Possible role of biochemiluminescent photons for lysergic acid diethylamide (LSD)-induced phosphenes and visual hallucinations

The extracted text does not describe a formal methods section or a systematic review protocol. Instead, the paper is a narrative synthesis and theoretical proposal that integrates prior experimental findings from biochemical assays, cell and tissue studies, animal work, neuroimaging/MEG in humans, and clinical observations (including reports from blind subjects). Kapócs and colleagues explicitly base their argument on their earlier published work and on selected reports from the literature rather than on a newly reported empirical study. Evidence types drawn together include measurements and characterisations of ultra‑weak photon emission (UPE) from biological tissue and cells, biochemical experiments demonstrating chemiluminescent reactions of LSD with peroxidases, neurophysiological and imaging data showing LSD effects on visual cortex activity and connectivity, and clinical/experimental reports of phosphene induction by drugs, ionising radiation, transcranial stimulation and in blind individuals. Where available, the authors also incorporate quantitative laboratory results (for example, comparative chemiluminescence intensities) and anatomical/physiological parameters (such as hypercolumn dimensions and neuronal density) to support mechanistic inferences.

The paper assembles several strands of evidence that the authors argue are consistent with a biophoton‑based mechanism for LSD‑related visual phenomena. First, the phosphene phenomenon is reviewed: phosphenes can be elicited by mechanical, magnetic, electrical, chemical and radiation stimuli; they reflect retinotopic organisation and can occur in blind individuals who had prior visual experience, indicating a cortical substrate in some cases. Second, the authors summarise findings on ultra‑weak photon emission (UPE). Living cells emit very low intensity photons (biophotons) across roughly 200–800 nm, mainly as byproducts of oxidative chemistry such as lipid peroxidation, mitochondrial respiration, catecholamine oxidation and other radical reactions. Reported correlations between UPE and cerebral energy metabolism, blood flow, oxidative processes and electrical activity in animal work are cited to suggest neural activity‑dependent photon emission. Experiments mentioned by the authors indicate that glutamate can increase biophoton intensity and that biophotons may be conducted along neural fibres; a recent computer simulation is noted to support photonic conduction along axons. The text also cites psychophysical work indicating human sensitivity to very small numbers of photons (reports of detection thresholds on the order of a few photons and even single‑photon perception), which the authors use to argue that endogenous biophotons could in principle be consciously perceived if produced above a threshold. Third, evidence is summarised linking LSD pharmacology to processes that could increase UPE. LSD acts on multiple monoamine receptors, notably 5‑HT2A, and enhances glutamatergic transmission: activation of 5‑HT2A receptors on thalamocortical projections can excite cortical pyramidal cells to release glutamate. The authors propose a cascade in which glutamate release activates NMDA receptors, stimulates NADPH oxidase and mitochondrial metabolism, transiently increases free radical production and thereby elevates UPE in retinotopic cortex. Neuroimaging and electrophysiological findings in healthy volunteers are described: LSD increases cerebral blood flow to visual cortex, reduces alpha power, and expands functional connectivity of primary visual cortex (V1); the extent of these changes correlated with ratings of visual hallucinations. A small resting‑state study of 10 volunteers reportedly found that early visual areas (V1 and V3) under eyes‑closed LSD behaved as if receiving spatially localised visual input. Fourth, biochemical experiments are cited showing that LSD can undergo oxidation reactions that produce chemiluminescence in vitro. Peroxidases such as horseradish peroxidase (HRP) and myeloperoxidase (MPO) metabolise LSD to known metabolites and these reactions were chemiluminescent and inhibited by reactive oxygen scavengers, implicating reactive oxygen species (ROS) and a peroxidase cycle. The HRP/H2O2 system produced high chemiluminescence in the cited assay; PMA‑activated neutrophils produced smaller chemiluminescence (about 10% of the HRP system), dependent on reagent additions. The authors note that MPO is expressed not only in immune cells but also at low levels in neurons and microglia, and that neuronal cell lines and primary cultures express MPO protein, suggesting the enzyme is present in brain tissue where it could contribute to in situ chemiluminescent reactions. Fifth, the authors draw parallels from other phosphene inducers: retinal phosphenes induced by ionising radiation are reported to be mediated by lipid peroxidation producing chemiluminescent photons absorbed by photoreceptors. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) can induce phosphenes in sighted and late‑blind individuals but not in congenitally blind subjects; the authors argue these techniques may also act by increasing local glutamate release and transient free radical production, thereby producing UPE. Reports that chemical hallucinogens increase the intensity and complexity of electrically induced phosphenes are also invoked as consistent with a shared biophotonic basis. Finally, the authors present quantitative and mechanistic considerations: they cite a proposed V1 functional unit (a hypercolumn approximately 1 × 0.7 mm in surface area and spanning ~2 mm depth) and a cortical neuronal density of about 50,000 neurons per mm3, from which they infer that a few hundred to a few thousand neurons might be sufficient to generate a conscious phosphene if UPE were synchronised across that population. Constraints and caveats are acknowledged in the results narrative: in vitro chemiluminescence assays used relatively high (millimolar) LSD concentrations and some experimental setups (luminometers rather than high‑sensitivity photomultipliers) may have underestimated weak photon emission; the actual in vivo photon flux inside cells is unknown and could be higher than ex vivo measurements.

Kapócs and colleagues interpret the assembled evidence as supportive of a unified hypothesis: LSD‑induced phosphenes and some visual hallucinations may arise when LSD’s pharmacological effects produce a transient excess of endogenous biophotons in early retinotopic visual areas. They argue that multiple, potentially convergent mechanisms could generate such excess ultra‑weak photon emission under LSD: glutamate‑driven oxidative chemistry in cortex following 5‑HT2A activation; direct drug oxidation by peroxidases such as MPO that can produce chemiluminescence; and metabolic processes associated with enhanced neural activity and blood flow in visual cortex. The presence of MPO and peroxidase activity in brain tissue is used to support the plausibility of local LSD‑driven chemiluminescent reactions. The authors situate this proposal relative to prior observations: the similarity between LSD’s effects on visual cortex and external visual stimulation (increased CBF, reduced alpha power, expanded V1 connectivity), the occurrence of LSD‑induced visual experiences in blind people with prior visual experience, and experimental demonstrations that very low photon counts can be perceptible are all presented as convergent lines of support. They also suggest a mechanistic commonality with phosphenes induced by ionising radiation, TMS and tDCS, insofar as these manipulations can increase free radical production or glutamatergic release and thereby potentially elevate UPE. Key uncertainties and limitations acknowledged by the authors include the lack of direct in vivo measurements of neuronal biophoton production at the intensities required for perception, the unknown threshold of endogenous photon emission necessary to elicit conscious light sensation, and methodological limitations of some biochemical assays (notably the use of high substrate concentrations and detection methods that may underestimate weak photon emission). The authors note that these gaps do not invalidate the hypothesis but mean it remains to be tested with more sensitive, targeted experiments. In terms of implications, Kapócs and colleagues propose that recognising a biophotonic contribution to phosphenes and hallucinatory imagery could advance mechanistic understanding of visual phenomena and potentially inform clinical or experimental modulation of hallucinations. They briefly contrast LSD’s specific serotonergic and glutamatergic actions with the more nonspecific currents produced by TMS or tDCS, suggesting LSD may uniquely engage biochemical pathways that generate biochemiluminescent photons. The authors conclude by urging that the UPE framework be considered and empirically tested as a scientifically tractable mechanism underlying phosphenes, retinal dark noise and related visual experiences.