the methods involve measuring theta, medium gamma and high gamma bands of the subject before administration of psilocybin or psilocin.

[0052] The inventors have found that an optimal dose of psilocybin or psilocin causes certain changes in network density, specifically a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes. Accordingly, the methods involve determining the density of posterior theta and frontal high gamma network and determining coupling status of theta phase and gamma amplitudes using the EEG.

[0053] A dose of psilocybin or psilocin that is non-optimal is either insufficient to cause the changes above, or is too great, in which case the doses result in one or more of the brain network state is dominated by the high gamma network; decreased posterior theta density compared to un-dosed or optimally dosed subjects; or weakened frontoparietal medium gamma connectivity compared to un-dosed or optimally dosed subjects.

[0054] Notably, the inventors have identified particular changes in network density in subjects who have received a relatively high dose of psilocybin. These include the brain network state being dominated by the high gamma network. Alternatively, or in addition, the posterior theta density is decreased compared to density observed at an optimal dose or in a subject that has not received a psychedelic. The frontoparietal medium gamma connectivity can also be weakened compared to density observed at an optimal dose or in a subject that has not received a psychedelic. If one or any combination of these is observed the methods include stopping or reducing the amount of psilocybin or psilocin administered to the subject.

[0055] The theta, medium gamma and high gamma bands of the subject can be observed using an EEG according to any known methods. In some embodiments the theta bands have a frequency of 4-10Hz. In some embodiments the medium gamma bands have a frequency of 70-110 Hz. In some embodiments the high gamma bands have a frequency of 110-150 Hz .

[0056] It will be understood that a skilled person will be adept at obtaining and interpreting electroencephalograms and will be able to operate an encephalograph to obtain electroencephalograms to measure the theta, medium gamma and high gamma bands.

[0057] As described herein an optimal dose of psilocybin or psilocin causes a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes.

[0058] In one embodiment a network is defined as a set of nodes (i.e., electrodes) that represent interconnected brain regions of the brain (see for example Figure 5).

[0059] The density of the network is a measure of how many connections are made to each node, which can be described as the 'node degree', i.e. the number of links connected to the node. Accordingly, one measure of network density can be node degree.

[0060] Node degree can be assessed by any means known in the art such as by using weighted phaselag index (wPLI). For example, to compute wPLI for a given pair of electrodes x and y, it is generally necessary to extract the signal of each electrode, this may required filtering (for example a FIR bandpass filter) and transformation (for example a Hilbert transform) of the monopolar EEG data. The complex conjugate of each pair can the be used to estimate the cross spectrum, Cxy. The component of Cxy, wPLI was then estimated as wPLIxyKM It may also be necessary to rule out spurious connectivity and this can be achieved, for example by shuffling the phases of each channel while maintaining the amplitude distribution to compute wPLIshuff. Repeating this procedure multiple times allows the mean,11sh , uff ’ and standard deviation,’ a s,hn„uffffto be clauclated and these can be used to determine normalized wPLIraw^shuff wPLI such that wPLInorm= - The channel-pair values of wPLInormcan then be averaged to^shuff estimate global wPLInorm. Local and global estimates of wPLInormcan then be averaged within a time perdiod (epoch). To compute node degree, binary undirected networks were computed from wPLInorm by binarizing each electrode matric (for example a 27 x 27 matrix) as used herein. Node degree is then computed by taking the sum of each row.

[0061] Accordingly, in one embodiment a high-density matrix is one with a node degree that is significantly increased (for example p<0.05) compared to the node degree before dosing.

[0062] As described herein an optimal dose of psilocybin or psilocin causes a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes.

[0063] A high-density posterior theta network refers to the network between the posterior nodes when measured using theta band, for example at a frequency of 4-10Hz.

[0064] A high-density frontal high gamma network refers to the network between the frontal nodes when measured using high gamma band, for example at a frequency of 110-150 Hz.

[0065] Oscillating neural activity can have higher-order interactions in which oscillations at different frequencies interact. This cross-frequency coupling (CFC) appears to be nearly as ubiquitous as oscillations themselves, occurring during learning and memory, varying across different states of arousaland unconsciousness, and changing in relation to neurological and psychiatric disorders. Distinct oscillations stem from specific neural circuit architectures and time constants and thus cross-frequency coupling serves as a way of coordinating activity among otherwise disparate circuits and system. In one type of interaction, the phase of a low-frequency wave (such as theta) modulates the amplitude of higher- frequency bands such as gamma. This type of cross-frequency coupling is known as phase-amplitude coupling. That is, phase-amplitude coupling (PAC) is the coupling of the phase of slower electrophysiological oscillations with the amplitude of faster oscillations.

[0066] Theta and gamma bands occur in the same brain regions and interact with each other, often called cross-frequency coupling or simply coupling. It has been postulated that the dual waves or bands form a code for representing multiple items in an ordered way and this coding scheme coordinates communication between brain regions and is involved in both sensory and memory processes. Without being bound by any particular mechanism the decoupling of the theta and gamma bands, particularly in the cortical regions of the brain, by an appropriate dose of psilocybin (or psilocin) is useful in psilocybin- assisted psychotherapy and assists with rectification of aberrant thinking patterns in a subject.

[0067] With reference to Figure 4, decoupling of theta phase from gamma amplitudes refers to the loss of interaction between theta and either or both of medium-gamma or high gamma bands. The decoupling may be complete in which all detectable coupling is lost across an EEG recording period. Alternatively, the decoupling may be incomplete in which the level of coupling is decreased compared to that observed before administration of psilocybin or psilocin

[0068] The methods described herein also provide that if the frontoparietal medium gamma connectivity is weakened compared to that observed at an optimal dose, then the administration of the psilocybin or psilocin is stopped or reduced.

[0069] Alternatively, one or more 5HT2A, 5HT1 A, 5HT2B / 2C, and / or D2 receptor antagonists may be administered to reverse or partially reverse the effects of psilocybin or psilocin. Suitable 5HT2A receptor antagonists include risperidone, olanzapine, mirtazapine or mianserin.

[0070] The frontoparietal network is a control network that is involved the ability to coordinate behaviour in a rapid, accurate, and flexible goal-driven manner by flexibly interacting with other control and processing networks. The slow-frequency components that define it are correlated with relatively slow oscillations in the frequency range sensitive to electrophysiological recordings (0 / a band) supporting its role in coordination of whole-brain network activity. Thus weakening of this network may be associated with a reduced ability to coordinate behaviour.

[0071] Weakening of the frontoparietal medium gamma connectivity can be observed (with reference to Figure 5) as the relative loss of connectivity between nodes. This weakening can be relative to the optimal dose, or relative to un-dosed subjects, or relative to pre-dose readings.

[0072] In embodiments where additional doses of psilocybin or psilocin have been administered to obtain an optimal dose, weakening of the frontoparietal medium gamma connectivity is an indication that the optimal dose has been exceeded and administration of psilocybin or psilocin can be stopped.Similarly, if an initial or single dose causes weakening of the frontoparietal medium gamma connectivity for example as seen in Figure 5, this is an indication that the optimal dose has been exceeded and administration of psilocybin or psilocin can be stopped. Alternatively as the half-life of psilocin is one tothree hours, the administration rate of psilocybin or psilocin can be reduced to move the dose administered to the subject back towards an optimal dose.

[0073] That is, the methods use intermittent or continuous EEG monitoring of the subject to allow titration of the dose of psilocybin or psilocin to achieve the EEG response described above, and avoid the EEG response associated with high doses of psilocybin or psilocin that may be indicative of adverse events.

[0074] The titration may involve increasing the infusion rate, decreasing the infusion rate, administering a bolus, or any combination thereof.

[0075] Additionally or alternatively domination of the brain network state by the high gamma network is an indication that the optimal dose has been exceeded and administration of psilocybin or psilocin can be stopped or the administration rate reduced to move the total dose administered to the subject back towards an optimal dose.

[0076] In this context domination of the brain network state refers to more than 50% of the network density is provided by the high gamma network.

[0077] Additionally or alternatively decreased posterior theta density compared to un-dosed or optimally dosed subjects is an indication that the optimal dose has been exceeded and administration of psilocybin or psilocin can be stopped or the administration rate reduced to move the total dose administered to the subject back towards an optimal dose.

[0078] In embodiments of the invention a 'dose' refers to a single dose, or an infusion of psilocybin or psilocin at a defined rate, for example via an intravenous route. Accordingly, in embodiments where the optimal dose has not yet been reached the infusion may be allowed to continue or the infusion rate increased. When the optimal dose is reached the infusion rate may be reduced to maintain the subject in a state characterised by a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes.

[0079] In embodiments where subjects are administered psilocybin or psilocin by infusion, the methods can involve reducing the infusion rate, or temporarily suspending the infusion if any one or any combination of the following is observed: the brain network state is dominated by the high gamma network; the posterior theta density is decreased compared to density observed at an optimal; the frontoparietal medium gamma connectivity is weakened compared to that observed at an optimal dose.

[0080] It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0081] In order that the present technology may be more clearly understood, preferred embodiments will be described with reference to the following examplesEXAMPLES

[0082] The present invention will now be illustrated by the following examples, which are not to be construed as limiting the present invention in any manner and are only examples of the various embodiments described herein.

[0083] The inventors used cortex-wide high-density (27 electrodes) electroencephalographic recordings to characterize the effect of psilocybin (0.1 mg / kg, 1 mg / kg, and 10 mg / kg) delivered intravenously over one hour, in Sprague Dawley rats (n=6 male and 6 female). First spectral decomposition of the electroencephalogram (EEG) data was performed to identify the primary oscillatory components that responded to psilocybin administration. These analyses showed that psilocybin altered three oscillatory components in the theta (4-10 Hz), medium gamma (70-110 Hz), and high gamma (110-150 Hz) bands, which were used for further analyzing the changes in phase-amplitude coupling and network organization. Psilocybin disrupted theta-gamma coupling and induced multiscale reorganization of cortical connectivity as shown by simultaneous increase in frontal high gamma connectivity and posterior theta connectivity, and a decrease in posterior medium gamma network connectivity. The results presented herein show increased posterior theta and frontal high gamma network density, which is a measure of the number of functional connections at any given electrode. These findings illustrate that high-frequency network reorganization, decoupled from local theta-phase, is an important signature of the psychedelic state produced by psilocybin.Example 1 : Methods

[0084] Adult Sprague Dawley rats (n=12, 6 female, 6 male, weight 300-350g, Charles River Laboratories Inc., Wilmington, MA) maintained on 12:12 light: dark cycle (lights on at 8:00 am) and with ad libitum food and water, were used for all experiments. The experiments were approved by the Institutional Animal Care and Use Committee at the University of Michigan, Ann Arbor, and were conducted in compliance with the Guide for the Care and Use of Laboratory Animals (Ed 8, National Academies Press) and ARRIVE Guidelines.Surgical procedures

[0085] Under surgical isoflurane (Piramal Enterprises, Telangana, India) anesthesia, rats were implanted with stainless steel screw electrodes (J. I. Morris Miniature Fasteners, Oxford, MA, USA; #FF000CE094) to record electroencephalogram (EEG) from 27 sites across the cortex and bilateral wire electrodes (Cooner Wire Company, Chatsworth, CA, USA; # AS 636) to record electromyogram (EMG) from dorsal nuchal muscles. An in-dwelling chronic catheter (Micro-Renathane tubing, MRE-040, Braintree Scientific, MA) was positioned in the jugular vein for infusion of psilocybin (Cayman Chemical, Ml; CAS 520-52-5) and 0.9 % saline (Hospira, Lake Forest, IL, USA; #00409-4888-20). The jugular venous catheter was flushed with 0.2 mL of heparinized (1 unit / mL, Sagent Pharmaceuticals, Schaumburg, IL) saline and locked with 0.05 mL of Taurolidine-Citrate Catheter lock solution (TCS-04, Access Technologies, Skokie, IL) every 5-7 days to maintain catheter patency. Subcutaneous buprenorphine hydrochloride (Buprenex ®, Reckitt Benckiser Pharmaceuticals Inc., Richmond, VA; 0.01 mg / kg) and carprofen (Hospira, Inc., Lake Forest, IL; 5 mg / kg) were used for pre-surgical analgesia. Post-surgical analgesia was achieved with buprenorphine hydrochloride (0.03 mg / kg) administration every 6-8 h for 48 h. All rats were allowedat least 7-10 days of post-surgical recovery, during which they were conditioned to the EEG acquisition system.Experimental design

[0086] The experimental design is illustrated in Figure 1 . All experiments were conducted between 9:00 am and 2:00 pm. On the day of the experiment, rats were connected to the EEG recording system and allowed to habituate for a minimum of 1 h. Following habituation, baseline EEG was acquired for 20 minutes. Thereafter, one of the three doses of psilocybin (0.1 , 1 .0, or 10 mg / kg) was delivered (intravenous) over an hour. On a separate day, the rats received 0.9% saline (vehicle control) for over an hour. The EEG data were collected continuously throughout the baseline, psilocybin / saline delivery, and for 60 minutes post-infusion. To maintain a constant behavioural state, rats were kept awake throughout the procedure with gentle tapping on the recording chamber. All rats received each of the three doses of psilocybin as well as vehicle control (0.9% saline), in a counter-balanced manner with a minimum of 5-7 days in between experiments to allow for drug washout.Electrophysiological data acquisition

[0087] Electrophysiological signals were recorded using the Cereplex Direct recording system (Blackrock Neurotech, Salt Lake City, UT). Monopolar EEG (0.1-300 Hz, sampling rate 1 kHz) and bipolar EMG (bandpass filtered between 0.1 and 125 Hz and sampled at 500 Hz) were recorded continuously throughout the experiment. The recording head-stage was equipped with a motion sensor for which the data were bandpass filtered between 0.1-50 Hz and sampled at 500 Hz. EEG data were manually inspected for quality; segments or channels with excessive noise were excluded from further analysis. Finally, EEG data were downsampled to 500 Hz prior to computational analysis.Spectral analysis

[0088] Spectral characteristics of the EEG data were estimated at each channel in 2-second nonoverlapping windows using a multitaper wavelet decomposition as implemented in Fieldtrip (Oostenveld, et al. Comput. Intell. Neurosci. 2011 , (2011)) Using the FOOOF algorithm (Donoghue, T. et al. Nat. Neurosci. 20202312 23, 1655-1665 (2020)) we estimated the aperiodic offset and aperiodic exponent of the power spectrum and removed the 1 / f component to facilitate peak frequency detection. Maximum peaks were estimated for the theta (4-10 Hz), medium gamma (70-110 Hz), and high gamma (110-150 Hz) bands. For statistical analysis, frequency band amplitude and peak frequency were averaged across 10-minute non-overlapping windows and across channels for global analysis.Phase-amplitude coupling

[0089] Phase-amplitude coupling (PAC) was estimated for artifact-free 10-second epochs according to the method first described by Canolty (Canolty, et al. Science 313, 1626-1628 (2006)), and expanded by Onslow (Onslow, et al., Prog. Biophys. Mol. Biol. 105, 49-57 (2011)). PAC was computed between low frequencies (LF), bandpass filtered in 2 Hz steps, centered from 2 to 18 Hz, and high frequencies (HF), bandpass filtered in 5 Hz steps, centered from 27 to 197 Hz. Data were filtered and converted into analytic signals using a wavelet convolution (Morlet wavelet, width=7). The instantaneous phase, 0, and amplitude, A, were extracted from each signal and combined to create a third composite signal, X, such that X(t) = AHF(t)eieLF(t)where t is time. In a given window and channel, PAC was calculated asPACraw= |n1£"=iX(t) | where n is the number of samples in a window. To ensure that values of PAC are independent of large power fluctuations or nonuniform phase distributions, we then applied permutation testing to generate normalized values of PAC in each window and channel. In each window, the amplitude time series extracted from the Morlet wavelet transformation were shuffled prior to computing a new PAC value, PACshuff. This procedure was repeated 50 times, then the mean, pshuff, andPAC yaw P huff standard deviation, <rshuff, were used to compute normalized PAC such that PACnorm= - Mean^shuffPACnorm was computed for each 10-minute epoch at each channel and at the global level. PACnorm values in specific frequency band pairs, e.g. theta-medium gamma coupling, were computed by averaging PACnorm values within each frequency-frequency range.Weighted phase-lag index

[0090] Weighted phase-lag index (wPLI) is a measure of functional connectivity that estimates the consistency of the phase relationship between two signals and is robust to volume conduction. To compute wPLI for a given channel pair of electrodes x and y, the inventors first applied a FIR bandpass filter and Hilbert transform to the monopolar EEG data to extract the analytic signal of each electrode.The complex conjugate of each channel pair was next computed to estimate the cross spectrum, Cxy.Next, taking the imaginary component of Cxy, wPLI was then estimat Mled as wPLIxy. To ruleE{|M out spurious connectivity due to the spectral distribution, the phases of each channel were shuffled while maintaining the amplitude distribution, using an FFT-based approach to compute wPLIshuff. Analogous to the approach taken with PAC, this procedure was repeated 50 times, then the mean, pshuff, and standard wPLIrawPshuff deviation, <rshuff, were used to compute normalized wPLI such that wPLInorm= - Thechannel-pair values of wPLInormwere averaged to estimate global wPLInorm. Local and global estimates of wPLInormwere averaged within each 10-minute epoch for statistical analysis. Finally, to compute node degree, binary undirected networks were computed from wPLInorm by binarizing each 27 x 27 matrix according to a threshold of p=0.05, equivalent to wPLInorm=1 .67. Node degree is then computed by taking the sum of each row.Statistical analysis

[0091] Statistical analyses were conducted in consultation with the Consulting for Statistics, Computing and Analytics Research unit at the University of Michigan (Ann Arbor, Michigan) using R (version 4.0.2). To facilitate statistical analysis, each EEG measure was averaged into 10-minute non-overlapping windows. Linear mixed models were computed at the global level for spectral analysis with rat as a random factor and i) dose, ii) time, iii) weight, and iv) sex as fixed factors. For channel-level analysis, the model was repeated for each channel, post-hoc comparisons between saline and each drug condition were extracted, and associated p-values were false discovery rate (FDR)-adjusted with an alpha=0.05.Example 2: Results and Discussion

[0092] All rats were implanted with electrodes to record EEG from across the cortex and received an hour-long intravenous infusion of three different doses of psilocybin and 0.9% saline (vehicle control), in acounterbalanced manner with at least 5-7 days of inter-experiment interval. The analysis was focussed on 90 minutes of EEG data comprising a 10-minute pre-psilocybin infusion baseline period, 60 minutes spanning the intravenous psilocybin (0.1 mg / kg, 1 mg / kg, and 10 mg / kg) or 0.9% saline infusion time, and 20 minutes immediately after the end of psilocybin or saline infusion (Figure 1).Psilocybin altered spectral power in theta and gamma bands and dynamically shifted dominant EEG frequencies.

[0093] Comparisons of the power spectrum between each dose of psilocybin and saline control indicated that psilocybin-related changes in spectral characteristics are not broadband but localized in frequency space and shifting overtime (Figure 2A-C). In order to focus our analysis on the localized oscillatory changes, we applied the FOOOF algorithm (Donoghue, T. et al. Nat. Neurosci. 2020231223, 1655-1665 (2020)) to all EEG data. The FOOOF algorithm removes the aperiodic (1 / f) component from the power spectrum, enabling unbiased estimation of the peak frequency and amplitude of oscillatory components (for representative spectral detrending see Figure 2D). This step is crucial to avoid confounding a change in the oscillatory peak frequency and amplitude with a change in the broadband component. Detrending the power spectrum revealed that the primary oscillatory components affected by psilocybin infusion corresponded to the theta (4-10 Hz), medium gamma (70-110 Hz), and high gamma (110-150 Hz) bands (Figure 2D).

[0094] Analysis of the peak frequency and amplitude of each component over the duration of the recording period showed that there was no statistically significant effect of 0.1 mg / kg psilocybin infusion on EEG oscillatory components (p>0.05), but clear dose-dependent effects were observed during both 1 mg / kg and 10 mg / kg infusions (Figure 2E-J). Relative to saline infusion, peak frequency in the theta band (Figure 2E) briefly increased 10 minutes after the start of 1 mg / kg psilocybin infusion (p=0.0074), while the 10 mg / kg psilocybin produced a sustained decrease in theta peak frequency beginning after 30 minutes of infusion. The peak frequency in medium gamma band (Figure 2F) was significantly increased after 10 minutes of 1 mg / kg psilocybin infusion, which remained elevated (p<0.039) for the duration of the infusion period. By contrast, the peak frequency in the medium gamma band (Figure 2F) showed a significant increase within the first 10 minutes of 10 mg / kg psilocybin infusion. The increase lasted for 40 minutes of infusion (p<0.0014), after which the peak frequency decreased below saline levels (p<0.0018). Finally, the high gamma peak frequency (Figure 2G) showed a transient decrease after 10 minutes of 1 mg / kg psilocybin infusion (p=0.036), and a sustained decrease after 30 minutes of 10 mg / kg psilocybin (p<0.0026).

[0095] In addition to altering the peak oscillating frequency in theta, medium gamma, and high gamma bands, psilocybin infusion dose-dependently altered the peak amplitude in these bands. Relative to saline infusion, theta peak amplitude (Figure 2H) decreased after 40 minutes of 1 mg / kg psilocybin infusion (p<0.020) and after only 10 minutes of 10 mg / kg psilocybin infusion (p<0.039). In contrast, the peak amplitude in the medium gamma band (Figure 2I) showed a significant increase (p<0.0032) after 20 minutes of 1 mg / kg psilocybin infusion and within 10 minutes of 10 mg / kg psilocybin (p<0.00050), both of which remained elevated for the duration of the recording. Similarly, peak amplitude in the high gamma band (Figure 2J) showed a significant increase (p<0.044) after 30 minutes of 1 mg / kg psilocybin infusion and within 10 minutes of 10 mg / kg infusion (p<0.040), after which high gamma power remained elevated throughout the recording period (Figure 2J).

[0096] To reveal the relationship between changes in medium and high gamma power, and rat movement, we quantified rat activity - body or head movements - using a gyroscope built into the recording head-stage. Analysis of the mean 3D angular velocity throughout the recording session showed that rat movement was dissociated from the changes in theta and gamma-band power (Figure 3). As compared to saline infusion, 0.1 mg / kg psilocybin had no effect on rat movement (p>0.05). The 1 mg / kg dose induced a brief period (~10 minutes) of increased movements after 10 minutes of infusion (p=0.0069), after which the level of movement returned to that observed after saline infusion. The 10 mg / kg psilocybin produced a significant decrease in rat movements between 30-60 minutes of infusion (all p<0.023).

[0097] In summary, spectral analysis of EEG dynamics during continuous psilocybin infusion indicated two distinct EEG states during the 10 mg / kg infusion. The initial period during 10 mg / kg infusion and later period during 1 mg / kg infusion were characterized by decreased theta and increased medium and high gamma power, along with a faster medium gamma peak frequency. As the 10 mg / kg infusion continued, it diverged from the lower dose, characterized by slowing theta and gamma peak frequencies and a notable increase in high gamma power. These data suggest that increasing doses of psilocybin may not have a linear effect on brain oscillatory dynamics.Psilocybin disrupted theta-gamma coupling in a dose-dependent manner

[0098] Theta- and gamma- range oscillations are known to be phase-amplitude coupled, with the phase of theta acting as a timing mechanism for local gamma amplitude. This coupling is believed to support cognitive functions, such as memory and attention, and is altered during changes in states of consciousness. Furthermore, recent studies have reported altered timing between spikes and the phase of local field potentials in rodents during lysergic acid diethylamide (LSD) and 2,5-Dimethoxy-4- lodoamphetamine (DOI) administration. As compared to saline infusion, 0.1 mg / kg psilocybin did not produce any statistically significant changes in either theta-medium gamma or theta-high gamma PAC (p>0.05; Figure 4). In contrast, both 1 mg / kg and 10 mg / kg psilocybin infusion diminished theta-medium gamma PAC across the entire cortex (Figure 4A). After 20 minutes of 1 mg / kg infusion, there was a decrease in theta-medium gamma PAC in the extreme frontal (p<0.047) and posterior / occipital areas (p<0.049), which, during the last 20 minutes of 1 mg / kg infusion, spread to the rest of the cortex (p<0.045). The PAC values started to recover back to saline values after the cessation of psilocybin infusion but remained significantly low at the end of 20 minutes post-psilocybin period (p<0.038). The effect of 10 mg / kg psilocybin on theta-medium gamma PAC (Figure 4A) was similar, but the onset time was faster (10 minutes after 10 mg / kg vs 20 minutes after 1 mg / kg psilocybin). Interestingly, theta-high gamma PAC (Figure 4B) was only mildly affected by 1 mg / kg of psilocybin and with late onset (after 40 minutes of infusion). The decrease was restricted primarily to the frontal regions (p<0.050), which returned to saline values within 10 minutes after cessation of psilocybin infusion. The 10 mg / kg dose of psilocybin showed a much stronger effect on theta-high gamma PAC, which showed wide-spread decreases across the cortex after 10 minutes of infusion (p<0.048) and which remained significantly low through the post-infusion period (Figure 4B). In summary, psilocybin infusion dose-dependently disrupted local theta-gamma coupling across the cortex, but particularly in frontal cortex, potentially dysregulating information coordination.Psilocybin induced multi-scale reorganization of cortical connectivity in a dose-dependent manner

[0099] Functional network reorganization is a key component of current neuronal models of the psychedelic state. Therefore, the inventors assessed if the psilocybin-induced dysregulation of local timing between theta and gamma oscillations is accompanied by reorganization of connectivity patterns and network structure in these frequency bands. To characterize psilocybin-induced changes in network organization, node degree was assessed. Node degree is an index of network density or the number of functional connections at a given electrode, and edge-wise wPLI-based connection strength (Figure 5), before, during, and after psilocybin infusion.

[0100] In accordance with the spectral and PAC analyses, there was no effect of 0.1 mg / kg psilocybin infusion on network density or network connectivity strength in any of the bands measured, while both 1 mg / kg and 10 mg / kg infusions resulted in pronounced multiscale network alterations (Figure 5). The posterior theta network density (Figure 5A) was transiently increased after 60 minutes of 1 mg / kg psilocybin infusion, before returning to saline levels within 20 minutes post-infusion (p<0.045). By contrast, the 10 mg / kg psilocybin infusion rapidly increased theta network density, particularly at posterior electrodes, within 10 minutes of infusion (p<0.046). This effect peaked after 20 minutes of infusion and returned to saline levels after 40 minutes of infusion. Paralleling the observed changes in theta network density, during the 1 mg / kg infusion, frontoparietal theta network connectivity was strengthened only across a few electrodes starting after 30 minutes infusion (p<0.047), whereas the 10 mg / kg psilocybin infusion showed a strong, dynamic effect on theta frontoparietal networks. Theta connection strength increased within 10 minutes of 10 mg / kg infusion (p<0.049), peaked after 30 minutes of infusion, then began to decrease, returning to saline levels by 20 minutes post-infusion.

[0101] Unlike the theta network, none of the psilocybin doses altered medium gamma network density relative to saline (p>0.050; Figure 5B). Although network density was constant, both the 1 mg / kg and 10 mg / kg doses of psilocybin had a biphasic effect on medium gamma frontoparietal network strength. Medium gamma frontal network synchronization was initially strengthened beginning after 20 and within 10 minutes of 1 mg / kg and 10 mg / kg infusions, respectively (p<0.050). After continued infusion, both the 1 mg / kg and 10 mg / kg doses of psilocybin induced widespread weakening of posterior-clustered medium gamma network connections beginning after 30 and 10 minutes of infusion, respectively (p<0.050).

[0102] High gamma network density and synchronization were strongly affected by psilocybin infusion (Figure 5C). Compared to saline, psilocybin caused a widespread increase in network density and synchronization strength, particularly in long-range connections to and from the frontal cortex, reflecting a marked change in brain network organization. Both the 1 mg / kg (p<0.049) and 10 mg / kg (p<0.050) doses of psilocybin infusion resulted in increased frontal and posterior node degree beginning after 20 and 10 minutes of infusion, respectively. Similarly, local- and long-range frontoparietal synchronization was increased by both 1 mg / kg (p<0.050) and 10 mg / kg (p<0.048) doses, again in a dose-dependent manner, beginning after 20 minutes and within 10 minutes of infusion, respectively.

[0103] In summary, psilocybin / psilocin strengthened and broadened the frontal high gamma network in a dose-dependent manner, whereas psilocybin dose has a nonlinear effect on both posterior theta network density and connection strength, as well as medium gamma frontoparietal connectivity, suggesting twodistinct states for lower and higher doses of psilocybin. These reorganized connectivity patterns are enabled by psilocybin-associated loss of local PAC-based modulation of theta and gamma band temporal dynamics.

[0104] The rodent model of psychedelic-related network dynamics described herein was used to establish that intravenous psilocybin infusion has a nonlinear effect on brain network dynamics, resulting in two distinct brain network configurations that emerged over the course of infusion. The 1 mg / kg infusion and the first half of the 10 mg / kg infusion period were primarily characterized by a high-density posterior theta and frontal high gamma network, with strengthened frontoparietal medium gamma connectivity, and cortex-wide decoupling of theta phase from gamma amplitudes. During the later portion of the 10 mg / kg infusion, the brain network state became dominated by the high gamma network as the posterior theta density decreased and frontoparietal medium gamma connectivity continued to weaken.

[0105] This is the first study to report network dynamics during psilocybin administration in rodents. A notable feature of the network results presented herein is the simultaneous change in the theta posterior network and the frontal high gamma network, which partially overlap. Several reports of human fMRI data indicate that psilocybin likely results in a reorganization of functional network topology. The increased frontal high gamma network density, nonlinear changes in posterior theta network density, and broad remodulation of frontoposterior connectivity strengths across theta and gamma bands are consistent with human fMRI data indicating increased long-range between-network connectivity as well as reports that during psilocybin administration the spatial distribution of long-range networks varies overtime.

[0106] The increased high gamma network activation and associated increased gamma power also has relevance for the neuroplastic effects of psilocybin / psilocin and links psychedelic-induced high gamma activity to changes in neuroplasticity.

[0107] Overall, the results presented herein demonstrate nonlinear, multiscale changes in network organization with two distinct phases of theta network density and medium gamma network strength. This illustrates that rather than having a linear effect on brain network dynamics, higher doses of psilocybin produce a brain state distinct from lower doses.Example 3: Human Study

[0108] This proposed study will involve intravenous administration of psilocin in 3 cohorts of healthy men and women 18 to 55 years of age, inclusive. Three cohorts are planned but additional intermediate cohorts may be added, or a dose may be repeated as needed. A participant who does not receive the full infusion for reasons other than safety may be replaced. Participants will be prescreened for interest and eligibility and, after completion of the informed consent form (ICF), will complete screening assessments. In each cohort, the 3 participants will receive psilocin IV infusion in an open label fashion. At least a 24- hour interval will be scheduled between the start of psilocin administration for the first and later participants within a cohort.

[0109] In Cohort 1 , participants will receive a total of 7.5 mg psilocin; Cohort 2 will receive a total of 10 mg psilocin, and Cohort 3 will receive a total of 14.5 mg of psilocin. In particular, cohort 1 will receive 7.5 mg total psilocin (1 .5 mg / 20 minutes [0.075 mg / min] + 6 mg / 120 minutes [0.05 mg / min]). Cohort 2 will receive 10 mg total psilocin (5 mg / 20 minutes [0.15 mg / min] + 5 mg / 120 minutes [0.09 mg / min]). Cohort3 will receive 14.5. mg total psilocin (8 mg / 30 minutes [0.225 mg / min] + 6.5 mg / 120 minutes [0.13 mg / min]).

[0110] Participants will be monitored by EEG before and during psilocin administration and theta, medium gamma and high gamma bands of the subject will be measured. These will be used to determine the density of posterior theta and frontal high gamma network and the coupling status of theta phase and gamma amplitudes. This will be used to determine the optimal dose that causes a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes.

[0111] The initial 20-30 minute loading dose infusion will provide a therapeutic dose of psilocin that will be maintained by infusing 6 mg, 5 mg, or 6.5 mg psilocin by IV over 120 minutes.

[0112] The ascending doses are chosen for evaluation in the current clinical study were determined using published studies in healthy volunteers. In one study, a single escalating dose of orally administered psilocybin (0.3, 0.45, and 0.6 mg / kg) was used to evaluate the PK in 12 healthy adults. The PK of psilocin were linear within the 2 fold range of doses, and the t1 / 2 of psilocin was approximately 3 hours (SD 1 .1). The Cmax of plasma psilocin after oral doses were as follows:16 ng / mL (±14.5 to 17.2) at 0.3 mg / kg26 ng / mL (±22.7 to 35.1) at 0.45 mg / kg37.6 ng / mL (±27.7 to43.2) at 0.6 mg / kg

[0113] The estimated blood concentration over time for IV infusion of 2.5 mg psilocin over 60 minutes versus oral administration of 15 or 25 mg psilocybin as presented in Figure 6, the dose range used in published studies. Time 0 on the graph is adjusted to represent the timepoint plasma psilocin is first detectable. This model predicts that plasma psilocin levels will decrease more sharply after the end of drug infusion than seen with oral dosing. The plasma psilocin levels after IV infusion are expected to return to undetectable levels much faster than oral psilocybin administration due to the latter’s prolonged absorption phase.

[0114] Figure 7 provides PK modelling for dose regimens to be employed in the proposed study, with mean concentration-time profile for each psilocin dose showing dose-proportional plasma psilocin concentrations over time for the 3 dose levels targeting psilocin blood levels of 10 ng / mL, 20 ng / mL, and 30 ng / mL.From a clinical research perspective, psilocin provides a mechanism to explore both the depth and duration of the psychedelic experience and how these parameters affect clinical outcomes. Infusing psilocin with a 1 .5, 3, or 4.5 mg infusion over the first 20 minutes (loading dose) allows attainment of Cmax in a controlled protocol and subsequent infusions of 6, 11 , or 16 mg over 120 minutes allows for maintenance of the psychedelic experience at a therapeutic dose. IV administration allows for the physician to control and optimize the psilocin dose and exposure. Collecting EEG data (intermittent or in real time) provides an objective means of monitoring when a subject enters the the psychedelic state. Furthermore such EEG monitoring provide a means to assess whether a subject is in an optimal psychedelic state and thus allows the dose of psilocybin or psilocin to be adjusted to achieve and maintain an optimal psychedelic state.

Claims

CLAIMS:

1. A method of identifying an optimal dose of psilocybin, psilocin or combination thereof for a subject, the method comprising a. administering a dose of psilocybin, psilocin or a combination thereof to the subject; b. measuring theta, medium gamma and high gamma bands of the subject using an electroencephalograph (EEG) c. determining the density of posterior theta and frontal high gamma network using the EEG, and determining coupling status of theta phase and gamma amplitudes using the EEG wherein the optimal dose causes a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes.

2. A method of inducing a high-density posterior theta network, a high-density frontal high gamma network, and decoupling of theta phase from gamma amplitudes in the brain of a subject, the method comprising d. administering a dose of psilocybin, psilocin or a combination thereof to the subject; e. measuring theta, medium gamma and high gamma bands of the subject using an electroencephalograph (EEG) f. determining the density of posterior theta and frontal high gamma network using the EEG, and determining coupling status of theta phase and gamma amplitudes using the EEG. wherein an optimal dose of psilocybin, psilocin or a combination thereof induces the high-density posterior theta network, the high-density frontal high gamma network, and the decoupling of theta phase from gamma amplitudes.

3. The method of claim 1 or 2, wherein the decoupling of theta phase from gamma amplitudes is substantially cortex-wide.

4. The method of any one of claims 1 to 3, wherein the decoupling of theta phase from gamma amplitudes is complete or partial.

5. The method of any one of claims 1 to 4, wherein the dose of psilocybin or psilocin is administered by intravenous infusion.

6. The method of any one of claims 1 to 5, wherein, if the dose of psilocybin, psilocin or a combination thereof is the optimal dose, the method further comprises administering additional psilocybin,psilocin or a combination thereof to maintain in the subject a high-density posterior theta network, a high- density frontal high gamma network, and decoupling of theta phase from gamma amplitudes.

7. The method of claim 6, wherein the administering additional psilocybin, psilocin or a combination thereof comprises reducing the infusion rate, reducing the concentration of the psilocybin, psilocin, or combination thereof in the infusion, or both.

8. The method of any one of claims 1 to 4, wherein if the dose of psilocybin, psilocin or combination thereof is not the optimal dose, the method further comprises administering an additional dose of psilocybin, psilocin or a combination thereof and repeating steps b and c.

9. The method of any one of claims 1 to 8, wherein if the brain network state is dominated by the high gamma network then administration of the psilocybin, psilocin or combination thereof is stopped or reduced.

10. The method of any one of claims 1 to 9, wherein if the posterior theta density is decreased compared to density observed at an optimal dose then the administration of the psilocybin, psilocin or combination thereof is stopped or reduced.11 . The method of any one of claims 1 to 10, wherein if the frontoparietal medium gamma connectivity is weakened compared to that observed at an optimal dose, then the administration of the psilocybin, psilocin or combination thereof is stopped or reduced.

12. The method of any one of claims 1 to 11 , wherein the density of the posterior theta network and / or the frontal high gamma network are characterized by a node degree that is significantly increased compared to the node degree before administration of the dose of psilocin, psilocybin or combination thereof.

13. The method of any one of claims 1 to 12, wherein the optimal dose causes an increased frontal and / or posterior node degree compared to a subject that has not been administered psilocybin, psilocin or combination thereof.

14. The method of any one of claims 1 to 13, wherein the optimal dose causes an increase in local- and / or long-range frontoparietal synchronization compared to a subject that has not been administered psilocybin, psilocin or combination thereof, or compared to pre-dose readings.5 The method of any one of claims 1 to 14, wherein the theta bands are measured at a frequency of 4-10Hz.

16. The method of any one of claims 1 to 15, wherein the medium gamma bands are measured at a frequency of 70-110 Hz.

17. The method of any one of claims 1 to 16, wherein the high gamma bands are measured at a frequency of 110-150 Hz .

18. The method of any one of claims 6 to 17, wherein the additional psilocybin, psilocin or combination thereof is administered by intravenous infusion.

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