This post was made by Floris Wolswijk in cooperation, and co-published↗, with the MIND Foundation

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.  

Serotonin (5-hydroxytryptamine or 5HT) was identified in the 19^th 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. 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.

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.

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 adaptability 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 signalling on a molecular, neurological, and psychological level. 

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

Top 12 Psychedelics and Serotonin Receptors Papers Walkthrough 

1. Structure, dynamics and lipid interactions of serotonin receptors: excitements and challenges*

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) family (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 this review by Sarkar and colleagues (2020). 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 further in Kim and colleagues (2020).

*Unlike some of our other posts, some of the links (green instead of blue) go directly to the papers as some don’t speak directly about psychedelics

2. The Discovery of Serotonin and its Role in Neuroscience

In 1999, Patricia Whitaker-Azmitia authored an article where she discusses the profiles of researchers whose contributions were crucial for serotonin research developments. Among them Betty 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 these mollusks, and a few years later, discovered it in the mammalian brain. In 1953, Betty 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.

3. Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways

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. 

4. Serotonin and Brain Function: a Tale of Two Receptors

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 bipartite model focusing on a tandem of receptors 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 psychedelics (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.  

5. 5HT and stress coping

Since coping is the primary determinant of stress resilience, its mechanisms have been researched extensively. Puglisi and Andolina (2015) 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. 

6. Psychedelics Promote Structural and Functional Neural Plasticity

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 by Ly and colleagues (2018) demonstrated a robust psychoplastogenic response to DMT, 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. These results suggest that psychedelics mediate structural plasticity by increasing the density of dendritic spines on cortical neurons.

7. Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States

In the search for a better understanding of the subjective effects of psychedelics, Katrin Preller and colleagues (2018) 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. 

8. Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans

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 by Stenbaek and colleagues (2020), the SDI was taken 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 Subjective Drug Intensity 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. 

9. Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation

Neuroimaging studies suggest comparable neuronal activation patterns during the REM sleep phase and psychedelic experiences in temporal lobe regions. 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 by Kraehenmann and colleagues (2017) 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.

10. LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation

Kraehenmann and colleagues (2017) 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.

11. The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

5HT2A receptors are abundantly expressed in the amygdala, where the activity is directly affected by psychedelics. The amygdala is involved in threat-processing and in pathophysiological conditions its hyperactivity might be modulated by 5HT2Ar agonists, leading to antidepressant and anxiolytic (anxiety) effects. This article analysed 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.

12. Rostral Anterior Cingulate Thickness Predicts the Emotional Psilocybin Experience

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 (2020) 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.