“Hallucinogenic Compounds use as Target Models for Schizophrenia By Blake Endres”



Model psychosis is the use of psychoactive and hallucinatory compounds for empirically
understanding via experimentation the cellular mechanics and behavioral manifestations in relation to developed disorders of atypical perceptual/delusional/hallucinatory thoughts, such as is the case in Schizophrenia. In recent years, with the advantageous aspect of increasing technological methods, certain hypothesis are being questioned; chief among them, the dopamine hypothesis. In regard to a paradigm shift, the (5-HT 2A) serotonin hypothesis stands rather prominent. As stated by the Research Department of Psychiatric University Hospital Zürich, Switzerland, “Support for this hypothesis stems from observations that schizophrenia patients show alterations in cortical serotonin receptor binding; novel atypical antipsychotics have potent antagonistic action at 5-HT2A receptors; and classic indoleamine hallucinogens, which interfere with the serotonin system, can elicit schizophrenia-like symptoms in humans.”. The similarity present in the relationship between 5-HT2 agonist effects and natural effects seen in early stages of Schizophrenia are extremely interesting to the possible connection of the two conditions. Given the circumstance that there is a relation between the neuropharmacological aspect of psilocin and Schizophrenic psychosis, it could incite new areas of interest, such as:understanding how neuronal networks are instrumental for the specifics of induced individual psychosis. The discussion in this article contains the investigation of the possible ways to record the similarities between Schizophrenic psychosis and psilocybin induced psychosis, by the following methods:Functional Magnetic Resonance Imaging with functional connectivity between target areas {FMRI)-FC}, and dose-dependent antagonistic serotonin-2A ketanserin during psilocin agonism/Schizophrenic psychosis.


In many cases with people who are afflicted with pathological psychosis, the observation of psychoses are severely limited to direct behavioral observation and self report documentation from the patient. This is a very inefficient and ineffective way to document variety of psychosis that is occurring within the patient, and does not allow for further progression in understanding the pathology behind the psychosis. If discriminant variety of psychosis can be observed in a multitude of ways, then a biological connection could be found and traced between induced and disordered psychosis. Successively, if a consistent pattern of observed pathological psychosis is documented for a specific variety of psychosis, then it can be used as a model comparison for disordered psychosis. Model psychosis is a synthetic version of recreating Schizo-type behavior and hallucinatory occurrences with the use of psychoactive compounds such as MDMA, amphetamines, cannabinoids, and psilocin, which all are analogs or isotopes of endogenous neurotransmitters.

The goal of model psychosis, is to present an empirical object to directly study all of its effects in relation to a comparison to the controlled variable of schizophrenic variety psychosis. But first, the controlled variable of Schizophrenic psychosis must be explained in biological mechanisms and traced neuronal network in innervation sites, so that an accurate comparison may be issued with confidence, rather than speculation. With the many different hypothesis for Schizophrenia, it is extremely hard to determine a fundamental basis on which to compare biological/pathological mechanisms on model psychosis neural innervation to Schizophrenia neural innervation. Since the target compound of choice for this article, psilocin, is a 5-HT2a agonist,the fundamental basis for biological comparison will be with the serotonin system recently thought to be involved in Schizophrenia. Thus all the representative data found via the chosen methods in model psychosis studies pertaining to the serotonin system will be superimposed on data found in Schizophrenic psychosis using the same methods, for an ideal isolated comparison.

FMRI on target areas of interest

Topic preliminary questions to think about: 1. Will the idea of superimposed FMRI activity orthogonality result in any noticeable similarities when using two different people for the comparison, as in one patient with induced psychosis and one patient with Schizophrenic psychosis. Meaning, will each individual’s connectome provide enough microstructural similarity to accurately propose a valid means of comparison?

        In an extensive study conducted by Centre for Neuropsychopharmacology, Imperial College London, on the functional connectivity between target areas of interest (AoI) pre and post intravenous injection of psilocybin, the study was meant to measure the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC). With primary analysis focused on the changes caused by psilocybin on functional connectivity in the default-mode network (DMN) which supplements introspection, and the task-positive network (TPN) which support externally focused attention ( Carhart-Harris et al.2013) . While the DMN and TPN are polar opposites in functionality, they interestingly enough show orthogonality in fMRI time series in spontaneous activity (Carhart-Harris et al.,2013). Meaning that in fMRI time series studies, spontaneous activity in both DMN and TPN overlap in sensory mapping, even when both networks individually uphold different functions. The DMN consists of many regions that all retain relative functional connectivity to each other. The anatomical subsections that derive the DMN are as follows: posterior cingulate cortex; medial prefrontal cortex, mPFC; and lateral inferior parietal cortex (Carhart-Harris et al.,2013). The idea of measuring the functional connectivity between DMN and TPN in detail, was due to some previously learned data sets that show increased FC within the DMN and TPN is seen in psychotic, mediatory and sedative states, which is similar to the classical psychedelic state induced by hallucinogenic compounds, like psilocin.

        From the premises mentioned above, the research group at Imperial College London (Carhart-Harris et al.,2013), was able to conclude the following ideas:

 1.)           “ DMN-TPN FC is related to the separateness of internally and externally focused states.   We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenology and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

2.) “  If, however, activity in the DMN and TPN was to become less orthogonal, then this might cause a confusion of states and a disturbance of cognition such as is seen in early psychosis.”

An unfortunate fact that persists to surface in this field of research, is the lack of pre-existing baseline mechanic explanations for a disordered pathophysiology for use in comparison with the model data found. Thus, in this case, “early psychosis” remains as an undefined variable.

Psilocin effect on FC within the DMN and TPN

Topic hypothesis: “If, however, activity in the DMN and TPN was to become less orthogonal, then this might cause a confusion of states and a disturbance of cognition such as is seen in early psychosis.”

        The test subjects consisted of 13 males and 2 females (mean age = 32, standard deviation of 8.9) , all of which were inexperienced with hallucinogenic drugs. fMRI tests implemented for DMN- TPN FC consisted of a 12 minute closed eye time lapse BOLD fMRI scan on two occasions spaced at 7 day intervals, the first was placebo (10ml saline, 60-s intravenous injection), the second being psilocybin (2mg dissolved in 10ml saline). The 60-second intravenous infusion began at 6 minutes into the scan, so that a baseline could be established during the same time series fMRI (Carhart-Harris et al.,2013). The volumes of time series images were processed in an ICA (independent component analysis), which produced 11 “meaningful”  RSN (resting-state networks). Basically, the fMRI images were analyzed for prospect of images that can be compared to a chosen dependent variable ( aDMN; anterior loaded DMN), and yield support for the topic hypothesis . {I could not discern precisely word for word, why they chose the aDMN for the dependent variable, when it was concurrently a “meaningful” RSN. I speculate, it was due to the need for models of an after psilocybin DMN activity time series to compare with after psilocybin TPNs.}

        The 11 “meaningful” RSN, consisted of the following: anteriorly loaded DMN (aDMN), posteriorly loaded DMN (pDMN), right- and left-lateralized frontoparietal networks (rFPN & lFPN), an auditory network (AUD), salience network (SAL), visual network, (VsN), precuneus network (PcN), dorsal attention network (DAN), cerebellar network (CereN), and sensorimotor network (SmN), (Carhart-Harris et al.,2013). For clarification, essentially all of these RSN (resting-state networks) are TPN (task-positive networks), the term RSN is used due to the cognitive behavior of  “ resting ” while in the fMRI, thus not being “ task-positive” because the lack of locus of control or isolation of a task.

The results of the fMRI dependent-independent variable analysis were given as side by side comparison in the form of the time series volume images of the 11 RSNs collected via ICA involving placebo v.s psilocybin.

        In a short elaboration on the results of DMN-TPN FC that Carhart-Harris et al. found between aDMN and the various 11 RSN to support the hypothesis, “ decreased orthogonality between the DMN and TPNs would predict experiences of disturbed ego boundaries and cognition”.  Carhart-Harris et al. implemented linear regression to assess the FC strengths between the aDMN and 11 RSN. Listed are the statistically significant FC strengths that will be considered result of psilocybin agonistic action on 5-HT2a receptors, which caused the gradient of FC to increase, as seen when compared to the baseline time series of postinjection.

  1. aDMN-SAL (P = .0002) salience network showing the most dramatic increase in FC
  2. aDMN-rFPN (P = .0003) right frontoparietal network
  3. aDMN-AUD (P = .0006) auditory network
  4. aDMN-DAN (P = .0009) dorsal attention network

{P representing the product strength using pearson’s correlation coefficient analysis via linear regression}(Carhart-Harris et al.,2013).

Default mode network functional connectivity in schizophrenia in relation to default mode network functional connectivity in psilocybin induced psychosis

McKiernan et al. found interesting complementary data in Schizophrenic fMRI scans, “task-induced deactivation of the default mode network increased as task difficulty increased in a subsequently administered cognitive probe. They hypothesized that this was due to a reallocation of processing resources from the default mode network to areas used in task performance.”. Similarly, the Carhart-Harris et al. hypothesis “decreased orthogonality between the DMN and TPNs would predict experiences of disturbed ego boundaries and cognition”, adds a supporting point for the role of compromised DMN in Schizophrenic psychosis and drug induced psychosis. Conclusively, it could be stated that statistically significant increases in functional connectivity observed by linear regression between aDMN- (1-4) RSN caused by psilocin ( 5-HT2a), causes decreased orthogonality.In turn, this hints at the association between 5-HT2a receptors (serotonin system), and abnormal functional connectivity in aDMN region, that results in schizotypal behavior/cognition.


        The results from the Carhart-Harris research and the sub-conclusion insinuated by McKiernan et al., all dictate the direction in which the scientific community involved with studying model psychosis, should take; traceable biological comparisons for understanding pathology in disordered psychosis. As for a conclusion to the article, it is conclusively seen that the particular orthogonality that is disrupted between aDMN and TPNs via functional connectivity strengths is seen with psilocin agonistic action on the 11 meaningful RSNs. This increase of FC in some areas between the aDMN and the most drastically increased RSN that is hypothesized to result in psychotic states of Schizophrenia, is also the case within psychotic states resulting from Psilocin agonistic action. Therefore inciting a key component for this theory ; The serotonin system ( in regard to receptor concentration of the networks involved in the 11 meaningful RSNs) has an instrumental role in psychotic states, either due to reverberation effect of the serotonin analog on the orthogonality of the DMN and TPNs, or by other means which are not yet known.




      Reference list

  1. Carhart-Harris, R. L., R. G. Wise, A. Feilding, D. J. Sharp, J. Evans, J. M. Stone, T. M. Williams, D. Erritzoe, R. Leech, and D. J. Nutt. “Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis.” Schizophrenia Bulletin 39.6
  2. Garrity, A. G., Pearlson, G. D., McKiernan, K., Lloyd, D., & al, e. (2007). Aberrant “default mode” functional connectivity in schizophrenia. The American Journal of Psychiatry, 164(3), 450-7. Retrieved from 1343-1351. Print.
  3. Mason MF, Norton MI, Van Horn JD, Wegner DM, Grafton ST, Macrae CN.Wandering minds: the default network and stimulus-independent thought. Science.2007;315:393–395
  4. Nicasio Mdel P, Villarreal ML, Gillet F, Bensaddek L, Fliniaux MA. Variation in the accumulation levels of N,N-dimethyltryptamine in micropropagated trees and in in vitro cultures of Mimosa tenuiflora. Nat Prod Res. 2005; 19(1): 61–7.
  5. Simonienko, K. , Waszkiewicz, N. , Szulc, A. (2013). “Psychoactive Plant Species”.
  6. Winkelman MJ. (2007). “Therapeutic bases of psychedelic medicines: psychointegrative effects”.
  7.  Winkelman MJ, Roberts TB. Psychedelic Medicine: New Evidence for Hallucinogenic Substances as Treatments 1. Westport, Connecticut: Praeger. pp. 1–19.
  8. Vollenweider FX, Geyer MA. (2001). “A systems model of altered consciousness: integrating natural and drug-induced psychoses”. Brain Research Bulletin. 495–507

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