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Substances of Abuse and Hallucinogenic Activity: The Serotoninergic Pathway - Focus on Classical Hallucinogens and Entactogens

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Hallucinations in Psychoses and Affective Disorders

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Abstract

The chapter focuses on the mechanisms through which the serotoninergic system can induce hallucinations, altering sensory perceptive functions. The hallucinogenic activity of the serotoninergic receptors has been noticed since perceptual alterations induced by the consumption of some recreational drugs, such as LSD and ecstasy, were observed. Hallucinogenic effects and specific molecular mechanisms of action are discussed in this chapter. Hallucinogens and entactogens can both produce hallucinations through an increase of the serotoninergic pathway activity, which is thought to be one of the pathophysiological processes underlying positive symptoms. LSD and MDMA seem to act with a different molecular mechanism. The main molecular effect of classical hallucinogens consists of increasing 5-HT brain levels, since they act as 5-HT receptor agonists. 5-HT2A receptors, mainly localized in medial prefrontal cortex, thalamic reticular nucleus, locus coeruleus and raphe nucleus, seem to be the most important hallucinogenic target, even if it has been demonstrated that 5-HT2C receptors could also be required. Hallucinogens therefore alter ascending sensory information processed through the thalamus. This could be mediated through alterations in different systems leading to a sensorial information overload. Classical hallucinogens should be considered as potent modulators of cortex network activity through the augmented 5-HT2A agonist activity in the medial prefrontal cortex, the reduced inhibitory activity by thalamic reticular nucleus, the altered firing of raphe nucleus, and the increased activity in the locus coeruleus. Entactogens seem to act increasing intracellular and extracellular 5-HT levels by inhibiting the SERT activity, reversing its action through TAAR1 agonism, inhibiting VMAT2, and inhibiting the MAO enzymes. Entactogens also act on NET, and to a lesser extent on DAT. The hallucinogenic effect of entactogens is probably also due to a partial agonist activity on 5-HT2A activity.

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Acknowledgments

This chapter was supported by a grant from the AIFA (Proposal AIFA-2016-02364852). pathway involved in substance-induced hallucinations.

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Authors and Affiliations

  1. Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

    Matteo Lazzaretti, Gian Mario Mandolini, Alfredo Carlo Altamura & Paolo Brambilla

  2. Department of Psychiatry and Behavioural Neurosciences, University of Texas at Houston, Houston, TX, USA

    Paolo Brambilla

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  1. Matteo Lazzaretti
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  2. Gian Mario Mandolini
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  4. Paolo Brambilla
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Correspondence to Paolo Brambilla .

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  1. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

    Paolo Brambilla

  2. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

    Massimo Carlo Mauri

  3. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

    Alfredo Carlo Altamura

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Lazzaretti, M., Mandolini, G.M., Altamura, A.C., Brambilla, P. (2018). Substances of Abuse and Hallucinogenic Activity: The Serotoninergic Pathway - Focus on Classical Hallucinogens and Entactogens. In: Brambilla, P., Mauri, M., Altamura, A. (eds) Hallucinations in Psychoses and Affective Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-75124-5_2

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