Serotonin and brain function: a tale of two receptors

This theory-building article (2017) argues that the serotonin (5-HT) 2a receptor (psychedelics) is responsible for active coping (plasticity) of adversity, whereas the 5-HT1a receptor (SSRIs) only leads to passive coping (stress reduction). The theory offers an explanation for the different pathways and outcomes of psychedelics and more traditional medications/ways of coping.

Abstract

“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.”

Authors: Robin L. Carhart-Harris & David J. Nutt

Notes

This paper is included in our ‘Top 12 Articles on Psychedelics and Serotonin (5HT) Receptors‘

“We suggest that the 5-HT1AR and its associated functions dominate 5-HT transmission under normal conditions but that 5-HT2AR signalling also serves a role that becomes increasingly important during extreme states when 5-HT release is elevated. We propose that 5-HT mediates stress moderation and plasticity-mediated adaptability in response to different levels of stress and adversity, via its postsynaptic 1A and 2A receptors respectively.”

The function of serotonin in the brain is not well understood yet so the authors “argued that the riddle of 5-HT can only be solved by focusing on its individual receptor subtypes” … “we have chosen to concentrate on the 5-HT1A and 5-HT2A receptors.”

“In humans, the density of 5-HT2AR expression is relatively high throughout the cortex and especially so in high-level associative cortex – such as regions belonging to the so-called default-mode network”

“5-HT2A receptors are most densely expressed on the dendrites of excitatory glutamatergic pyramidal neurons, particular in layer V of the cortex” … “

“5-HT1AR is densely expressed in midbrain, limbic and cortical regions” … “The 5-HT1AR is highly expressed on serotonergic neurons in the dorsal and median raphe nuclei where it functions as a presynaptic autoreceptor – exerting a strong homeostatic control over 5-HT neuron firing rates and thus, 5-HT efflux in the forebrain” … “The majority of 5-HT1A receptors are expressed postsynaptically in many brain regions, particularly the limbic system (especially the hippocampus) and cortex”

On the psychological functions associated with brain 5-HT: “most reliable behavioural effects of reducing 5-HT transmission in the brain is to increase impulsive and aggressive behaviours”

On the anti-aggresion effects of psychedelics: “The anti-aggression effects of 5-HT enhancing compounds led to them being called ‘serenics’ (Olivier and Moss, 1990), a fitting term in our view, and one that is also apt in relation to the subjective effects of MDMA, a particularly potent 5-HT releaser. Related to these hypotheses, is the notion that 5-HT transmission enables a person to better tolerate delay (Soubrie, 1986), and the patience-promoting properties of 5-HT have recently received significant experimental support.” And “There are solid grounds to believe that the anti-aggression and impulsivity effects of 5-HT are mediated by postsynaptic 5-HT1A receptor signalling.”

Summary

Overview

The aim of this paper is to discuss the function of brain serotonin (5-HT) transmission by focusing on two of its major receptor subtypes, the 5-HT1AR and 5-HT2AR. A fuller understanding of 5-HT1A and 5-HT2A receptor signalling motivates a revision of current thinking on the function of brain serotonin transmission, with 5-HT1ARs mediating passive coping and 5-HT2ARs mediating active coping.

We accept the charge that our neglect of other serotonin receptors means that the present paper cannot be considered a fully comprehensive model of brain serotonin function. However, we propose that the functioning of signalling at other serotonin receptors may be comfortably incorporated into either (or both) arms of the bipartite model we introduce below.

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. We propose that the 5-HT1A and 5-HT2A receptors are involved in two distinct adaptive responses to adversity, and that different drugs can enhance these responses in different ways.

Brain serotonin functioning is seen through postsynaptic 5-HT1A and 5-HT2A receptor signalling. 5-HT1A receptors dominate 5-HT transmission under normal conditions, but 5-HT2AR signalling becomes increasingly important during extreme states when 5-HT release is elevated. We propose that combined signalling at the 5-HT1A and 2A receptors facilitates stress relief and a flexibility of mind, which is conducive to positive mood.

The function of brain serotonin is an enigma

The function of the serotonin system remains elusive due to the many receptor subtypes, extensive innervation of the brain and paracrine style of transmission. The riddle of 5-HT can only be solved by focusing on its individual receptor subtypes.

Accordingly, one strategy for understanding the serotonin system is to focus on a select number of receptor subtypes that have been particularly well characterised. The 5-HT1A and 5-HT2A receptors are the most prevalent serotonergic receptors in the brain, and show diametrically opposite responses to their endogenous ligand. This contrast is intriguing, and motivates us to ask why this should be the case.

As noted above, 5-HT receptors other than the 2A receptor may also modulate unrelated physiological and behavioural functions, and blockade of certain 5-HT receptors may complement pathway 1 (below).

In what follows, focus is directed to 5-HT1A and 5-HT2A receptor signalling and research pertaining to their associated functions. Potent serotonergic compounds such as MDMA and psilocybin are discussed, as well as a review of the literature on human research with such drugs.

MDMA’s 5-HT releasing properties are many times greater than its catecholamine releasing properties, and its subjective effects are also distinct from those of other more conventional amphetamines.

The 5-HT2AR is one of at least 14 different 5-HT receptor subtypes expressed in the mammalian brain, and is the main excitatory GPCR of the serotonin receptor family.

The 5-HT2AR is predominantly a cortical receptor, with high density in high-level associative cortex and minimal/negligible expression in the cerebellum and brain-stem. This places the 5-HT2AR at a high evolutionary and hierarchical level.

5-HT2A receptors are expressed on the dendrites of excitatory glutamatergic pyramidal neurons, particularly in layer V of the cortex, and are sensitive to changes in synaptic serotonin concentrations. They play a crucial role in regulating the release of serotonin in the cortex.

What is the 5-HT1AR and where is it expressed?

The 5-HT1AR is a subtype of 5-HT receptor that is highly expressed in midbrain, limbic and cortical regions. It functions as a presynaptic autoreceptor and is responsible for homeostatic control over 5-HT neuron firing rates and thus, 5-HT efflux in the forebrain.

Serotonin 2A versus 1A receptor signalling

5-HT2AR activation increases the excitability of the host neuron, resulting in increased firing of the host neuron and increased inhibition of the neurons to which it projects. When endogenous 5-HT is released in the cortex, it should elicit a mostly excitatory effect. However, the effect is modulated via postsynaptic 5-HT1ARs, and chronic dorsal raphe stimulation decreases metabolism in limbic regions, alongside decreases in depressive behaviours.

The 5-HT1AR and 5-HT2AR receptors in the PFC have opposite effects on single cell activity, with 5-HT1AR signalling having a hyperpolarising (inhibitory) effect, and 5-HT2AR signalling causing a depolarising (excitatory) effect. The 5-HT2A receptor is still likely to be functionally relevant during states of exceptionally high adversity.

ECS/ECT appears to decrease 5-HT1A receptor expression while increasing 5-HT2AR functioning in rats, primates, and humans, an effect that is more consistent with conventional antidepressant medications as well as direct 5-HT2AR agonism.

Impulsivity and aggression

Reduced 5-HT transmission in the brain increases impulsive and aggressive behaviours. This is consistent with the idea that 5-HT serves to suppress behavioural response to pain, anxiety and aversive stimuli more generally. 5-HT enhancing compounds have been found to reduce aggression and impulsivity, and tryptophan depletion, acute MDMA administration, acute fenfluramine administration and chronic 5-HT reuptake inhibitor administration have all been found to increase 5-HT.

The anti-aggression and anti-impulsivity effects of 5-HT are mediated by postsynaptic 5-HT1A receptor signalling, with some contribution from postsynaptic 5-HT1B receptors. However, it is complicated to assess the functional effects of 5-HT1A receptor manipulations, owing to the opposing influences of pre- and postsynaptic 1A receptor activation.

The 5-HT1AR is the most prevalent and well-distributed 5-HT receptor in the brain, and 5-HT1AR-rich regions have higher 5-HT concentrations and higher serotonin levels than 5-HT2AR-rich regions during basal conditions. This may explain why 5-HT lesions and depletion promote impulsivity and aggression, whereas stimulating serotonin function reduces these behaviours.

The table 1 summarises findings that support various associations between 5-HT, signalling at its post-synaptic 5-HT1A and 5-HT2A receptors and relevant psychological phenomena. Some of these associations require qualification, e.g. 5-HT2AR agonism can have opposite acute and longer-term effects. The effects of 5-HT2AR agonism on mood and mental health are highly context sensitive, and the evidence base for psychedelics for depression is still developing. Therefore, we describe the association between 5-HT2AR signalling and depression as resting on ‘reasonable’ evidence.

This table shows significant associations between 5-HT, its 1A and 2A receptors and specific psychological phenomena of interest. A careful reading of the surrounding text is encouraged to properly understand the relevant associations.

In rodents, 5-HT2AR agonism increases impulsivity, but in humans the relationship between the 5-HT2AR and impulsivity and aggression is somewhat ambiguous. 5-HT2AR agonist psychedelics may even possess some pro-social properties in certain contexts.

5-HT1AR signalling is involved in anxiety, stress and impulsivity. 5-HT1AR stimulation in the forebrain has been found to reduce anxiety, and this effect is mediated by postsynaptic 5-HT1AR signalling.

Postsynaptic 5-HT1A receptors are densely expressed in limbic regions and particularly the hippocampus. 5-HT1AR stimulation has an inhibitory influence on pyramidal neuron activity and reduces metabolism and blood flow in limbic regions with acutely administered MDMA, buspirone, fenfluramine and chronically administered SSRIs. The increased ability to tolerate negative stimuli with acute MDMA and chronic SSRI treatment may be due to elevated levels of synaptic 5-HT activating inhibitory postsynaptic 1A receptors in stress-sensitive limbic regions.

Punishment is one of the most effective means of stimulating 5-HT release, and it is suggested that this function is mediated by postsynaptic 5-HT1AR signalling, serving to quell hyperactivity in stress-sensitive circuits, particularly under conditions of mild-moderate adversity.

The 5-HT2AR has been implicated in anxiety, stress and depression. 5-HT2AR signalling has an anxiogenic effect that is opposite to the anxiolytic effect of postsynaptic 5-HT1AR activation, and 5-HT2C receptor agonism has been associated with anxiety and inversely with ‘assertiveness’ in rats.

The effects of 5-HT2AR signalling on cognition and emotion are highly context sensitive. The acute labile state can be used to facilitate emotional approach and eventual acceptance with potentially enduring beneficial effects.

Consistent with a recent hypothesis on the function of brain 5-HT, we predict that 5-HT2AR-mediated plasticity enhances the influence of environmental factors on the individual and opens a window of plasticity during which significant therapeutic work can be done.

The extra-pharmacological model of drug effects is inspired by recent empirical and theoretical work on the psychedelic state and aims to explain the many determinants of the acute and longer-term effects of psychoactive drugs in general, albeit with special reference and relevance to psychedelics. The environment can be influential at all stages of the process of change associated with drug action, including symptoms of a specific psychiatric condition such as depression. The EP model may prove useful in future studies of psychedelics, for example to determine the weighting or relative influence of different predictor variables on the quality of the acute state and longer-term outcomes.

Chronic treatment with SSRIs has been associated with increased neurogenesis and some improvements in learning and cognition, albeit with some contradictory findings. The 5-HT1AR is thought to be the principal site of action of SSRIs.

Despite the association between 5-HT1AR signalling and neurogenesis, there is evidence to suggest that postsynaptic 5-HT1AR stimulation is impairing to learning and cognition. Therefore, how can we reconcile these things?

The 5-HT2AR is different to the 5-HT1AR in that it is associated with improvements in certain aspects of cognition and learning, as well as an unlearning or ‘extinction’ learning. It is also associated with neurogenesis, which may explain the type of cognitive and learning enhancements that are associated with its functioning.

Cognitive flexibility is thought to be positively modulated by 5-HT2AR functioning, and 5-HT2AR agonists may enhance cognitive flexibility and creative thinking, potentially in an enduring way. Serotonin depletion and inactivation has been shown to impair cognitive flexibility, and 5-HT2AR signalling is the key mediator of this effect.

Serotonin, depression and mood

Serotonin was first isolated and named in the late 1940s, and was found in the brain in the early 1950s. It was speculated that abnormal serotoninergic functioning may underlie certain mental disorders, and LSD was used extensively as psychotherapeutic aids for the treatment of depression and anxiety.

The earliest evidence for the involvement of monoamines in mood regulation came with the observation that reserpine induces depressed mood in some individuals, and that monoamine oxidase inhibitors and tricyclic antidepressants increase synaptic monoamines.

The idea that serotonergic mechanisms are involved in the pathogenesis and treatment of depression was controversial in the 1960s, but gradually gained traction in the 1980s and into the 1990s with the development of SSRIs and particularly fluoxetine.

MDMA, a potent mood-enhancing agent, has marked 5-HT releasing properties, and pre-treatment with the SSRI citalopram, D2 antagonist haloperidol, and DA reuptake blocker methylphenidate did not have a supplementary influence on positive mood. Mephedrone’s popularity as a party-drug may be explained by its pronounced serotonin-releasing properties, in conjunction with DA release, with users likening its euphoric effect to that of MDMA.

In summary, 5-HT is involved in the regulation of mood but exactly how it does this is not properly understood. 5-HT1A and 5-HT2A receptor signalling have a complementary effect on mood by promoting stress moderation and patience.

Postsynaptic 5-HT1AR signalling is important for the therapeutic action of serotonergic antidepressants, and selective 5-HT1AR agonists work in a similar way to traditional serotonergic antidepressants, with a delayed onset of action of 7 – 14 days due to the gradual desensitisation of the presynaptic 5-HT1A autoreceptors.

Due to the unavailability of selective 5-HT1AR antagonists for human research, it is difficult to determine the importance of the 5-HT1AR to the mechanisms of action of MDMA and classic psychedelics. Buspirone and pindolol have only partial agonism and weak antagonism of 5-HT2A receptors, which precludes us from making strong inferences about their effects in pre-treatment studies. However, depletion of brain serotonin may augment the behavioural effects of classic psychedelics.

MDMA’s acute effects reflect combined signalling at postsynaptic 5-HT1AR, 5-HT2AR and catecholamine receptors to produce a state of improved stress tolerability, increased cognitive flexibility and emotional lability, enhanced focus, motivation and confidence, and a positive mood.

5-HT2AR signalling, depression and mood. 5-HT2AR agonism has been viewed as potentially harmful to mental health.

Recent studies have begun to challenge the notion that 5-HT2AR agonism is an undesirable property for a psychotropic medication, and several studies have found associations between 5-HT2AR polymorphisms and SSRI response. Additionally, 5-HT2AR signalling may be an important component of antidepressant action of SSRIs.

Studies demonstrating the antidepressant potential of 5-HT2AR agonist psychedelics, including a pilot study by our team, as well as a population study showing lower rates of psychological distress and suicidality in relation to psychedelic drug use, support a rethink on the role of 5-HT2AR signalling in the pharmacology of depression.

Human PET imaging work shows a positive relationship between 5-HT2AR signalling and trait psychological health, and increased 5-HT2AR binding and associated pessimistic thinking may be a corollary of deficient 5-HT2AR signalling.

Postmortem studies show increased 5-HT2AR availability in unmedicated depressed patients and suicide victims, which is consistent with the hypothesis that there is an adaptive upregulation of 5-HT2A receptors in response to deficient 5-HT2AR signalling in depression.

The effect of electroconvulsive shock on 5-HT2AR densities and functioning is important to address, particularly given the notable efficacy of electroconvulsive therapy in terms of reducing depressive symptoms for a period. Interestingly, functional brain changes one day after psilocybin for treatment-resistant depression compare best with those of ECT.

Early rat work revealed increased 5-HT2AR functioning and cortical 5-HT2AR expression after ECS, but later primates and humans showed decreased 5-HT2AR binding post ECS/ECT. This finding is more consistent with the effects of conventional antidepressant medications and classic psychedelics.

Stress has been found to increase 5-HT2AR density and affinity in rats, and extreme stress is hypothesised to engage ‘pathway 2’ in our bipartite model, which is mediated by 5-HT2AR signalling and characterised by a rapid plasticity.

Some effective drugs for depression have 5-HT2AR antagonist properties, and 5-HT2AR antagonist antipsychotic drugs can augment the antidepressant efficacy of SSRIs in treatment-resistant depression. However, 5-HT2AR antagonism presents additional side-effects to those of first-line antidepressants such as SSRIs. Selective 5-HT2AR antagonists have not been trialled as stand-alone treatments for depression, and have largely failed as stand-alone treatments for schizophrenia. They may augment other pharmacological mechanisms, such as SSRIs, by decreasing the ability of top-down circuits to inhibit serotonergic neurons in the midbrain.

5-HT2AR agonists and antagonists may achieve the same outcome but via different routes, and may even be antithetical.

5-HT2AR agonist psychedelics can be acutely psychotomimetic and yet have long-term beneficial effects on well-being and mental health. It has been proposed that the acute state produced by 5-HT2AR agonist psychedelics does not directly modulate the valence of mood.

MDMA, LSD, psilocybin and ayahuasca are attenuated by pre-treatment with a 5-HT2AR antagonist, but anxiety and psychosis-like symptoms are also often seen acutely with psychedelics. Moreover, psychological preparation and support were generally provided, which biased the experience in a positive direction.

A proposed solution to this apparent paradox is that the acute and longer-term effects of psychedelics are distinct, with the acute effects being marked by emotional arousal and lability rather than positive mood per se.

A recent study found that the psychological difficulty of an acute psychedelic experience was predictive of longer-term improvements in well-being, although the duration of such difficulty was also predictive of long-term decreases in well-being. Moreover, acute ‘entropic’ brain changes under the drug were predictive of long-term increases in the personality trait openness.

5-HT2AR mediated plasticity

There is increasing evidence that 5-HT2AR signalling produces a plastic state, which is important for the acute and long-term action of 5-HT2AR agonist psychedelics, including their ability to elicit long-term beneficial and (albeit less common) harmful changes.

Plasticity and the entropic brain

The ‘entropic brain’ hypothesis, introduced by us in 2014, proposes that psychedelics induce a plastic state, where the brain exhibits increased entropy. This hypothesis is consistent with countless other studies that report findings that are consistent with the entropic brain principle.

Entropy is an index of uncertainty, but its origins lie in thermodynamics. Information theory-based entropy is merely an applied and contextualised version of thermodynamic entropy.

The excitatory effect of 5-HT2AR signalling on the brain may be analogous to the process of annealing, whereby a metal is heated to make it more malleable. This entropic state may work to reset reinforced priors in depression.

5-HT2AR induced plasticity mediates environmental sensitivity

The evolutionary value of neural and behavioural plasticity is well recognised, and the role of serotonin in mediating plasticity is becoming increasingly well appreciated.

Serotonin is known to play a vital role in brain development and has been found to reverse processes of maturation, both at the cellular and brain network level, likely via 5-HT2AR related mechanisms.

Early development is key for 5-HT2AR signalling, as it facilitates intense learning and the ‘de-weighting’ of prior knowledge. 5-HT2AR availability decreases with adulthood, and psilocybin and LSD are associated with increased openness and a susceptibility to become immersed and absorbed in one’s inner or outer world.

High doses of psychedelics may cause an excessive flexibility that is unconducive to accurate reality testing and conventional cognition and behaviour. However, recent anecdotal reports suggest that semi-regular use of very low doses of psychedelics may facilitate creative problem solving and improve mood.

More work is required to test the recent finding that psychedelics tune the brain closer to criticality, and what the functional and therapeutic implications of this might be.

Much has been written about differential vulnerability to stress in medicine and psychiatry, and recent revisions of the stress-diathesis model possess considerable appeal. These revisions suggest that serotoninrgic mechanisms mediate sensitivity to the environment, and that increased plasticity with SSRIs and increased 5-HT transmission more generally may support this view.

5-HT2AR polymorphisms are associated with increased sensitivity to stressful and enriching environments, increased 5-HT2AR affinity, increased 5-HT2AR densities, increased 5-HT2AR availability during critical development periods, and increased 5-HT2AR signalling in humans experiencing psychedelic drug trips.

5-HT2AR-mediated plasticity: an adaptive response to extreme adversity

Anxiety and stress are potent non-pharmacological inducers of 5-HT release, and 5-HT release is especially marked during asphyxiation and cardiac arrest. It has been speculated that elevated levels of the endogenous 5-HT2AR agonist psychedelic DMT may account for spontaneously occurring psychedelic-like states.

Similar phenomenologies may be found in near-death experiences and the psychedelic state, as well as in the incipient phase of a psychosis, such as a fragmenting self/ego, muddled thinking, bizarre thought content, de-realisation, mystical-type experiences and/or religious conversation or epiphany, putative insight, magical thinking, etc.

A bipartite model of stress-induced upregulation of 5-HT2AR signalling is presented, which could be an unacknowledged factor in the pathogenesis of psychosis. If this hypothesis is confirmed, it could have important implications for how we understand and perhaps treat psychosis.

5-HT mediates passive coping (or an improved ability to tolerate stress) under adverse conditions via postsynaptic 5-HT1AR signalling. This enhanced coping may be advantageous during difficult conditions but may also be counterproductive.

We propose that enhanced 5-HT1AR signalling is a logical, adaptive response to moderate levels of adversity, but enhanced 5-HT2AR signalling is optimal when the level of adversity reaches a critical point.

The rapid and transient downregulation of hippocampal 5-HT1ARs seen with severe acute stress may be one mechanism by which this hypothesised transition to 5-HT2AR dominance under extreme adversity occurs, and increased limbic 5-HT release with mild stress compared with cortical 5-HT release with more intense stress may be another.

Serotonin and positive mood

According to the central hypothesis of this paper, brain serotonin facilitates adaptive responses to adverse conditions via two distinct pathways. This paper has concentrated on adversity because it is relatively easy to experimentally induce.

MDMA and mephedrone induce positive mood, which may be explained by their potent 5-HT releasers. PET imaging work using potent 5-HT releasers and receptor-selective ligands sensitive to this release may shed new light on the association between enhanced 5-HT transmission and positive mood.

It would be relevant to better understand why more selective 5-HT releasers such as fenfluramine do not produce the same kind of euphoria associated with MDMA and mephedrone, and why the pharmacology of fenfluramine’s metabolite, norfenfluramine, is different to that of its parent compound.

5-HT2AR agonist psychedelics are not hedonic drugs in the classic sense, and typically patterns of use are relatively sporadic with protracted periods of abstinence. However, extreme positive mood is not infrequently reported with larger doses of psychedelics, particularly when taken in supportive environments.

It is intriguing to consider that enhanced 5-HT2AR signalling may be a non-negligible component of the neurobiology of positive mood itself, and that 5-HT2AR-mediated plasticity may be an underappreciated component of the antidepressant action of SSRIs.

‘The secret to happiness is freedom’. (Thucydides c. 450BC)

It is presumed that the brain functions in a freer, less constrained manner during creative states, as during positive mood, and that potent serotonergic compounds may help in this regard. Moreover, fMRI data suggest a potential neurobiological counterpart to the psychological notion of ‘reset’.

Limitations

This review discusses only two serotonin receptor subtypes, and does not address the role of heterodimers, functional selectivity, agonist trafficking, or glutamatergic mechanisms that follow 5-HT2AR signalling and how these are involved in plasticity. The 5-HT2AR is the key 5-HT receptor in psychedelics, and the 5-HT1AR attenuates rather than augments these effects. More selective 5-HT2AR agonists appear to have the same quintessential psychological effects as the less selective psychedelics.

We acknowledge that this is a simplified and therefore incomplete picture of brain serotonin function, but we wanted to distil it down to some key principles. The 5-HT1A and 2A receptors have opposite effects on single cell activity, which implies that the 5-HT system is not just diverse, but adaptive.

This paper has focused too much on 5-HT2AR agonist psychedelics and MDMA, but we believe that their scientific and medicinal value has not yet been properly appreciated, and that human studies with these compounds can be done safely if appropriate safeguards are heeded.

It could be argued that the emphasis placed on extreme states in this paper is not relevant to normal physiological conditions. However, it is reasonable to infer that states induced by MDMA and 5-HT2AR agonist psychedelics may be possible to achieve without these drugs, if only at an attenuated level.

The 5-HT2AR is densest in evolutionary recent brain regions, and is associated with high-level psychological functions, such as self-consciousness and the ‘self’ or ‘ego’ itself. It has been hypothesised that ingestion of naturally occurring psychedelics catalysed the evolution of the human neocortex.

Non-linearities in the serotonergic system conferred optimal adaptability, including a capacity to switch to greater 5-HT2AR signalling when conditions demand it.

Regarding neuroimaging the psychedelic state, it is a nascent and fast-moving field, but the brain is uncharacteristically ‘entropic’, reflecting a greatly heightened plasticity in which old material may be unlearned and new ideas and associations learned.

The present contribution on the function of brain serotonin has been much inspired by previous models but also integrates recent and perhaps overlooked data on the brain and behavioural effects of potent serotonergic drugs such as MDMA and the 5-HT2AR agonist psychedelics.

Regarding specific past contributions, we acknowledge the work of Deakin and Graeff, Cools et al., Crockett et al., 2009, Wise et al., 1970, and others, and relate these to our hypothesis that postsynaptic 5-HT1AR signalling mediates passive coping in response to adversity.

We acknowledge the perspectives of Branchi (2011), Belsky et al. (2009) and others (Homberg, 2012) concerning serotonin and plasticity, and believe that our bipartite model is more psychologically focused, receptor specific, and consistent with the classical view that enhanced 5-HT transmission is conducive to positive mood.

Conclusions: the function of brain serotonin

This paper proposes that brain serotonin has two functions: (1) enhancing adaptive responses to adverse conditions via a passive coping pathway; and (2) improving an organism’s ability to identify and overcome source(s) of stress by changing outlook and/or behaviour.

The two functions of 5-HT1AR-mediated stress relief and 5-HT2AR-mediated plasticity may be mutually oppositional, but may also be complementary, e.g. in the case of enhanced serotonin functioning with chronic SSRI use.

Despite their complementarity, conventional serotonergic antidepressants and classic psychedelics may become competitive options for the treatments of certain disorders such as depression. However, if evidence supporting the therapeutic value of psychedelics accrues, then this may open-up new and potentially empowering options for patients and clinicians.