INTRODUCTIONThere are some overlaps in the effects of serotonergic psychedelic drugs such as LSD, peyote, psilocybin mushrooms and also the state of mind that newborn infants and young children are in. These drugs induce an alteration of the senses, some of which can be viewed as byproducts of plasticity and learning. This will be explained throughout the essay. The reason for these ‘psychedelic’ visual effects might be a byproduct of calibration of the senses. The effects of psychedelic drugs on the user’s brain may resemble the childhood critical period. In this research proposal, the aim is to compare measures of brain activity with an fMRI of infants, adults, and adults on psychedelics to see what similarities and differences exist between these groups.
Psychedelia and AgePsychedelic drugs and children have been shown to have some overlaps that raise interesting questions about why such similarities might exist. Child- and infant-hood show biological patterns that resemble the effects of psychedelics drugs. For example, psychedelics seem to induce neurogenesis (Catlow, Jalloh, & Sanchez-Ramos 2016), which is increased in infanthood (Stiles & Jernigan 2010). Infants also show increased brain plasticity (White, Hutka, Williams, & Moreno 2013), which mirrors the induction of plasticity that occurs with psychedelic drugs (Ly, Greb, Cameron et al 2018). Increased perceptual acuity is a reported effect of psychedelic drugs (Fischer 1968) and children are more able to distinguish phonetic sounds of foreign languages than adults are (Kuhl 2004), which might signify increased auditory acuity. When adults learn language they often develop phonetic impairments that we call accents. The psychedelic drug known as MDMA has also been shown to bring back a childhood critical period for social learning (Nardou, Lewis, Rothhaas et al 2019). This suggests that serotonin may play a role in the critical periods of childhood. Children are observed to have increased serotonin activity which decreases with age (Whitaker-Azmitia 2001). What’s particularly interesting is that the main target of psychedelic drugs, the serotonin 5HT2a receptor, is shown to have reduced binding as we age (Meltzer, Smith, Price et al 1998). The 5HT2a receptor has been shown to be important in thalamocortical plasticity (Barre, Berthoux, De Bundel et al 2016) and prefrontal cortex plasticity (Berthoux, Barre, Bockaert et al 2019). A paper on psilocybin found evidence of increased hippocampal plasticity and neurogenesis (Catlow, Song, Paredes et al 2013). This appears to be dose-dependent, where high doses may actually reduce neurogenesis and plasticity, which mirrored the effects of the 5HT2a receptor antagonist, ketanserin. There is also evidence that psychedelic 5HT2a receptor agonists induce neuritogenesis, spinogenesis, and synaptogenesis (Ly, Greb, Cameron et al 2018). The loss of 5HT2a activity observed with aging and also schizophrenia (Hashimoto, Kitamura, Kajimoto et al 1993) may help to explain the loss of plasticity observed in aging (Rosenzweig & Barnes 2003) and in schizophrenia (Barre, Berthoux, De Bundel et al 2016). Stimulation of the 5HT2a receptor seems to enhance associative learning and memory (Zhang & Stackman Jr 2015) which is impaired in schizophrenia as well (Diwadkar, Flaugher, Jones 2008). Strangely, schizophrenics appear to have accelerated brain aging, with observations of their brains being almost a decade older in early adulthood (Hajek, Franke, Kolenic et al 2019). Alzheimer’s patients also reveal decreased binding of 5HT2a receptors (Lorke, Lu, Cho, & Yew, 2006). Beta-amyloid has been implicated in both schizophrenia and Alzheimer’s disease (Religa, Laudon, Styczynska et al 2003). Injections of beta-amyloid were found to reduce 5HT2a receptor density (Christensen, Marcussen, Wörtwein et al 2008). Reduced 5HT2a receptor activation is has been observed in patients with mild cognitive impairment (Hasselbalch, Madsen, Svarer et al 2008). These studies suggest that aging may impact cognitive ability, partly through reductions in the activity of psychedelic-related mechanisms and that aging may reduce ‘psychedelia’ on some level. The effects of psychedelics on learning in general seem mixed. These effects are likely dose-dependent as well. One study found that psilocin impaired acquisition in rats and the high dose even impaired retrieval (Rambousek, Palenicek, Vales, & Stuchlik 2014). Another study on psilocybin found enhanced fear extinction learning that was dose-dependent, occurring more at the lower doses (Catlow, Song, Paredes et al 2013). MDMA enhanced associative and non-associative learning in rabbits (Romano & Harvey, 1994). MDMA was found to enhance plasticity with repeated neurotoxic doses in rats (Morini, Mlinar, Baccini, & Corradetti 2011). MDMA also enhanced fear extinction learning, which is relevant for PTSD (Young, Andero, Ressler, & Howell 2015). LSD was found to enhance associative learning in rabbits (Gimpl, Gormezano, & Harvey 1979) and intrahippocampal LSD was found to accelerate learning in rabbits (Romano, Quinn, Li et al 2010). Another study found that repeated LSD dosing restored impairments to learning in ‘depressed’ rats (Buchborn, Schröder, Höllt, & Grecksch 2014). A recreational dose of LSD (100ug) revealed cognitive impairments in humans, including deficits to executive function, working memory, and mental flexibility (Pokorny, Duerler, Seifritzet al 2019). Another study claims that cognitive flexibility is increased after the acute dose of LSD (Carhart-Harris, Kaelen, Bolstridge et al 2016). Dosing LSD in rats was found to accelerate reversal learning, which involves making a choice in a decision making task after learning to make the opposite choice (King, Martin, & Melville 1974). Psychedelics may be able to stimulate cognitive change this way. This seems to be paradoxical to the ‘decreased flexibility’ observed in the other study on LSD. The reversal of learning discussed in the next section is not necessarily reversal learning, but it could be related. Below the described effect is a biological ‘reversal of learning’.
Reversal of LearningChildren are known to have more synapses which are later pruned away with aging through synaptic pruning. Synaptogenesis observed with dosing psychedelic drugs can be viewed as a reversal of synaptic pruning, perhaps even a reversal of learning on some level. Dendritic arborization is linked to cognitive deficits, possibly existing as a shadow of ‘non-learning’. Dendrites may normally disappear as structured neuron responses develop, so that the brain doesn’t test neuron pathways that are already determined to fail in learned circumstances. For example, learning to walk you may try every possible movement until you find the right ones. Dendrites that lead to neurons with ‘wrong’ movements might be pruned away. In the case of children growing older, the loss of phoneme awareness might be a product of synaptic pruning. There is a study on nicotine that revealed increased dendritic arborization in the motor cortex, producing enhanced motor skills but reduced motor learning (Gonzalez, Gharbawie, Whishaw, & Kolb 2005). The enhanced motor skill may be due to enhanced acuity of the senses. There may be some trade off between awareness of fine sensory details and also behavioral and cognitive automation (learning), which may involve reducing sensory details and highlighting the primed responses, filtering out wrong responses, at the cost of filtering out details. This study is complicated due to the fact that nicotine can stimulate increasing dynorphin activity (Isola, Zhang, Tejwani et al 2009) which has been associated to cognitive impairment, including Alzheimer’s disease (Ménard, Herzog, Schwarzer, & Quirion 2014). The learning impairment observed may not reflect anything related to the arborization but be confounded by upregulation of cognitive impairing mechanisms like dynorphin. Dendritic arborization is linked to low intelligence (Genç, Fraenz, Schlüter et al 2018). This is complicated due to schizophrenia involving reduced dendrites in the prefrontal cortex (Glantz & Lewis 2000), the cerebral cortex (Garey, Ong, Patel et al 1998), the auditory cortex (Sweet, Henteleff, Zhang et al 2008). and also associating to low intelligence (David, Malmberg, Brandt et al 1997). Low intelligence might mean less synaptic pruning, perhaps because learning is not occurring and so there is no pruning to sculpt the neural paths. So if psychedelics increase dendritic arborization, this may not necessarily harm learning ability, but rather it may be that low learning ability produces high dendrite preservation in those with learning impairments. Autism is thought to involve increased dendritic spines (Hutsler, & Zhang 2010) and impaired pruning (Tang, Gudsnuk, Kuo et al 2014). This is particularly interesting because auditory processing disorder is associated to autism (O’connor 2012) and sometimes eidetic memory (Cesaroni & Garber 1991). This idea came to me when a reader contacted me about preserved phoneme sensitivity in adulthood. This individual noted that he began studying language and phonetics as well. Then I asked the individual if he was diagnosed with autism and he reported yes, he is. It may be that pruning reduces the sensitivity to phonetic details that are usually neglected, such as those from foreign languages. This individual may have less pruning and thus higher acuity for phonemes. This is extremely anecdotal, and real research would be needed to back this notion up, but it is still interesting and we may eventually find savantism, sensory overload, and eidetic memory to associate to excess connectivity in autism as well. The excess pruning in the auditory cortex of schizophrenia may produce enhanced “recognition” of sounds in unrecognizable noise, producing hallucinations. In autism, the lack of pruning may lead to a decreased ability to recognize language, perhaps perceiving more auditory events as more ‘noisey’. These speculations warrant further investigation in future research on these topics. Autism and schizophrenia seem to share impaired 5HT2a receptor functioning. Have caution in assuming differences between these two disorders, as it is common to describe them as opposites, when there are also many overlaps. It is important to consider that, while 5HT2a receptors may play a role in plasticity, and while psychedelics may induce plasticity, that doesn’t mean that plasticity crucially depends on this receptor. 5HT2a receptors work by modulating glutamate release through an interaction with mGlur2 glutamate receptors (Moreno, Holloway, Albizu et al 2011). This may be one of the key factors in the observed plasticity with psychedelic use since glutamate NMDA and AMPA receptors are hugely critical to plasticity (Lüscher & Malenka 2012). These receptors likely function in the absence of 5HT2a receptors. The endogenous role of the 5HT2a receptor may be to slow or even reverse the loss of plasticity due to environmental circumstance. This function might be key to slowing the loss of plasticity in children and maintaining a kind of ‘openness’ to change that allows for normal child development. When psychedelic drugs stimulate 5HT2a receptors, the effect may bring back secondary plasticity mechanisms that are functioning independent from the 5HT2a receptor itself. With low 5HT2a receptors, a child might develop differently. For example, there is evidence of decreased 5HT2a receptor activity in autism (Cook & Leventhal 1996).
Brain Differences Between Adults, Children, and Adults on PsychedelicsCarhart-Harris, a popular psychedelic researcher (Martin, R., & Carhart-Harris 2016), and Alison Gopnik, a researcher of Psychology at UC Berkeley (Gopnik 2019), have both stated that the effects of psychedelics seem to resemble the mind of an infant. Research using fMRI scans on children and LSD users seems to hint at this. There have been comparisons of adults’ and infants/childrens’ brains on an fMRI that revealed differences in theory-of-mind related networks and pain related networks (Richardson, Lisandrelli, Riobueno-Naylor, & Saxe 2018). The researchers found that adults have less between network activation compared with children, specifically they measured theory-of-mind and pain networks, showing that adults have anti-correlated activity, while children have more between network activity. A study on individuals given the psychedelic drug LSD showed increased global functional connectivity in the brain according to the fMRI scans (Tagliazucchi, Roseman, Kaelen et al 2016). This study found that brain regions that normally don’t communicate increased communication during the LSD effect. This might resemble a reduction in ‘anti-correlated’ activity observed in the adults of the study comparing infants to adults. This may also resemble the increased ‘between network’ activity observed in the infants. Another study on LSD found increased thalamic resting-state connectivity, which were found to correlate to the visual alterations of LSD (Müller, Lenz, Dolder et al 2017). Children have been observed to have decreased default mode network (DMN) activity compared to adults (Fair, Cohen, Dosenbach et al 2008), something that is observed in psychedelic users as well (Carhart-Harris, Erritzoe, Williams, et al 2012). The DMN is thought to be involved with ‘resting state consciousness’ and sometimes described as task-negative, due to observations that tasks requiring one’s attention seem to suppress this network (Fox, Snyder, Vincent et al 2005). The DMN may not be as strong in the children because they have yet to develop strategies of automating tasks or doing ‘auto-pilot’ work, resulting in tasks requiring immediate awareness more than adults. For example, driving a car the first time cannot be done on auto-pilot and neither can living life generally. It is something that develops with time, which we may observe the DMN to increase in correlation with such a development. The increased global functional connectivity might be something we observe in children, perhaps due to a less conditioned state of mind. When the brain has not yet fully automated and learned to habitually respond to environmental circumstances, there may be more brain activity as the brain tries to figure out what pathways, actions, decisions, and reactions are most effective to solve the novel problems one faces. As the situation becomes less novel, connectivity could decline, because it may be excessive, unnecessary, and resource intensive. After effective behavioral and cognitive solutions are found for the novel problem, other activity, and perhaps synapses themselves are pruned, reducing the cognitive flexibility, overall functional connectivity, and the diversity of ways one can react to the situation. On the other hand, psychedelic may upregulate the synapses, increase connectivity, and restore the mind to an unconditioned state, which may help to explain the strange perceptual effects of the drugs. One may begin to see the world as if they were uncertain about it. As if one must consciously observe the situation and cycle through possible judgements, interpretations, and perceptual gestalts in order to resolve the uncertainty. Children live in a world that is uncertain and novel. They are pushed into a world for which they have yet to automate their responses to. They may need to have a kind of ‘higher state of consciousness’, which is later pruned with aging, familiarity, and habituation of behaviors. The childhood psychedelia may prevent us from defining the external world too quickly, allowing us to accumulate more samples over time. Without this, the child may define their world too quickly, jumping to conclusions, both perceptually, situationally, logically, and so on. Since autism and schizophrenia reveal an impairment to the 5HT2a receptor, the lack of such childhood psychedelia may lead to developmental aberration.
Perceptual CalibrationBesides having the ability to distinguish more nuances in phonetic sounds, children have also been known to have eidetic (photographic) memory at times, whereas adults virtually never do (Haber 1979). There is a similar phenomenon in which many report that they cannot ‘see’ anything in their imagination. This is known as aphantasia. It may be that aphantasia is also lost with aging, due to the unnecessity and excessiveness it brings. The loss of mental imagery from eidetic memory and aphantasia may occur because of more efficient strategies developing that utilize abstraction and reduced levels of detail. For example, an infant has no words to use in memory yet. Many adults will remember narratives, sentences, words, and symbols in order to remember events and details. The lack of such strategies may force us to use photographic memory which may be very intensive and inefficient. After we stop using visual imagery, both eidetic memory and aphantasia, we may end up neglecting it and nearly forgetting it. This is particularly interesting because there has been a case report of aphantasia being ‘cured’ by a serotonergic psychedelic drug (dos Santos, Enyart, Bouso et al 2018). This could be an effect of returning to the child’s state of mind. There is an old study that explored long term changes to visual perception in color distinction in LSD users (Abraham 1982). The researchers tested using a white circle with a yellow outline and asked to report the color of the circle and not the yellow outline. Those who have used LSD in the past showed worse performance on this task. Humans also are reported to lose their color distinction abilities and cones with age (Salvi, Akhtar, & Currie 2006). It is also known that color perception involves optical illusions, usually due to shading and lighting as well as other contextual cues. One of these illusions is known as color constancy, in which people will perceive colors that are not present.
An example of color constancy is below:This image is not really red, it is grey and blue. While grey contains ‘red’ in it, it is not a color we usually consider to be red. This shows that color perception is relative to context, where grey and red can look like the same color under different conditions. This could be a learned trick that we acquire early in childhood while we are still developing our visual perception systems. We may track the common patterns and properties of visual perception, learning to see depth, color, adapt to lighting, and so on. It could be that something like color constancy maintains our normal color perceptions of the world, despite the degradation of cones in the eye. This may involve a process of referring to memory as guidance for perceptual experiences, as opposed to dominantly referring to information coming from the eyes. This may be true of most optical illusions, which do seem learned, considering that they differ by culture (Ahluwalia 1978) and can be shut down by amnesiac drugs (Jacobsen, Barros, & Maior 2017). The child may adapt their perception and build a library of perceptual samples to refer to when building their perceptual landscape during the early years of life, or perhaps in just the first month or even days. Serotonin was able to induce visual cortex plasticity in adult rats (Vetencourt, Tiraboschi, Spolidoro et al 2011), something that might apply to psychedelics too since they are serotonin agonists. If the psychedelic drugs induce visual system plasticity, then this could account for long-term alterations of visual perception after the use of the drug. Some of the effects observed after psychedelic use, such as HPPD, seem more like seizure and migraine aura. This makes some sense as glutamate NMDA receptors are critically involved in plasticity (Lüscher & Malenka 2012) and also migraine and seizure (Rogawski 2008). During the psychedelic effect, users may access modalities of sensory experience that have been long abandoned since very early childhood. Perceptual modalities that adults aren’t even aware of. These may be functional in childhood but vestigial and often pruned away as adults. One might observe the return of their imagination, eidetic memories, and visual processing styles that are ‘hyper-dimensional’ compared to our relatively 2-dimensional adult styles. In the same way that imagination and eidetic memory add depth to experience, the psychedelic may add similar layers of depth to auditory processing, visual processing, cognition, memory and so on. These may sometimes be dysfunctional and useless for navigating the world compared to the advantages of learned and habitual navigation that replaces these modalities.
ParticipantsThe participants will be gathered through an advertisement on Google targeted to California residents. The participants will be selected based on willingness to consume psychedelic drugs and also no underlying medical conditions or mental health problems. This is somewhat a convenience sample and may introduce selection bias due to filtering for those willing to partake in the psychedelic experimental condition. This may not be a problem though, as it isn’t expected that Google users or those willing to take psychedelics would have more child-like brains. It is possible that previous users of psychedelic users will have long-term changes that alter the outcomes, so we will survey the participants to find out if they have previously used psychedelic drugs. This may prove to be valuable for the results if the participants who have prior psychedelic use end up revealing differences from the other groups. The aim is to have at least 50 adult participants with only 25 of the paticipants having had previous exposure to psychedelic drugs. Half of the adult participants will be assigned to take a medium dose of psilocybin through random assignment using coin flips to determine which group each participant is in. The child participants will be selected from elementary schools in various regions of the state of California. The participants do not need to be attending the school, so for example younger siblings may be opted in. The participants’ parents will be offered payment through which we will suggest treating the children with. To acquire infant participants, we will ask new parents at various hospitals using flyers that offer financial incentive. The hope is to have at least 30 participants in the infant group, 10 being under 2 years, 10 being under 5 years and 10 being under 7 years old. This will allow observations of differences between different ages.
ProcedureAdult participants will be selected into two groups based on the flip of a coin. One group is the adult control group, where no drug is given. The second group is the psychedelic dose group. The control group will be given a placebo (sugar pill) just to ensure that the act of giving the drug does not produce the observed results. The environment for the intoxication state is a comfortable lounge where casually dressed researchers will comfort and entertain the participants. This is to ensure that the experience is positive. There will be lorazepam onsite in case any participant wishes to abort. Each participant will be scheduled for the lounge one at a time, for privacy and to reduce confounds introduced by the social environment. The drug used is psilocybin which has been gaining traction for use in research in recent years. The dose will be 20mg/70kg which is considered to be a somewhat medium dose of the drug according to common recreational use. This dose is also thought to produce the least amount of negative effects while still producing lasting positive outcomes (Griffiths, Johnson, Richards et al 2011). At the beginning of the experiment participants will be given their dose or placebo and be expected to stay in the lounge area for the duration of the effects, 5-6 hours at least. As the dose is kicking in the participants will be requested to not engage any of the entertainment that is available, such as toys, games, movies, and so on, due to reducing confounds up until the brain scans are performed. After all of the testing, the participants are free to enjoy themselves with the entertaining stimuli. Before the scanning begins, the lounge assistant accompanying the participant will interview the participants about how they feel and what they think. First they will be asked to rate their mood and emotional state on an EGWA-based scale. This is so that we might be able to detect if these moods and emotions play any role in the outcomes of the brain scans. After 2 hours post-dose, the participants will begin the fMRI test. The fMRI will be modified to reduce the sound, so that it is more suited for the infant group. The scans will first be done with a movie playing. The film that plays will be non-English and cartoon. This will reduce the effects that meaningful information may have since this could be a confound if the children cannot process the information while the adults can. We will ask if the participant has heard of the obscure film and if they understand the language of the film beforehand to ensure that participants are not familiar. If any are familiar, we will observe whether this has an effect and keep track of participants who have familiarity. In this test, the fMRI protocol will mirror the study performed by Tagliazucchi, Roseman, Kaelen et al in 2016. A second test will be how observing a social interaction from a film changes brain states on the fMRI. The observed interaction will be of two people having a casual conversation, laughing, and hugging to say goodbye. This is chosen due to the reported differences in theory of mind networks observed in children. The fMRI protocol will mirror the study performed by Richardson, Lisandrelli, Riobueno-Naylor, & Saxe in 2018.
AnalysisIn the Tagliazucchi study they used a two tailed t test to compare the degree of spatial overlap between brain network activations in both LSD users and a placebo group. From their study: “The overlap was determined by comparing the percentage of voxels in the networks included in the FCD/seed correlation difference maps to the same numbers obtained from 500 instances of spatial randomisation of the networks (preserving the first-order statistics of the images)” (Tagliazucchi, Roseman, Kaelen et al 2016). This process will be imitated but with the addition of an infant/child group, in order to see if the young group produces similar results as the psilocybin users, with the aim of seeing if psilocybin influences the brain in a way that produces a state comparable to a child’s.
DISCUSSIONIf the brain states of psilocybin users and children are similar, this could have implications for altering human development, re-entering developmental phases, learning, and treatment of developmental disorders that may involve altered 5HT2a receptor function. There was a study that was cancelled during the banning of LSD that showed that children with autism or ‘childhood schizophrenia’ could potentially be treated by frequent (approximately monthly) and repeated large doses of LSD and psilocybin (Fisher 1997). There was improvement in many of the participants, some were even able to return to school after being institutionalized previously. Although there are definite ethical worries with such research, it shows us that the drug could potentially be beneficial in these cases of developmental aberration. The findings could have implications for language acquisition. We could imagine a future in which a 2-6 weeks language learning course utilizes psychedelics to speed up language acquisition. Similarly, we may find that general learning capabilities are enhanced or perhaps only for specific kinds of learning. A course of psychedelics could be found effective in helping restore a youthful and plastic mind in Alzheimer’s disease or schizophrenic patients. We may even find that psychedelics improve cognition in mentally ‘normal’ individuals. This kind of use has been emerging in today’s culture with people microdosing for learning improvement. Lastly, the results may help us understand what it is like to be an infant. If the psychedelics do bring back the childhood critical period, this could also mean that, like the child, extreme developmental sensitivity occurs as well. Consuming cannabis on psychedelics could be similar to giving young children cannabis. Being traumatized on psychedelics may be like traumatizing children, and so on.
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