Visual hallucinations originating in the retinofugal pathway under clinical and psychedelic conditions

This theory building (2024) elucidates a new understanding of psychedelic modulation in the retinofugal pathway (between the eye and primary visual cortex). It suggests that disruptions in communication between cortical and subcortical regions, influenced by serotonin receptors, may lead to perceptual alterations and hallucinations.

Authors

Kuypers, K. P. C.
Ramaekers, J. G.
Sorger, B.

Published

April 21, 2024

European Neuropsychopharmacology

meta Study

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Abstract

Psychedelics like LSD (Lysergic acid diethylamide) and psilocybin are known to modulate perceptual modalities due to the activation of mostly serotonin receptors in specific cortical (e.g., visual cortex) and subcortical (e.g., thalamus) regions of the brain. In the visual domain, these psychedelic modulations often result in peculiar disturbances of viewed objects and light and sometimes even in hallucinations of non-existent environments, objects, and creatures. Although the underlying processes are poorly understood, research conducted over the past twenty years on the subjective experience of psychedelics details theories that attempt to explain these perceptual alterations due to a disruption of communication between cortical and subcortical regions. However, rare medical conditions in the visual system like Charles Bonnet syndrome that cause perceptual distortions may shed new light on the additional importance of the retinofugal pathway in psychedelic subjective experiences. Interneurons in the retina called amacrine cells could be the first site of visual psychedelic modulation and aid in disrupting the hierarchical structure of how humans perceive visual information. This paper presents an understanding of how the retinofugal pathway communicates and modulates visual information in psychedelic and clinical conditions. Therefore, we elucidate a new theory of psychedelic modulation in the retinofugal pathway.

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Research Summary of 'Visual hallucinations originating in the retinofugal pathway under clinical and psychedelic conditions'

Introduction

Tipado and colleagues situate the paper in the longstanding effort to explain why classical serotonergic psychedelics such as LSD and psilocybin produce striking alterations in visual perception. Earlier work has emphasised cortical and subcortical loci of action—for example, visual cortex and thalamic gating mechanisms—but the mechanistic chain from early retinal processing to higher-level perceptual changes remains poorly specified. The authors note historical experimental claims that psychedelic-induced retinal activity can propagate to cortex and highlight clinical syndromes (e.g. Charles Bonnet syndrome) that produce hallucinations from visual-system pathology as potential pointers to under-explored peripheral contributions to psychedelic visuals. This paper sets out to synthesise anatomical, physiological and clinical evidence to propose that the retinofugal pathway—specifically interneurons in the retina called amacrine cells—may be a primary site at which psychedelics modulate visual signals before they reach thalamocortical circuits. The stated aim is to expand existing theories of psychedelic action (for example CSTC gating and REBUS predictive-coding models) by incorporating possible retinal modulation, and to articulate hypotheses and empirical observations that support a role for retinal serotonin-sensitive mechanisms in psychedelic visual phenomena.

Results

The review first summarises the anatomy and physiology of the retinofugal pathway. Photoreceptors (rods and cones) transduce light and relay signals to bipolar cells and then retinal ganglion cells in a ‘‘direct’’ route. An ‘‘indirect’’ route includes horizontal and amacrine interneurons in the inner plexiform layer; horizontal cells provide lateral interactions that shape spatial discrimination and light adaptation, while amacrine cells are largely inhibitory (GABAergic/glycinergic) and can both suppress and enhance signals relayed to retinal ganglion cells. Authors describe the major central visual relays downstream of the retina. Retinal ganglion cell axons form the optic nerve, decussate at the optic chiasm and project via the optic tract to the lateral geniculate nucleus (LGN) of the thalamus. The LGN segregates inputs into magnocellular (motion/spatial ‘‘Where’’), parvocellular (form/‘‘What’’) and koniocellular (colour) streams that project to layered visual cortical areas (V1–V6). The paper emphasises that receptive fields across this pathway use centre–surround organisation (ON/OFF responses) and that early perturbations propagate up the hierarchy, so incorrect retinal encoding could systematically bias higher-level representations. Predictive coding and hierarchical processing are reviewed as the dominant frameworks for perception. The authors describe how top-down predictions from cortex interact with bottom-up sensory evidence through recurrent exchanges; when prediction–error signalling or gating is altered, perceptual experience changes. Existing psychedelic theories (for example CSTC gating and REBUS) locate key effects in thalamocortical circuits and attribute visual alterations to altered sensory gating and relaxed priors, but the review argues that such models have not incorporated the possibility of retinal-level modulation. Clinical syndromes are presented as natural experiments. Anton–Babinski syndrome (ABS), typically post-stroke occipital damage, produces forced anosognosia and constructed visual narratives despite blindness; the extracted text reports 28 global cases over a 51-year period. Charles Bonnet syndrome (CBS), typically following vision loss in older adults, yields a spectrum from simple geometric phenomena and ‘‘visual snow’’ to complex eidetic hallucinations; patients are generally aware of the unreality of their percepts. These conditions illustrate how diminished or altered peripheral input can prompt internally generated visual content, supporting the idea that peripheral disruption may suffice to generate hallucinations. Phenomena related to occluded vision and closed-eye visuals are reviewed. The authors discuss biophotons, eigengrau (the intrinsic gray perceived with eyes closed) and phosphenes (pressure- or electrically-induced perceptions) as sources of endogenous retinal or cortical stimulation that can be amplified under psychedelics. A cited case of a congenitally blind individual reported no visual hallucinations under psychedelics but did experience altered sensations in other modalities, which the authors interpret as evidence that an intact optic nerve and prior visual experience may be necessary for psychedelic visual phenomena. On pharmacology, the review reiterates that classical psychedelics are serotonergic agonists with a prominent role ascribed to 5-HT2A receptors; blockade of 5-HT2A receptors by ketanserin reportedly prevents the subjective effects of psychedelics. The visual cortex and thalamus are dense in serotonin receptors, but the authors draw attention to evidence that serotonergic signalling is also present in retinal elements. Animal and histological data indicate serotonin uptake and 5-HT2A receptor localisation in retinal cells, and some amacrine subtypes contain high serotonin levels. The crux of the review is the proposed role of amacrine cells. These interneurons exist in many subtypes (estimates around thirty in human retina, more in mice) and are implicated in motion detection, edge and contour shaping, and modulation of ON/OFF pathways. Experimental manipulations in mice lacking a marker gene (Prdm13) for certain inhibitory amacrine subtypes produced ‘‘abnormally elevated visual sensitivities’’: increased optokinetic responses and the ability to detect lower-contrast objects. The authors connect three observations to justify their hypothesis: 1) loss of amacrine-mediated inhibition increases visual sensitivity in animals, 2) classical psychedelics are serotonergic agonists and serotonin-related mechanisms are present in amacrine cells, and 3) amacrine cells are the first intermediary between photoreceptors and ganglion cells that send information to thalamocortical circuits. They propose that serotonergic modulation of amacrine cells could alter lateral inhibition and receptive-field structure, thereby delivering already-modulated (biased) sensory input to the LGN and visual cortex and contributing to psychedelic visuals. The review notes practical challenges: direct measurement of amacrine activity requires intracellular recordings, which are technically difficult.

Discussion

Tipado and colleagues interpret the assembled anatomical, clinical and preclinical evidence as warranting inclusion of the retina—particularly amacrine-cell-mediated modulation—in models of psychedelic visual effects. They argue that retinal modulation need not replace existing central theories (for example thalamic sensory gating or cortical 5-HT2A activation) but could act in series with them: altered signals originating in the retina would be processed by subcortical relays and then interact with top-down predictive dynamics to produce the characteristic psychedelic visual phenomena. The authors acknowledge several uncertainties and limitations. Direct empirical evidence linking psychedelic action at retinal amacrine cells to human subjective visuals is limited; most supporting data are preclinical, anatomical or indirect (e.g. distribution of serotonin receptors). Recording from amacrine cells in vivo is technically demanding, and the extracted text does not report any new experimental data establishing causality. The review also notes that some clinical observations, such as the absence of visual hallucinations in a congenitally blind individual, are suggestive but not definitive proof of retinal necessity for psychedelic visuals. In terms of implications, the authors recommend that future research should address the visual domain more explicitly. They propose targeted experiments to test retinal contributions (for example retinal electrophysiology under psychedelics, pharmacological blockade at retinal targets, or animal models manipulating specific amacrine subtypes) and suggest that integrating peripheral and central mechanisms may yield a more complete explanatory framework for perceptual effects of psychedelics.

Conclusion

The paper concludes that perceptual effects, especially visual phenomena, have been relatively neglected in psychedelic research and that expanding enquiry to include retinal mechanisms could provide important insights. The authors urge greater focus on how psychedelics transform percepts, arguing that understanding early-stage visual modulation will enrich models of psychedelic action and advance knowledge about human visual perception more broadly.

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INTRODUCTION

Most of our initial understanding of the visual effects of classical psychedelics like psilocybin is attributed to the 19th-century German neuroscientist Louis Lewin who cataloged the experiences of a gamut of psychoactive substances in his book "Phantastica". This work served as the world's first categorization of various (and often natural) psychoactive substances from across the planet. The first experimental study on the effects of psychedelics on visual hallucinations was led by Chicago-based scientists. Under the belief that these experiences may entirely originate from the retina, this study used electroretinography (ERG) in forty-four cats. Electrodes were placed under the conjunctiva, a thin membrane that covers the sclera (the white of the eye). In one group of cats, researchers placed electrodes around the optic nerve of one eye and removed all other eye muscles and nerves to eliminate nonvisual physiological activity being recorded from ERG. In another group, an additional electrode was placed on the visual cortex to determine correlates between retina activity and the occipital lobe. Within the peritoneal cavity, they injected LSD, mescaline, dihydrocannabidiol, or the sedative pentobarbital into the cats and found spontaneous activity in the retina and visual cortex that was not related to ocular muscle activity with LSD. When the optic nerve was severed, there was no activity. These researchers believed LSD-induced cortical activity was dependent upon communication from the retina, even stating that LSD did not induce hallucinations by virtue of an effect on the central nervous system. Researchers further concluded that "the objective description of geometric hallucinations induced by LSD in reliable human subjects is best explained on the basis of intraocular structures.". While current theories of visual alterations from psychedelics suggest a dysregulation in thalamocortical communication, we hypothesize that modulation of visual information after taking psychedelics already happens earlier in the visual pathway, more specifically through neuroreceptors embedded within amacrine cells that are known to be affected by psychedelics via direct or indirect action on dopamine, Nmethyl-d-aspartate NMDA, acetylcholine, GABA, opioid, and serotonin (5-HT) receptors. In this paper we propose that, through interdependent top-down processing of receptive fields in the visual pathway, basic visual information initially affected by amacrine cells arrives in the rest of the brain already modulated by psychedelics. Visual information being sent to subcortical regions of the brain, like the thalamus, gets processed and ultimately delivered to the sensory regions through predictive coding. This is an existing proposed framework for experiencing sensory information that relies on circuits of predictions and error correction from the thalamus and sensory regions. In all the leading theoriesof the subjective effects of psychedelics, sensory predictions are skewed and gaited in subcortical regions of the brain due to these areas being densely populated with 5-HT receptors. This results in visual distortions, hallucinations, and even the fabrication of immersive environments. The notion of amacrine modulation through psychopharmacological intervention adds to current models of psychedelic action by expanding on ways in which visual sensory information may arrive at the rest of the brain in an already impaired state.

THE RETINOFUGAL PATHWAY

The retinofugal pathway is the infrastructure humans use to receive and process visual information from the external world. Photoreceptors serve as the first point of contact with our body and our world of visual sensations. All light is computed by the rod and cone photoreceptorsrods determining the light level and cones constantly evaluating color. These photoreceptors convert light radiation to electrical signals and transmit it to bipolar cells which fires this information immediately to retinal ganglion cells. This three-step process delivers visual information about our universe that is unmodulated by any other external (or internal) force. This route is called the "direct pathway"(Fig.). There is another pathway visual information uses to navigate the outer sensory world to our brain, called the "indirect pathway". Compared to the direct pathway, it includes two extra types of cells, the horizontal and amacrine cells, located in between the retinal ganglion cells and the photoreceptors. Horizontal cells can communicate information of many photoreceptorsto bipolar cells (Fig.). There is also evidence to suggest these horizontal cells are essential for the connection of bipolar cells to rod photoreceptors. This lateral interaction between horizontal and bipolar cells is believed to modulate visual information by enhancing spatial discrimination and light adaptation. Amacrine cells are mostly glutaminergic or GABAergicand have the unique ability to modify visual information. They appear to suppressand enhancevisual information sent from photoreceptors through bipolar cells. This modulated visual information from amacrine cells is then transmitted to retinal ganglion cells and eventually to the brain through the retinofugal pathway.

THE VISUAL PATHWAY

The journey that light radiation from our environment takes to travel to the eyes and convert itself into a chemical signal goes through the visual pathway. This infrastructure of visual perception being functional seems to be a requisite for experiencing visual hallucinations of a psychedelic(Fig.). Visual information (which has been modulated, augmented, suppressed, or enhanced through the indirect pathway) goes through the optic nerve and to the optic chiasma, a place where visual information from the right visual field of the left eye goes to the right side of the brain and the left visual field of the right eye goes to the left side. These bundled nerve fibers from both eyes via the retinal ganglion make up the optic tract and connect directly to the thalamus, which is a relay station for nearly all sensory perception. The thalamus is not a monolith structure in the brain. It is composed of smaller, more intricate areas that all have a significant role in how we process vision. The lateral geniculate nucleus (LGN) resides in the posteroventral region of the thalamus. Similar to decussation that occurs in the optic chiasma, the left LGN processes information from the left visual field of each eye, and the right LGN processes information from the right visual field of each eye. Axons from the optic tract on the left side connect with only three of the six layers of the left LGN. The remaining three layers are connected by axons coming from the right side. In the right LGN, this process is equal but reversed. These layers encode three specific streams of visual information and assign each stream to three types of functional layers: magnocellular (m-cells), parvocellular (p-cells), and koniocellular (k-cells) (see Fig.). The first two layersof the LGN, the magnocellular layers, consist of larger neurons, located in the ventral area of the LGN. These neurons transmit visual information related to spatial orientation and motion usually to the first layer of the visual area (V1) of the visual cortex. This flow of information from the magnocellular layers of the LGN to the visual cortex is called the dorsal stream, and because this information helps us identify our surroundings, it is often called the "Where" pathway (de. The parvocellular layers occupy the remaining four layers (3-6) of the LGN. These neurons are smaller than their magnocellular counterparts and also transmit visual information to somewhat deeper layers) (V2-V5) of the visual cortex. The information communicated from the LGN to the visual cortex within the parvocellular layers is associated with object recognition, including determining shapes and facial recognition. That is why this information stream is called the "What" pathway. Nestled in between each magnocellular and parvocellular cell lies even smaller cells known as koniocellulara total of six of these unique layers. The koniocellular layers transmit color information to the visual cortex. The way these k-cells transmit information (along with the exact information that is transmitted) is a bit more complexthan m-cell and p-cells, and so it is still an open question in perceptual research.

RECEPTIVE FIELDS

The receptive fields inside the LGN are the single neural mechanism that is inherently vital to receiving visual information from photoreceptors, bipolar cells, amacrine cells, and retinal ganglion cells within the eye, the visual cortex, along with magnocellular, parvocellular, and koniocellular cells. All receptive fields incorporate a center-surround area, a smaller circle within a larger circle, that can excite or inhibit the cell and/or its surrounding area. Not all receptive fields are the same, for example, the receptive fields of magnocellular cells are larger than parvocellular due to magnocellular neurons actively responding to moving objects. Receptive fields respond differently according to the visual information that is being encoded. However, all receptive fields fundamentally work the same in an ON and OFF process (Van Wyk et al., 2009) (Fig.).

FIG. 1.

A) All information from the retina flows down the optic nerve to the brain. The optic chiasm is where the decussation happens which is the cross-over of visual information in which the right visual field of the left eye goes to the right side of the brain and the left visual field of the right eye goes to the left side. The optic tract is a continuation of optic nerves that goes directly to the thalamus, specifically the lateral geniculate nucleus, after the decussation within the optic chiasm. The optic radiation represents the extension of the optic nerve bundles after passing through the lateral geniculate nucleus and before it enters the visual cortex. The visual cortex is the cortical region that serves as the destination for all information obtained within the visual pathway. B) The direct pathway of visual information in the retina. Here, photoreceptors use cones and rods to interpret light and transmit information to bipolar cells and then directly to retinal ganglion cells. In the indirect pathway, horizontal cells connect and interface with photoreceptors and bipolar cells and amacrine cells also connect with bipolar cells and retinal ganglion cells. When light hits the center circle of the receptive field on a cell in the ON state, it creates an action potential that allows the cell to fire, or activate. If light hits the surrounding circle, no action is created. In the case of receptive fields that are in the OFF state, they are only activated when light hits the surrounding circle. When light hits the center area, they are inactive. If in the case that light manages to touch both the center and surrounding circles in a receptive field in the ON or OFF state, the cell will give off a weak response, thus transmitting weak visual information. Receptive fields are not just exclusive to the LGN. They are a key feature of every component of the visual pathwayphotoreceptors, bipolar cells, amacrine cells, retinal ganglion cells, the LGN, and the visual cortex. The way receptive fields collect visual data and convey information to the brain is completely interdependent upon the lower level of input that precedes it within the visual pathway. In this bottom-up flow of visual information, the 'bottom' is represented by the visual data collected from our external world through receptive fields that reside within photoreceptors, our first point of experiencing visual sensory information. This bottom level transfers this information and informs the receptive fields of retinal ganglion cellswhich then take this information and travel down the visual pathway to the receptive fields in the thalamus (mostly through the LGN). This information gets further processed in the thalamus and eventually arrives at the receptive fields within the visual cortex which plays a highly crucial role in all visual experiences. Therefore if visual information collected in the receptive field of an amacrine cell in the retina is incorrect, then every ascending level of the bottom-up system will encode this inaccurate visual information and deliver this faulty data to the visual cortex to be displayed within the brain.

PREDICTIVE CODING

The brain is perpetually in a continuous process of constructing a person's external reality based on an array of probabilistic models. Predictive coding is the leading theory as to how we construct world models based on sensory information. These models are auto-generative; crafted from previous knowledge like how physics work, expectations of sensory stimuli, repeated exposure to similar scenarios, and evolutionary adaptations. The brain predicting reality also operates on a level of hierarchy. Higher levels of the nervous system, like the visual cortex, create top-down predictions that attempt to align with the expected sensory activity at every hierarchical levelall the way down to visual information obtained from the retina. Even within the visual cortex, predictions are made of a hierarchical nature across six visual layers(Fig.). Although these six visual layers may seem to operate in a classic hierarchy, a chain of events in which V1 passes information to V2, then so on until it gets to V6 -that is not necessarily the case. Quite often, information going down the hierarchy actually goes back up, then down again. For example, the LGN inside the thalamus may project visual information to V1, then jump to V4, only to go to V2 as its final destination. Sometimes information from the LGN skips V1 altogether and goes directly to V4 and goes back to V1. This jumbling of hierarchical visual information may seem chaotic, but it is necessary to validate initial predictions made by our brain of our visual field and if the prediction does not match up, it can correct these assessments with the actual sensory information. It is theorized the brain is always in a subtle but persistent level of auto-correction, a never-ending dance of going up and down (and then back up) the chain of visual hierarchy, redundantly checking predictions against sensory information. It is believed that Fig.. A) The optic tract is a continuation of optic nerves that goes directly to the thalamus after the decussation within the optic chiasm. The thalamus, specifically the lateral geniculate nucleus within, is where the optic nerves project into the magnocellular, parvocellular, and koniocellular cells. The optic radiation represents the extension of the optic nerve bundles after passing through the lateral geniculate nucleus and before it enters the visual cortex. Magnocellular cells (M-cells) represent layers 1 and 2 of the lateral geniculate nucleus. Parvocellular cells (P-cells) comprise layers 4-6 of the lateral geniculate nucleus. Koniocellular cells (Kcells) are small neurons found in between each layer of the lateral geniculate nucleus. B) When light hits the center of an ON field it results in an action potential (cell fires, depolarization). When light hits the surrounding area of an ON field, it results in no action (hyperpolarization). When no light hits any part of the field, there is no action. When light hits the center AND surround of an ON field, it results in weak response and firing. When light hits the center of an OFF field it results in no action (hyperpolarization). When light hits the surrounding area of an ON field, it results in an action potential (cell fires, depolarization). When no light hits any part of the field, there is no action. When light hits the center AND surround of an OFF field, it results in weak response and firing. task-evoked responses (like picking up a phone when it is dropped) make up for only 0.5-1 % of the brain's overall energy budgetwith the rest believed to be in a vigilant state of hierarchical prediction/correction. There is evidence that our brains are so preoccupied with this process that it is filled with seemingly pre-constructed models of our visual world that we defer to, especially when the level of stimuli is not adequate or absent.

NON-PSYCHEDELIC DISTORTIONS OF VISUAL REALITY

In most instances, damage to the infrastructure of the visual pathway, for example, damage to the optic chiasm, will result in field loss of vision in one or both eyes. A lesion to Meyer's loop within the optic radiation can cause so-called "pie in the sky" visual deficits) -a small area within your visual field that is blind. However, these examples represent structural damage to areas of the brain that are devoid of neuroreceptor activity. When areas that do express receptors for various neuromodulators are damaged or innervated, the brain has peculiar ways to compensate for this lack of visual information.

ANTON-BABINSKI SYNDROME (ABS)

The Anton-Babinski Syndrome (ABS), is a rare condition (only 28 global cases reported in a 51-year period)that is usually the result of a stroke involving the restriction of blood supply to the occipital lobes. This syndrome results in forced visual anosognosia, essentially a condition in which a person denies their vision loss. Denied vision loss acquired from ABS comes in the form of a person constructing seemingly realistic narratives that happen within a person's occluded field of vision that does not correlate with validated activity in their external world. These functional conditions do not arise from a person actively denying their vision loss, but instead, it is the result of a complete unawareness of their lack of vision due to the brain doing a great job of "filling in the gaps" of visual information.

CHARLES BONNET SYNDROME (CBS)

In another condition, coined Charles Bonnet Syndrome (CBS), visual alterations that are reminiscent of subjective visual effects of psychedelics are reported. Unlike Anton-Babinski syndrome, people that have CBS are generally aware of the unreality of their visual hallucinations. CBS is a condition usually acquired by elderly peopleand it is caused by the brain's adjustment to vision loss. The probability of CBS symptoms increases when a person is alone, in darkness, or in a familiar environment, like their bedroom. These symptoms, or visual disturbances, range from elementary hallucinations like enhanced colors to incredibly complex hallucinations, like unreal scenarios with human-like figures. Discovering patterns within these unstructured, seemingly chaotic textures also gives rise) to pareidolia, which is finding significance or meaning in ambiguity. Reports of metamorphopsia often occur, which is the incorrect perception of the size of objects and the environment. Both micropsia (objects appearing too small) and macropsia ("larger than life" Fig.. The hierarchical six-layer structure of the visual cortex.The visual cortex is arranged from the primary visual area (V1), V2, V3, middle temporal area (MT, also called V5), and finally the dorsomedial area (DM, also known as V6). The first layer, V1, allows for basic visual detectionlike the shapes of objects and each subsequent layer in the visual cortex hierarchy (aside from V4) reveals a higher complexity of detection. V6 allows for egocentric orientation of one's entire visual field and the ability to navigate within one's environment. appearance of objects) are generally reported in CBS. Other spatial distortions like teleopsia, which is the appearance of objects being further away than normal along with frequent perceptions of lilliputianism, specifically people appearing smaller than normal. In the case of these elementary hallucinations, objects do not have to be the source of visual distortion. In some instances of CBS, entire fields of vision can be affected by monochromatic perceptual alterations like achromatopsia, which is the inability to perceive color. "Visual snow" is another common occurrence of CBS, essentially one's entire field of vision being dominated by small, congruent geometric objects that take on the appearance of "static" on a television. Not all visual hallucinations with CBS are this amorphous. In more complex hallucinations, people report hypercomplex or eidetic hallucinations that have every detailed indicator of being "photo realistic" and sometimes perceived as "more real" than reality. These hallucinations can land anywhere from distinct zoopsia, which is seeing fully-formed animals or creature-like entities, like mythological beings to terrifying depictions of disembodied and bloody people.

CLOSED-EYE VISUALS AND OCCLUDED VISION

The concept of closed-eyed visuals, or experiencing effects of psychedelics with the occlusion of one's eyes, is a staple of the ayahuasca experienceand a topic of heavy interest in psychopharmacology. Studies have shown that listening to music even results in an enhancement of the visual closed-eye psychedelic experience due to increased functional connectivity in the visual cortex. But it can be questioned how this psychedelic-induced visual experience can happen with a lack of visual information being transmitted from the eyes to the brain. There are a few potential reasons, like retinal-producing biphotonic lightthat contributesto the "dark noise" of closing one's eyes. Biphotons are light particles generated from the body and in the case of the biophotonic light coming from the eye, the retina picks up these faint glimmers which constructs the pseudo-darkness we see. Closing one's eyes does not fully equate to being blind. The void of light inherent to a person that is congenitally blind is impossible to achieve with closed eyes. In fact, when a person closes their eyes they do not experience pitch-black "darkness", but instead they see a very specific color called "eigengrau"or intrinsic gray. This fuzzy, quasi-dark gradient is mostly the result of a person's closed eyes looking at the biological "wallpaper" of the back of eyelids. This thin layer of skin obfuscates visual information received but does not completely prevent it. Simply closing one's eyes and waving a hand in front of their face will prove this. Another reason is the phenomenon of phosphenes, geometric and often colorful shapes emerging, either due to pressure one's eyelids exerts on the eye orwith electrical stimulation directly to the visual cortex.Coincidentally, "electrically-induced" phosphenes after a small dose of LSD have been shownto produce more elaborate patterns within one's field of vision. In darkness, retinal cone photoreceptors become depolarized and release glutamate. This glutamate release inhibits the receptive fields of ON retinal ganglion cells and excites OFF retinal ganglion cells. The subjective effects of acute doses of psychedelics have also been known to be accompanied by shifts in regional glutamate in the brain. Despite the similarities between both neuromechanical processes, it has yet to be determined if an increase in glutamate through eye occlusion can be associated with glutamate shifts while under psychedelics.

CONGENITAL BLINDNESS

The unequivocal factor of congenital blindness and the occluded vision of closed-eye visuals is the non-functionality of the optic nerve, the primary infrastructure that brings visual information to the rest of the brain (A. M.. While the optic nerve may not be the reason why one would have a psychedelic visual experience, it might be the reason why a person would not have one. In 2018, a case study of a congenitally blind man taking psychedelics was published. This represents the first insight science has into perceptual alterations under psychedelics within a "blind-at-birth" individual. One of the most intriguing findings was that despite substances like LSD and psilocybin which implore visual hallucinations, the congenitally blind person had no visual hallucinations when experiencing psychedelics. Instead of visual hallucinations, this person had experiences that were dominant in other sensory domains that are not usually associated (or tested) with classical psychedelics. Retrospective accounts of this person's psychedelic experiences exemplified that when people were speaking, he could only hear the auditory tones and could not quite decipher any linguistic meaning from the sounds. Within the domain of touch, this congenitally blind person experienced hallucinatory sensations that were surprisingly reminiscent of visual disturbances that are usually reported with LSD use. For example, when this person touched a person's face to identify someone, he noticed the fine details of their face like their eyes, nose, and mouth were distortedreminiscent of the "melting faces" which is a heavily reported visual hallucination associated with LSD. All of these visual conditions may stem from obstructed, partial, or complete vision loss and the brain attempting to consolidate this sensory impairment by constructing our external world. This process of the brain "autocompleting" our visual world is not exclusive to any conditionthis neuromechanical process is innate in every human being.

PSYCHEDELIC EFFECTS ON VISION

In the case of classical serotonergic psychedelics, areas of the brain that express serotonin (5-HT) receptors become the site of psychedelic neuromodulation. However 5-HT receptors are not unaccompanied without its various subtypes, about fourteen in total. While most serotonergic psychedelics are non-selective agonists, the receptor type that appears to be responsible for the sensory altering subjective effects of psychedelics is 5-HT2A. We know this mostly due to the effects of ketanserin, a 5-HT2A antagonist that, when administered in humans, appears to completely block the subjective effects of psychedelics. The visual cortex is an area dense in pyramidal cells that contain 5-HT2A receptorssychedelic activation, along withthe subjective effects that follow, can be seen throughout these areas. Going further into the visual pathway, the thalamus along with the LGN also seem to be actuatedby psychedelic intervention due to the density of 5-HT receptors within (D. F.and has been suggested to play a central role in how psychedelics exert its perceptual experience on the user. In the cortico-striato-thalamo-cortical (CSTC) feedback loop theory, the thalamus is vitalfor the regulation of the CSTC loop, which is a circuit of subcortical and cortical areas that is responsible for the homeostasis of general cognition. Any impairment of this CSTC feedback loop originating from the thalamus may result in sensory impairmentalong with specific visual impairment like hemianopia, which is a loss of vision in a portion of the visual field. This CSTC theory was later further supported and expanded upon through fMRI evidence of thalamus activity. The thalamus also serves a vital role in the 'Relaxed Beliefs Under Psychedelics' or REBUS theorywhich proposes psychedelics causes a disruption of top-down information flow within the thalamus to other sensory regions of the brain. This results in a reduction of sensory gating from the thalamus which in turn makes sensory information sent to cortical regions less hierarchically selective.

THE ROLE OF AMACRINE CELLS IN VISUAL EFFECTS OF PSYCHEDELICS

The functionality of amacrine cells is poorly understood in retinal neuroanatomy. Currently, it is estimated that around thirty human amacrine subtypes based on morphology, potential functionality, and neurotransmitters that are expressed in specific cellsMice may have up to sixty-three subtypes. Amacrine cells are found in the inner plexiform layer (IPL) of the retinaand are mostly inhibitory neurons that also use GABA or glycine as neurotransmitters. While there are many subtypes of amacrine cells, the most studied type is 'starburst amacrine cells' which are believed to be responsible for modulating detection-sensitive motion visual information received by photoreceptors to retinal ganglion cells. Amacrine cells (which are usually grouped by the size of their receptive field; narrow-field, medium-field, and wide-field) have been theorized to modulate visual information related to shaping spatial perceptionalong with early edge detection, contour, and other testable visual sensitivities. Narrow-field amacrine cells are believed to create 'cross-talk' between the pathways of ON and OFF receptive fields within inner retinal cells. Wide-field amacrine cells are thought to be more inhibitory in nature within these ON and OFF pathways. AII amacrine cells (a specific type of narrow-field amacrine cell) are mostly attached to ON-center cone photoreceptors). When glutamate antagonists (e.g., cyanquixaline and 6,7-dinitroquinoxaline-2,3-dione) are applied to AII amacrine cells, it increases the ON-center response of these cells, but decreases the OFF-surround response. After the application of GABA antagonists (picrotoxin and bicuculline), the ON-center response of these cells were also increased while the OFF-surround were completely attenuated. These results further illustrate that the OFF-surround response of AII amacrine cells are highly responsive to lateral inhibition from neighboring amacrine cells. There is preclinical data that shows amacrine cells are reactive towards exogenous serotonin; as mentioned earlier, classical psychedelics are well-known stimulators of serotonin receptors. We also know that serotonin is detected at extremely high levels in amacrine cells that have large somaswhich is the cellular area responsible for receiving information from other cells. Interestingly, bipolar cells can absorb exogenous serotonin along with endogenous serotonin produced by amacrine cells but have no means to transport this neurotransmitter. This accumulation of serotonin in bipolar cells simply degrades, the reason for this process is currently unknown. Amacrine cells serve as the first intermediary between raw visual data obtained from photoreceptors and retinal ganglion cells that extend directly to the LGN. If subcortical structures like the thalamus have served as core neurological sites that explain perceptual alterations of psychedelics, then perhaps parts of the retina that express serotonin receptors like amacrine cells as well as retinal ganglion cells may also constitute an important mechanism that contributes to the cascade of perceptual changes while under a psychedelic experience. Since amacrine cells are mostly inhibitory, it is believedthe primary purpose of these varied cells is to 'filter down' the visual information received by photoreceptors (via bipolar cells) and deliver a reduction of visual information onto retinal ganglion cells. Identifying the functionality of interneurons like amacrine cells is extremely difficult, however, in 2015, a study was conducted that identified a gene called Prdm13 which is carried by GABAergic and glycinergic amacrine cells. The gene was used as a marker to identify these specific amacrine cells. When researchers obtained mice that lacked this Prdm13 gene, which also denoted a lack of this subtype of amacrine cells that carried this gene, they took note of some interesting visual modulations that occurred within these mice. Through reflexive eye movement tests, researchers found abnormally high spatial, temporal, and contrast sensitivities in vision. Specifically, mice that lacked inhibitory amacrine cells could detect significantly lower contrast objects compared to normal mice and overall displayed 'abnormally elevated visual sensitivities'. This increase in optokinetic response was measured using a reflexive eye movement test that analyzed the eye's response to visually detecting a moving object. This measurement looked at early movement (500 ms after visually sensing an object move) and late movement which involves the eye resetting to its initial position after the object has moved out of the field of vision. Researchers found that mice that lacked the Prdm13 amacrine subtype had eye speeds that were 'significantly' higher' than those mice with the amacrine subtype. Contrast tests were also implemented and mice that lacked Prdm13 amacrine subtype were able to detect 'significantly lower contrast objects' that mice that had Prdm13. The Prdm13 gene is an indicator of amacrine cells and it is known that 5-HT2A serotonin receptors are located in these same cells. In fact, amacrine cells even produce their own endogenous serotonin. 5-HT2A uptake within the retina has been seen in a variety of mammals. In this framework of retinal visual processing, amacrine cells and their ability to inhibit cascades of other cells, hold a crucial role in this process. Disruption of this inhibition of visual information from photoreceptors to retinal ganglion cells via serotonergic agonism of amacrine cells would result in a gait effect of this anticipatory process. As noted in CSTC, thalamic sensory gating is theorized to be responsible for psychedelics sensory-altering subjective effects. It is conceivable therefore that serotonergic psychedelics, directly or indirectly, increase inhibitory action of amacrine cells which results in peculiar visual processing. In sum, the current notion that amacrine cells might be contribute strongly to the psychedelic visual experience is based upon three scientific observations: 1) Abnormal visual sensitivity occurs in animals lacking amacrine cells 2) Classical psychedelics are serotonergic agonists, serotonin receptors are an inherent to amacrine cells 3) Amacrine cells serve as the first intermediary between the retina and thalamocortical circuits that process and produce visual sensory information. Currently, theories of psychedelic modulation do not include any consideration of a potential role of the retina, i.e., possible effects on amacrine cells. As shown in Fig., within the visual pathway, all areas that include a receptive field and a receptor profile that can be expected to be responsive to psychedelic modulation have the potential to augment visual information. Including the potential role of retinal amacrine cells as the initial modulator of visual information from psychedelic innervation does not negate any current theory on the psychedelic experience . The claim is not that the entirety of a psychedelic visual experience solely occurs within the eye, but instead that the retina, specifically amacrine cells, have been an under-looked functional element of this very underresearched perceptual phenomenon. However, measuring activities of amacrine cells require intracellular recordings which are challenging to do. However, considering the elementary role amacrine cells may have on the visual data that is received from the external environment, \ it would be vital to include potential modulation of these cells within existing and future theories of psychedelic visual alteration.

FIG. 4.

A simplified representation of the visual pathway and the areas that have both serotonin receptors and a receptive field. Examples of visual distortions that are reported within the visual pathway due to psychedelicsand visual conditions.

CONCLUSION

With all the strides science has made with its rapidly evolving understanding of psychedelics being used in therapeutic contexts, our knowledge of the perceptual effects of these substances has not progressed at the same pace. Perhaps the visual effects produced by psychedelics are seen as an aside. Even something to be expunged entirely considering the recent line of research that attempts to essentially remove the psychedelic experience from the psychedelic itself. This paper chimes for a new perspective, one that also focuses on the perceptual modulations arising from psychedelics. At the time of publication, research into the visual domain of psychedelics only account for a small fraction of studies. Therefore there should be no surprise that our comprehension of how psychedelics exert its unique effect on visual perception is poorly understood. That is unfortunate considering it is the single most common characteristic attributed to nearly all psychedelics. Holding a greater understanding of how percepts are transformed will not only broaden our knowledge of how psychedelics affect us, but may give us new insight on how we perceive our external reality.