Table 1.

Structure and Function of the Classical Psychedelics, Their Ability to Modulate the DMN, and Associated Therapeutic Outcomes

Psychedelic	Neuropharmacology	Subjective effects	DMN modulation	Therapeutic effects	Relevant studies
Psilocybin	Psilocybin is tryptamine derivative, and its chemical structure is comprised of an indole ring linked to an ethylamine substituent. Upon ingestion of psilocybin, it is dephosphorylated to psilocin, which is an agonist of several serotonin receptors with its highest affinity for 5-HT1 and 5-HT2 receptors.	Psilocybin significantly impacts time distortion, where users feel that “time is standing still.” The experience usually lasts 4–6 h. Users having a pleasant experience generally have a feeling of euphoria, oneness, and connectedness. However, an unpleasant experience can also occur, which is usually characterized by intense fear, anxiety, and distress.	Psilocybin robustly decreases FC within the DMN and increases global brain connectivity. Specifically, decoupling between key DMN nodes such as the mPFC and the PCC has been documented. Furthermore, psilocybin has been reported to decrease DMN integration and reduce local modularity and segregation up to 3 wk after administration in depressed patients.	Psilocybin has been shown to reduce end-of-life anxiety in patients who were terminally ill, improve smoking and alcohol cessation, reduce cluster headaches, and decrease symptoms of depression and PTSD.	(Sewell et al., 2006; Wittmann et al., 2007; Carhart-Harris et al., 2012; Nichols, 2016; Preller and Vollenweider, 2016; Nour and Carhart-Harris, 2017; Thomas et al., 2017; Smigielski et al., 2019; Daws et al., 2022; Mason et al., 2020a; Mertens et al., 2020; Grandjean et al., 2021)
Ayahuasca	Ayahuasca is a psychoactive decoction and is usually made from the Banisteriopsis caapi vine, the Psychotria viridis shrub. The B. caapi vine, importantly contains harmala alkaloids, which render the hallucinogenic component DMT orally active.	Individuals who have consumed ayahuasca often report it as being a profound spiritual and mystical experience. Often people feel more connected to nature and the earth and start to understand their place in the world. The experience can last 2-6 h and can involve “purging,” which is characterised by vomiting and diarrhea.	In a similar fashion to other psychedelics, ayahuasca disrupts normal DMN function during the psychedelic experience. It has been shown that long-term ayahuasca use has led to increased thickness of the ACC and decreased thickness of the PCC (a key DMN node). Finally, ayahuasca increases local and decreases global network integration, while increasing Shannon entropy across networks.	Ayahuasca possesses antidepressant and anxiolytic effects. It has been reported to increase acceptance and trait mindfulness and may have some efficacy for treating addictions and trauma.	(McKenna, 1998; Shanon, 2002; Barbosa et al., 2012; Bouso et al., 2015; Palhano-Fontes et al., 2015; Sampedro et al., 2017; Viol et al., 2017; Uthaug et al., 2018; Murphy-Beiner and Soar, 2020; dos Santos and Hallak, 2021; Zeifman et al., 2021)
LSD	LSD is an ergoline derivative, often synthesised via reactive mechanisms. For instance, diethylamine is reacted via activating reagents with the ergoline alkaloid precursor lysergic acid, forming LSD. LSD binds to both dopamine and serotonin (especially 5-HT2 and 5-HT1) receptors, although it labels all 5-HT receptors except 5-HT3.	Due to the binding of both dopamine and serotonin receptors, the LSD experience generally feels more fast paced and energetic compared with psilocybin. Subjective reports of LSD-induced experiences describe the experience as being highly significant and typically involving intense joy and a sense of spiritual enlightenment. Negative experiences can also occur, however, which include increased paranoia, fear of madness, and anxiety. Experiences last about 6–12 h.	LSD effects the DMN in a remarkably similar way to psilocybin. For instance, LSD decreases within-network connectivity (specifically the medial-posterior DMN) and increases between-network connections.	LSD has been shown to reduce alcoholism, and preliminary evidence shows that it can help reduce symptoms of depression, anxiety, and cluster headaches and may also possess analgesic properties.	(Hofmann, 1980; Sewell et al., 2006; Carhart-Harris et al., 2016; Speth et al., 2016; Tagliazucchi et al., 2016; Atasoy et al., 2017; Müller et al., 2018; Varley et al., 2020; de Gregorio et al., 2021; Nutt and Carhart-Harris, 2021)

Abbreviations: FC, functional connectivity; DMN, default mode network; mPFC, medial prefrontal cortex; PCC, posterior cingulate cortex; PTSD, post-traumatic stress disorder; DMT, dimethyltryptamine; ACC, anterior cingulate cortex; LSD, lysergic acid diethylamide.