The serotonin receptors activated by serotonin—mediating both excitatory and inhibitory neurotransmission—include seven major subtypes, namely 5-HT 1–7 . Moreover, 5-HT 1 receptors include 5-HT 1A , 5-HT 1B , and 5-HT 1D ; also, 5-HT 2 receptors include 5-HT 2A , 5-HT 2B , and 5-HT 2C subtypes (e.g., Riva 2016; for a review, see Saulin et al. 2012).

Serotonin 2A (5-HT 2A ) receptors are of special interest. Molecular, pharmacological, and neuroimaging research demonstrate the central role of 5-HT 2A receptors in mediating visual processing and visual hallucinations. Indeed, there are a high number of 5-HT 2A receptors in the visual cortex (Gerstl et al. 2008; Moreau et al. 2010). Alterations of the density of 5-HT 2A receptors in the visual cortex of patients with schizophrenia and Parkinson’s disease are associated with experiencing visual hallucinations (González-Maeso et al. 2008; Huot et al. 2010). Pimavanserin, the 5-HT 2A receptor inverse agonist, is used to treat visual hallucinations in Parkinson’s disease (Meltzer et al. 2010). Interestingly, 5-HT 2A receptors mainly mediate the visual hallucinations—and indeed uncanny mystical experiences and altered states of consciousness—that are induced by hallucinogenic drugs like lysergic acid diethylamide (LSD), mescaline, and psilocybin (e.g., Griffiths et al. 2008; Vollenweider and Kometer 2010; on hallucinogens vis-à-vis 5-HT 2A R, see also Nichols 2004). Research has shown that 5-HT 2A receptor activation induces visual hallucinations by increasing cortical excitability and altering visual-evoked cortical responses and that these effects of psilocybin on the visual system are blocked with the 5-HT 2A receptor antagonist ketanserin (Kometer et al. 2013).

5-HT 2A R activation also selectively affects self-representation in fronto-parietal cortical regions, including the default mode network (DMN; Raichle et al. 2001) (e.g., Tagliazucchi et al. 2016; Carhart-Harris et al. 2012). The DMN is known to mediate processing of self-related information and neural self-constructs (Buckner et al. 2008). For instance, as noted above, the TPJ (a region of the DMN) is directly implicated in OBEs and hallucinating human-like figures (Arzy et al. 2006). The fact that 5-HT 2A receptors are distributed in higher-level cortical networks such as the DMN including the TPJ is consistent with findings that hallucinogenic drugs like psilocybin and LSD (5-HT 2A R agonists) can induce OBE-type events, e.g., feelings of derealization and “ego dissolution” (e.g., Lebedev et al. 2015; Tagliazucchi et al. 2016). Also, one study in patients with depersonalization disorder found that short-term hallucinogen use could induce chronic symptoms of depersonalization (i.e., having a “fragmented sense of self”) (Simeon et al. 2003).

Moreover, research suggests that 5-HT 2A receptor activation underlies the propensity to ascribe meaning to “meaningless” stimuli. A recent study (Preller et al. 2017) found that activation of 5-HT 2A receptors, when induced by LSD—aside from generating hallucinations and feelings of “separateness from the self” (i.e., OBE-type states), leads to greater attribution of personal relevance to otherwise meaningless cues. This indicates that the 5-HT 2A receptor might play a role in the dysfunctional “personal relevance attribution” seen in psychiatric disorders such as schizophrenia; that is, all too often, patients with schizophrenia and related psychotic disorders find personal meaning in situations or places most healthy people interpret as meaningless (Preller et al. 2017). In fact, this may explain why the 5-HT 2A receptor is upregulated in untreated patients with schizophrenia (González-Maeso and Sealfon 2009), and indeed, many second-generation antipsychotic drugs precisely have an antagonistic effect on 5HT 2A receptors, stressing the possible role of 5HT 2A receptor activation in schizophrenia (Meltzer and Massey 2011; Rolland et al. 2014). Consistent with previous research, the aforementioned study found that the 5HT 2A R antagonist ketanserin was able to block these effects of 5-HT 2A receptors (Preller et al. 2017).