Recommended readings 2
Serotonin Receptors


This list was made by Jagoda Mackowiak in cooperation, and co-published, with Blossom.

Altered States of Consciousness (ASCs) can be generally induced by psychoactive substances or non-pharmacological methods. Such substances include psychedelics and their intake is characterized by profound psychological and cognitive changes. These changes can be observed in sensory perception, emotion, thought, and sense of self.1

Serotonin (5-hydroxytryptamine or 5HT) was identified in the 19th century as a substance involved in smooth muscle contraction, but its relationship with hallucinogens was first established shortly after the discovery of LSD by Albert Hofmann.2 In the 1980s it was proposed that serotonin receptors play a role in the cellular and behavioral mechanisms of action of psychedelics. This was verified in 2003 in experiments with genetically engineered mice lacking serotonin receptors.3

Today, it is established that serotonin is found in the whole body and the molecule has no odor, no flavor, and no single distinctive function. However, it is responsible for a broad spectrum of physiological processes, depending on its receptors’ location and subtype. Outside of the brain, serotonin acts mostly as a hormone involved in a multitude of functions, such as embryonic development and regulation of the gut contractions. Within the brain serotonin receptors are instrumental and represent a primary drug target in various clinical areas.4

Serotonin cannot cross the blood-brain barrier, and therefore it is synthesized from tryptophan (an essential amino acid found in food) within the brain, where it acts as a neurotransmitter. Serotonin receptors are found across all brain regions. The 5HT-system in the brain modulates cognitive and behavioral functions, such as sleep, mood, learning, memory, anxiety and stress, patience and coping, and plasticity-mediated adaptability5 to name just a few. The system’s malfunction can lead to the development of common mental disorders.

Our current understanding of 5HT receptor’s function predicts that the Altered States of Consciousness are highly likely to be induced by 5HT receptor agonists. Classical psychedelics, such as LSD and psilocybin, act as 5HT2A receptor agonists. The following articles discuss the putative effects of 5HT signaling on a molecular, neurological, and psychological level.

This list of recommended readings will explore the diversity among serotonin receptors, the history of their discovery, their relationships with psychedelics, and their mechanisms of mediating subjective experiences and therapeutic effects.

1. Geyer, M.A., and Vollenweider, F.X. (2008) Serotonin research: contributions to understanding psychoses. Trends Pharmacol. Sci. 29, 445–453.
2. Green, A.R. (2008) Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK. Br J Pharmacol. 154:1583–1599.
3. Gonzalez-Maeso, J., Yuen, T., Ebersole, B.J., Wurmbach, E., Lira, A., Zhou, M., Weisstaub, N., Hen, R., Gingrich, J.A., and Sealfon, S.C. (2003) Transcriptome fingerprints distinguish hallucinogenic and non-hallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci. 23:8836–8843.
4. McCorvy, J.D. and Roth, B.L. (2015) Structure and function of serotonin G protein-coupled receptors. Pharmacology & Therapeutics 150:129-142.
5. Carhart-Harris, R. L. and Nutt, D. J. (2017) Serotonin and Brain Function: a Tale of Two Receptors. Journal of Psychopharmacology, 31(9):1091–1120.

Serotonin is a ubiquitous molecule – it probably evolved around 700–800 million years ago and is found in a range of living organisms, from primitive single-cell eukaryotes to humans. Although 95% of the total body serotonin in humans is found outside of the Central Nervous System (CNS), serotonin receptors are located across all brain regions. There are 17 different 5HT receptor subtypes in humans, forming seven families that belong to the G-Protein Coupled Receptors (GPCRs) group (except for one, 5HT3, which is a ligand-gated ion channel). The structural diversity among 5HT receptors and their activation-inactivation switch’s molecular basis are explored in the review by Sarkar and colleagues. Today’s paradigm assumes that psychedelics act mainly upon 5HT2A type receptors (5HT2Ar). A detailed molecular structure of this specific receptor and the hallucinogenic and therapeutic effects it mediates are explored in Kim et al. 2020.

Sarkar, P., Mozumder, S., Bej, A. et al. (2020) Structure, dynamics and lipid interactions of serotonin receptors: excitements and challenges. Biophys Rev

Serotonin (5-hydroxytryptamine, 5-HT) is an intrinsically fluorescent neurotransmitter found in organisms spanning a wide evolutionary range. Serotonin exerts its diverse actions by binding to distinct cell membrane receptors which are classified into many groups. Serotonin receptors are involved in regulating a diverse array of physiological signaling pathways and belong to the family of either G protein-coupled receptors (GPCRs) or ligand-gated ion channels. Serotonergic signaling appears to play a key role in the generation and modulation of various cognitive and behavioral functions such as sleep, mood, pain, anxiety, depression, aggression, and learning. Serotonin receptors act as drug targets for a number of diseases, particularly neuropsychiatric disorders. The signaling mechanism and efficiency of serotonin receptors depend on their amazing ability to rapidly access multiple conformational states. This conformational plasticity, necessary for the wide variety of functions displayed by serotonin receptors, is regulated by binding to various ligands. In this review, we provide a succinct overview of recent developments in generating and analyzing high-resolution structures of serotonin receptors obtained using crystallography and cryo-electron microscopy. Capturing structures of distinct conformational states is crucial for understanding the mechanism of action of these receptors, which could provide important insight for rational drug design targeting serotonin receptors. We further provide emerging information and insight from studies on interactions of membrane lipids (such as cholesterol) with serotonin receptors. We envision that a judicious combination of analysis of high-resolution structures and receptor-lipid interaction would allow a comprehensive understanding of GPCR structure, function and dynamics, thereby leading to efficient drug discovery.

Kim., K., Che, T., Panova, O., DiBerto, J.F., et al. (2020) Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell, 182(6):1574-1588.e19

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions—both therapeutic and hallucinogenic—are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH—a prototypical hallucinogen—in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.

In 1999 Patricia Whitaker-Azmitia authored an article where she discusses researchers’ profiles whose contributions were crucial for serotonin research developments. Among them Betty Mack Twarog, who in 1949 started studying the edible mussel (Mytilus edulis) at Harvard. She identified serotonin as the neurotransmitter which regulated the smooth muscle in Mytilus, and a few years later, discovered it in the mammalian brain. In 1953 Twarog published her best-known article with Irvine Page, who had previously isolated serotonin from blood serum while studying hypertension.
An exploration of serotonin’s importance in psychedelic research and its historical context was written by Vollenweider and Kometer (2010). This article discusses the developments in therapeutic studies, presents a timeline of the research on psychedelics, and introduces the reader to the scales of assessing ASCs. It provides an insight into understanding the role of 5HT2A receptors in the mechanism of action of classical hallucinogens.

Whitaker-Azmitia, P. (1999) The Discovery of Serotonin and its Role in Neuroscience. Neuropsychopharmacol 21, 2–8

When reading the various stories of how serotonin was discovered, it immediately becomes apparent how fortuitous it was that serotonin was discovered at all. It started out as an annoying artifact that had to be gotten rid of before the real work of finding the cause of hypertension could be gotten to. It ended as one of the most important discoveries in neuroscience. Indeed, in many ways, serotonin gave birth to the field of neuroscience.

How did this good fortune arise? Clearly, the discovery was solely due to the uniqueness and genius of each of the researchers involved. Thus, to tell the study of how serotonin was discovered, it is best to describe the individual scientists and their goals, and how they came together to make their great discovery.

Twarog, B.M., Page, I.H. (1953) Serotonin content of some mammalian tissues and urine and a method for its determination. Am J Physiol 175: 157–161

Vollenweider, F., Kometer, M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 11, 642–651 (2010).

After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.

An introductory overview of the history of discovery and early studies on 5HT and 5HT receptors was published by López-Giménez and González-Maeso in 2018 (for an extensive review of the very early studies on 5HT see Green, 2008). In their review, the physiological functions influenced by serotonin receptors and their response to psychedelics are discussed in a great amount of detail. A close look is taken at ‘biased agonism,’ which is a phenomenon where both hallucinogenic and non-hallucinogenic agonists can activate the same 5HT receptors, and depending on the type of ligand, a different signaling pathway is triggered. The authors offer a detailed overview of these agonist-specific pathways and their molecular targets, which influence physiological (and pathophysiological) responses.

López-Giménez, J. F. & González-Maeso J., (2018) Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways. Curr Top Behav Neurosci. 36:45–73

The neuropsychological effects of naturally occurring psychoactive chemicals have been recognized for millennia. Hallucinogens, which include naturally occurring chemicals such as mescaline and psilocybin, as well as synthetic compounds, such as lysergic acid diethylamide (LSD), induce profound alterations of human consciousness, emotion, and cognition. The discovery of the hallucinogenic effects of LSD and the observations that LSD and the endogenous ligand serotonin share chemical and pharmacological profiles led to the suggestion that biogenic amines like serotonin were involved in the psychosis of mental disorders such as schizophrenia. Although they bind other G protein-coupled receptor (GPCR) subtypes, studies indicate that several effects of hallucinogens involve agonist activity at the serotonin 5-HT2A receptor. In this chapter, we review recent advances in understanding hallucinogen drug action through characterization of structure, neuroanatomical location, and function of the 5-HT2A receptor.

Green, A.R.(2008) Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK. Br J Pharmacol. 154:1583–1599

The vasoconstrictor substance named serotonin was identified as 5-hydroxytryptamine (5-HT) by Maurice Rapport in 1949. In 1951, Rapport gave Gaddum samples of 5-HT substance allowing him to develop a bioassay to both detect and measure the amine. Gaddum and colleagues rapidly identified 5-HT in brain and showed that lysergic acid diethylamide (LSD) antagonized its action in peripheral tissues. Gaddum accordingly postulated that 5-HT might have a role in mood regulation. This review examines the role of UK scientists in the first 20 years following these major discoveries, discussing their role in developing assays for 5-HT in the CNS, identifying the enzymes involved in the synthesis and metabolism of 5-HT and investigating the effect of drugs on brain 5-HT. It reviews studies on the effects of LSD in humans, including Gaddum's self-administration experiments. It outlines investigations on the role of 5-HT in psychiatric disorders, including studies on the effect of antidepressant drugs on the 5-HT concentration in rodent and human brain, and the attempts to examine 5-HT biochemistry in the brains of patients with depressive illness. It is clear that a rather small group of both preclinical scientists and psychiatrists in the UK made major advances in our understanding of the role of 5-HT in the brain, paving the way for much of the knowledge now taken for granted when discussing ways that 5-HT might be involved in the control of mood and the idea that therapeutic drugs used to alleviate psychiatric illness might alter the function of cerebral 5-HT.


Robin Carhart-Harris and David Nutt attempted to establish a unified theory of brain serotonin function. In 2017 they published ‘A Tale of Two Receptors’ – an extensive review of previous research results proposing a bipartite model of brain 5HT function. This model focuses on a tandem of receptors and implies that ‘the 5-HT1A and 5-HT2A receptors show diametrically opposite responses to their endogenous ligand, with 5-HT1A receptor signaling being inhibitory and 5-HT2A being excitatory.’ They further suggest that 5HT1Ar signaling corresponds to ‘passive coping,’ which is a psychological mechanism of increasing tolerance to uncomfortable stimuli, whereas 5HT2Ar induces ‘active coping,’ so an active attempt to deal with the source of distress by changing one’s relationship to it. The two researchers propose that activation of 5HT2Ar ‘opens a window of plasticity during which environmental-sensitivity is enhanced and significant therapeutic work can be done.’ The effects of 5HT2Ar agonism are time- and context-sensitive. Therefore, a complementary model is proposed – the Extrapharmacological Model – which aims to unify the variables of the acute state and long-term outcomes of 5HT2Ar activation. Considering elements such as biological and psychological predispositions of a patient, their attitude to hallucinogenic substances (set), the environment (setting), and dose, the model aims to predict the quality of the acute psychedelic state and the long-term effects of psychedelic-assisted psychotherapy.

Carhart-Harris, R.L. and Nutt, D.J. (2017) Serotonin and Brain Function: a Tale of Two Receptors. Journal of Psychopharmacology, 31(9):1091–1120

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.


Since coping is the primary determinant of stress resilience, its mechanisms have been researched extensively. Puglisi and Andolina summarized the studies on coping mechanisms and the neurobiology of 5HT receptors across evolution and environmental influences. In their review, they proposed a model of a serotonin-driven stress-coping brain network. In this model, external stress stimuli affect serotonergic neurons which trigger a chain of neuronal projections eventually reaching the amygdala. The changes in the amygdala lead to modulation of glutamate output to nucleus accumbens, resulting in prompting active or passive coping behavior. The model suggests that the regulation of adaptive and maladaptive stress responses requires a top-down control through 5-HT1A receptors.

Puglisi-Allegra, S. and Andolina, D. (2015) 5HT and stress coping. Behavioral Brain Research, 277:58-67

Coping is the necessary outcome of any stressful situation and the major determinant of stress resilience. Coping strategies can be divided into two broad categories, based on the presence (active) or absence (passive) of attempts to act upon the stressor. The role of brain serotonin (5-hydroxytryptamine, 5-HT) in coping behavior that is emerging from studies in animals and humans is the subject of this article. We have focused attention on studies that consider the coping behavior exhibited when the individual is faced with a new stressful experience. Coping styles characterize different species with different evolutionary histories, from fishes to mammals, and evidence shows that serotonin transmission in the central nervous system, with differences in transporter, receptor types and hormone or neurotransmitter influences is critical in determining coping behavior. Moreover, a major role of environmental challenges throughout the lifespan affects brain systems that control coping outcomes through 5-HT transmission. In particular early experiences, for their long-term effects in adulthood, and social experiences throughout the life span, for the effects on serotonin functioning, received attention in preclinical research because of their parallelism in humans and animals. Based on growing evidence pointing to a medial prefrontal cortex–amygdala system in mediating adaptive and maladaptive stress responses, we propose a brain circuit in which serotonin neurons in the dorsal raphe depending on the CRF (corticotropin releasing factor) regulatory action engage a prefrontal cortical–amygdala pathway through 5-HT1A receptors, GABA and Glutamate to moderate coping behavior.

In depression and other neuropsychiatric disorders, degradation of neurons and loss of dendritic spines is a common marker. Some studies on ketamine and serotonergic psychedelics suggest that these substances promote neuronal growth and the strengthening of synaptic responses by promoting plasticity. This study demonstrated a robust psychoplastogenic response to DMT and psilocin, MDMA, DOI, and LSD in rodents. The effect was inhibited in a dose-dependent fashion by increasing the ketanserin concentration, which is an antagonist of 5-HT2A receptors. The results suggested that psychedelics mediate structural plasticity by increasing the density of dendritic spines on cortical neurons.

Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., et al. (2018) Psychedelics Promote Structural and Functional Neural Plasticity. Cell Reports, 23(11):3170–3182

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.

The specifics of the relationship between the 5HT2A receptor occupancy, plasma psilocin levels, and the subjective psychedelic experience were investigated by Matsen et al. in 2019. Their pharmacokinetic model predicts maximum receptor occupancies as an alternative to radioligand testing. The data showed a correlation between 5HT2A receptor occupancy and psilocin plasma levels, which in turn correlates closely with the subjective psychedelic experience. The model could replace PET-imaging in future clinical trials and provide a more accurate way to predict the intensity of the subjective effects based on absolute substance dose.

Madsen, M.K., Fisher, P.M., Burmester, D. et al. (2019) Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacol. 44:1328–1334

The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin’s active metabolite, psilocin. We here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans. Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [11C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3–30 mg). 5-HT2AR occupancy was calculated as the percent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modeled using non-linear regression. Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores. We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin time-concentration curves varied but psilocin levels were closely associated with psychedelic experience.

In the search for a better understanding of the subjective effects of psychedelics, Katrin Preller and colleagues investigated the role of the 5-HT2Ar signaling in self- and other-initiated social interaction through the use of neuroimaging in patients treated with LSD, with and without ketanserin pre-treatment, and placebo. The change in brain activity was linked to subjective experience, and the data suggests that LSD causes a decrease in brain activity in the areas related to the Default Mode Network (DNM) and implicated in self-processing. In comparison to ketanserin or placebo, LSD resulted in decreased efficiency of establishing joint attention. These results mean that through the 5HT system, LSD caused a reduction in self-related processing, and therefore in a decrease of differentiation between the self and others during social interaction.

Preller, K. H., Schilbach, L., Pokorny, T., Flemming, J., Seifritz, E., and Vollenweider, F. X. (2018) Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study. The Journal of neuroscience: the official journal of the Society for Neuroscience, 38(14):3603–3611

Distortions of self-experience are critical symptoms of psychiatric disorders and have detrimental effects on social interactions. In light of the immense need for improved and targeted interventions for social impairments, it is important to better understand the neurochemical substrates of social interaction abilities. We therefore investigated the pharmacological and neural correlates of self- and other-initiated social interaction. In a double-blind, randomized, counterbalanced, crossover study 24 healthy human participants (18 males and 6 females) received either (1) placebo + placebo, (2) placebo + lysergic acid diethylamide (LSD; 100 μg, p.o.), or (3) ketanserin (40 mg, p.o.) + LSD (100 μg, p.o.) on three different occasions. Participants took part in an interactive task using eye-tracking and functional magnetic resonance imaging completing trials of self- and other-initiated joint and non-joint attention. Results demonstrate first, that LSD reduced activity in brain areas important for self-processing, but also social cognition; second, that change in brain activity was linked to subjective experience; and third, that LSD decreased the efficiency of establishing joint attention. Furthermore, LSD-induced effects were blocked by the serotonin 2A receptor (5-HT2AR) antagonist ketanserin, indicating that effects of LSD are attributable to 5-HT2AR stimulation. The current results demonstrate that activity in areas of the “social brain” can be modulated via the 5-HT2AR thereby pointing toward this system as a potential target for the treatment of social impairments associated with psychiatric disorders.

SIGNIFICANCE STATEMENT Distortions of self-representation and, potentially related to this, dysfunctional social cognition are central hallmarks of various psychiatric disorders and critically impact disease development, progression, treatment, as well as real-world functioning. However, these deficits are insufficiently targeted by current treatment approaches. The administration of lysergic acid diethylamide (LSD) in combination with functional magnetic resonance imaging and real-time eye-tracking offers the unique opportunity to study alterations in self-experience, their relation to social cognition, and the underlying neuropharmacology. Results demonstrate that LSD alters self-experience as well as basic social cognition processing in areas of the “social brain”. Furthermore, these alterations are attributable to 5-HT2A receptor stimulation, thereby pinpointing toward this receptor system in the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders.


The Subjective Drug Intensity (SDI) and the Mystical Experience Questionnaire (MEQ) are often used to measure subjective experiences induced by psychedelics, along with PET scans, which assess 5HT2Ar binding. In the recent study of Stenbaek et al. (2020), the SDI was measured every 20 min and MEQ at the end of the session. The data revealed that during the experience after a single dose of psilocybin, the real-time estimate of SDI correlated with the percentage of 5HT2Ar occupancy. The authors suggest that ‘longer peak plateau and a more rapid return to normal waking consciousness, as measured with SDI, are temporal subjective building blocks upon which a more profound mystical experience can unfold.’ More research is recommended since the study did not explore individual variability in psilocin pharmacokinetics.

Stenbæk, D. S., Madsen, M. K., Ozenne, B., Kristiansen, S., Burmester, D., Erritzoe, D., Knudsen, G. M., & Fisher, P. M. (2020) Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. Journal of Psychopharmacology

Background: Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness.
Aims: We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals.
Method: Sixteen participants completed a pre-drug [11C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2–0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models.
Results: Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score.
Conclusion: This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.

Neuroimaging studies suggest comparable neuronal activation patterns in temporal lobe regions during the REM sleep phase and psychedelic experiences. A common feature investigated by studies on the phenomenological structure of dreaming is termed cognitive bizarreness. It is a strange and irrational quality of dreams, where events, perception, and thoughts are imaginary and improbable. This double-blind study measured the cognitive bizarreness scores during a guided mental imagery task in a post-peak LSD-induced state, placebo, and LSD after pre-treatment with ketanserin. The data showed that LSD increased cognitive bizarreness, which was related to the subjective loss of self-boundaries and cognitive control. Ketanserin treatment caused 5HT2Ar inhibition and the failure of the dreamlike effect. These results contributed to the understanding of the basis of dreamlike waking imagery in LSD-induced states, regulated by 5HT2A receptors.

Kraehenmann, R., Pokorny, D., Vollenweider, L., Preller, K. H., Pokorny, T., Seifritz, E., & Vollenweider, F. X. (2017) Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation. Psychopharmacology, 234(13):2031–2046

Rationale: Accumulating evidence indicates that the mixed serotonin and dopamine receptor agonist lysergic acid diethylamide (LSD) induces an altered state of consciousness that resembles dreaming.
Objectives: This study aimed to test the hypotheses that LSD produces dreamlike waking imagery and that this imagery depends on 5-HT2A receptor activation and is related to subjective drug effects.
Methods: Twenty-five healthy subjects performed an audiorecorded guided mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). Cognitive bizarreness of guided mental imagery reports was quantified as a standardised formal measure of dream mentation. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) questionnaire.
Results: LSD, compared with placebo, significantly increased cognitive bizarreness (p < 0.001). The LSD-induced increase in cognitive bizarreness was positively correlated with the LSD-induced loss of self-boundaries and cognitive control (p < 0.05). Both LSD-induced increases in cognitive bizarreness and changes in state of consciousness were fully blocked by ketanserin.
Conclusions: LSD produced mental imagery similar to dreaming, primarily via activation of the 5-HT2A receptor and in relation to loss of self-boundaries and cognitive control. Future psychopharmacological studies should assess the differential contribution of the D2/D1 and 5-HT1A receptors to cognitive bizarreness.

Kraehenmann and colleagues used a similar double-blind, placebo-controlled study design on LSD with ketanserin as a 5HT2Ar antagonist. In this study, they investigated primary process thinking – an automatic mode of mental organization characterized by image fusions, contradictory and illogical events, feelings, and thoughts, typically occurring during altered states of consciousness (ASCs), for example dreaming. DMN characterizes secondary process thinking which is a higher-level mental activity, based on reflection, adaptability, rationality, and logic. Primary index (PI) was used to measure primary process thinking, and cognitive bizarreness was evaluated from the mental imagery scores as a measure for dream mentation. The results suggested that LSD increases primary process thinking, and the authors proposed that psychedelic states may be hybrid states between waking and dreaming consciousness, induced by 5HT2A receptor activation.

Kraehenmann, R., Pokorny, D., Aicher, H., Preller, K.H., Pokorny, T., Bosch, O.G., Seifritz, E., and Vollenweider, F.X. (2017) LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation. Front. Pharmacol. 8:814

Rationale: Stimulation of serotonin 2A (5-HT2A) receptors by lysergic acid diethylamide (LSD) and related compounds such as psilocybin has previously been shown to increase primary process thinking – an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects.
Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). The main outcome variable in this study was primary index (PI), a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) rating scale.
Results: LSD, compared with placebo, significantly increased primary index (p < 0.001, Bonferroni-corrected). The LSD-induced increase in primary index was positively correlated with LSD-induced disembodiment (p < 0.05, Bonferroni-corrected), and blissful state (p < 0.05, Bonferroni-corrected) on the 5D-ASC. Both LSD-induced increases in primary index and changes in state of consciousness were fully blocked by ketanserin.
Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and psychedelic states of consciousness.

5HT2A receptors are abundantly expressed in the amygdala, where the activity is directly affected by psychedelics. Amygdala is involved in threat-processing and in pathophysiological conditions its hyperactivity might be modulated by 5HT2Ar agonists, leading to antidepressant and anxiolytic effects. This article analyzed the data from a previous study of the group, trying to contribute to the growing body of evidence that the effects of psilocybin on threat processing possibly arise from the changes in amygdala connectivity. The data showed that psilocybin (in a placebo-controlled setting) reduces the modulatory effects of visual threats. Furthermore, the researchers suggest a model, where reciprocal connections between the primary visual cortex and amygdala and between the amygdala and lateral prefrontal cortex are critical in regulating negative emotions.

Kraehenmann, R., Schmidt, A., Friston, K., Preller, K.H., Seifritz, E., and Vollenweider, F.X. (2016) The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. NeuroImage: Clinical, 11:53-60

Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

Several studies in this list focused on the universal mechanisms of psychedelic-induced 5HT receptor response. The subjective effects, however, can significantly vary among patients. To understand the individual variability in subjective states, Candace Lewis and colleagues investigated subjective ratings in sub-scales of the Five-Dimensional Altered State of Consciousness (5D-ASC) with high emotionality in healthy participants who received either a high or a low dose of psilocybin. The group, which included Katrin Preller and Franz Vollenweider, hypothesized that cingulate cortex thickness could predict the subjective psilocybin experience. Indeed, the greater thickness of the anterior cingulate cortex (but not caudal and posterior c.c.), which expresses a high amount of 5HT2A receptors, predicted higher subjective ratings in sub-scales of the 5D-ASC.

Lewis, C. R., Preller, K. H., Braden, B. B., Riecken, C., and Vollenweider, F. X. (2020) Rostral Anterior Cingulate Thickness Predicts the Emotional Psilocybin Experience. Biomedicines, 8(2):34

Psilocybin is the psychoactive compound of mushrooms in the psilocybe species. Psilocybin directly affects a number of serotonin receptors, with highest affinity for the serotonin 2A receptor (5HT-2Ar). Generally, the effects of psilocybin, and its active metabolite psilocin, are well established and include a range of cognitive, emotional, and perceptual perturbations. Despite the generality of these effects, there is a high degree of inter-individual variability in subjective psilocybin experiences that are not well understood. Others have shown brain morphology metrics derived from magnetic resonance imaging (MRI) can predict individual drug response. Due to high expression of serotonin 2A receptors (5HT-2Ar) in the cingulate cortex, and its prior associations with psilocybin, we investigate if cortical thickness of this structure predicts the psilocybin experience in healthy adults. We hypothesized that greater cingulate thickness would predict higher subjective ratings in sub-scales of the Five-Dimensional Altered State of Consciousness (5D-ASC) with high emotionality in healthy participants (n = 55) who received oral psilocybin (either low dose: 0.160 mg/kg or high dose: 0.215 mg/kg). After controlling for sex, age, and using false discovery rate (FDR) correction, we found the rostral anterior cingulate predicted all four emotional sub-scales, whereas the caudal and posterior cingulate did not. How classic psychedelic compounds induce such large inter-individual variability in subjective states has been a long-standing question in serotonergic research. These results extend the traditional set and setting hypothesis of the psychedelic experience to include brain structure metrics.