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Pharmacological interventions
Published in Ilana B. Crome, Richard Williams, Roger Bloor, Xenofon Sgouros, Substance Misuse and Young People, 2019
This group of drugs has a diverse presentation. They include naturally occurring sources, such as fungi, to those that are produced in a laboratory, such as LSD. These drugs affect the serotonin receptors: 5HT2A, which cause the user to experience hallucinations, usually visual. The users’ experiences are very dependent on the direct pharmacological effects and the setting (e.g., who is around and what else is happening) and are guided by the mood or emotional state of each user. They can be powerful and are often a distortion of the particular user’s own reality. Thus, the experience can be fun or anxiety-provoking for the majority of users, but, occasionally, users can experience something more emotionally overwhelming. Intense fear and panic states may be triggered, with the drug magnifying these responses. This can result in young people presenting to emergency services. Patients require reassurance and support, but there is no specific pharmacological intervention suitable for this chemically-induced state. Time and a calm safe environment are the best solutions. Follow-up after this sort of experience can be useful because a small number of young people may experience triggering of ongoing mental health conditions and some young people may require assessment and care from the specialist child and adolescent mental health services (Specialist CAMHS).
Phytochemicals: Some Basics
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
Many of the hallucinogenic alkaloids, including psilocybin, mescaline, and dimethyltryptamine from ayahuasca or the Banisteriopsis caapi vine, derive their unique effects on consciousness largely by stimulating the serotonin type 2A receptor (5-HT2A) in the brain. Although often used for recreational purposes, there has recently been a revival of interest in using modest doses of these drugs in shamanistic or even standard psychotherapeutic settings for conditions such as obsessive-compulsive disorder or treatment-resistant MDD.25 However, in the current context, the actions of these 5-HT2A agonists are unusual. The receptors do not mediate inhibition of GSK-3β and stimulation of mTOR and eEF2, as we are coming to expect of antidepressant medications. Indeed, they do precisely the opposite.26 While this may be an over-simplified distinction, the psychotherapeutic effects of the 5-HT2A agonist hallucinogens are likely less due to ongoing changes in intracellular signaling than to temporary changes in the brain circuitry that underlies consciousness, including shifts in awareness and the so-called default mode network.27
Spice Drugs, Synthetic Cannabinoids, and ‘Spiceophrenia’
Published in Ornella Corazza, Andres Roman-Urrestarazu, Handbook of Novel Psychoactive Substances, 2018
Duccio Papanti, Laura Orsolini, John M. Corkery, Fabrizio Schifano
In the literature, there are controversial views on the treatment of substance-related/‘dual’ psychotic disorders. Although, according to San et al. (San, Arranz, & Martinez-Raga, 2007), second-generation antipsychotics may confer some advantages over first-generation antipsychotics, for the treatment of substance-induced psychotic disorders, other authors found no evidence of better outcomes with second-generation antipsychotics (Petrakis, Leslie, Finney, & Rosenheck, 2006). Furthermore, other studies found that both clozapine and olanzapine may present distinct advantages in reducing substance-induced psychotic symptoms without increasing craving in patients with concomitant cannabis-use disorders in comparison to patients treated with risperidone (MacHielsen et al., 2012; Machielsen, Veltman, van den Brink, & de Haan, 2018). Finally, clozapine has been reported to reduce substance misuse and improve psychosis, potentially ameliorating the dysfunction within the dopamine-mediated brain reward circuitry implicated in addiction (Green, Noordsy, Brunette, & O’Keefe, 2008). Additionally, second-generation antipsychotics act as antagonists at serotonin 5-HT2A receptors, the main target of most hallucinogenic drugs (Papanti et al., 2018; Valeriani et al., 2015). Further studies clearly need to be carried out to clarify these treatment and management issues.
Neural Plasticity in the Ventral Tegmental Area, Aversive Motivation during Drug Withdrawal and Hallucinogenic Therapy
Published in Journal of Psychoactive Drugs, 2023
Hector Vargas-Perez, Taryn Elizabeth Grieder, Derek van der Kooy
It is important to note that the expression of 5-HT2A receptors is increased in several pathologies, such as migraine (Srikiatkhachorn, Govitrapong, and Limthavon 1994), but in particular a dramatic increase in these receptors has been observed in the brains of patients with depressive disorders and in individuals who have committed suicide (Pandey et al. 2002). Moreover, the elevated expression of 5-HT2A receptors in the VTA increases the vulnerability of rats to the behavioral effects induced by cocaine, suggesting that 5-HT2A receptor in the VTA plays a role in regulation of responsiveness to stimulant substances (Herin et al. 2013). As occurs with other members of families of G-protein coupled receptors signaling through the 5-HT2A receptor produces a phenomenon of negative regulation of the same receptor (Buckholtz, Zhou, and Freedman 1988). Thus, each time these receptors are activated, there is a decrease in their expression, and the probability of their cell surface expression decreases (Buckholtz, Zhou, and Freedman 1988). In this way, the use of hallucinogenic substances decrease the production of 5-HT2A receptors (Raval et al. 2021), thus reversing the increase associated with pathological states, including depression and substance use.
Sexual dysfunction with major depressive disorder and antidepressant treatments: impact, assessment, and management
Published in Expert Opinion on Drug Safety, 2022
Joan Winter, Kimberly Curtis, Bo Hu, Anita H. Clayton
Serotonin binding at the post-synaptic 5-HT1A receptor produces antidepressant and anxiolytic effects, while increased binding at the 5-HT2A and 5-HT2C receptors leads to increased anxiety, insomnia, and sexual dysfunction. Multiple antidepressants (eg. mirtazapine, trazodone, several TCAs, and norquetiapine – the active metabolite of quetiapine) with fewer sexual side effects exhibit antagonism at 5-HT2. The release of dopamine and norepinephrine in the cortex is inhibited by stimulation of 5-HT2A and 5-HT2C receptors [9–10]. Norepinephrine and nitric oxide promote tumescence of sexual organs and lubrication. Dopamine is a key neurotransmitter of the reward system, which includes the nucleus accumbens/ventral striatum, ventral tegmental area (VTA), pre-frontal cortex, orbitofrontal cortex, anterior cingulate cortex, and amygdala. Dopamine promotes sexual function at varying concentrations at progressive stages of sexual engagement: from sexual desire to increased parasympathetic activation required for erections, and finally climax. Dopamine may also be involved in the medial preoptic area of the hypothalamus (mPOA) in the initial disinhibition of genital reflexes[12]. In addition to central effects, serotonin acts in the peripheral nervous system by directly suppressing spinal ejaculatory centers [10–11]. Thus, the increase of serotonin at the synaptic cleft as a result of antidepressant action can impact many levels of sexual functioning: decreased interest and arousal, inhibited/delayed orgasm, and diminished intensity and frequency of orgasm[13].
The serotonin toxidrome: shortfalls of current diagnostic criteria for related syndromes
Published in Clinical Toxicology, 2022
Angela L. Chiew, Nicholas A. Buckley
There are at least seven families of 5-HT receptors (5-HT1 to 5-HT7), some of which have multiple subtypes [4,5]. It is likely that no single receptor is responsible for serotonin toxicity. However, stimulation of the 5-HT1A and 5-HT2A receptors have been implicated in serotonin toxicity. The 5-HT1A receptors possibly contribute to some of the milder symptoms of serotonin toxicity including anxiety and hyperactivity [8,9]. Activation of 5HT2A receptors at high serotonin concentrations is implicated in severe serotonin toxicity in animal studies [10,11]. The 5-HT1A receptors have a higher affinity for serotonin than the low-affinity 5-HT2A receptors and are likely to be nearly fully occupied at much lower extracellular 5-HT concentrations [10]. This means that changes in 5-HT1A receptor occupancy and effects are likely to be dominant with small increases in 5-HT.