Think Your Creation Is Safe? 8 Ways You Can Lose It Today

How Psychedelic or Hallucinogenic Drugs Work

These experiments were very strong evidence that 5-HT2A receptor signaling was not generating a retrograde messenger. Different agonist ligands acting at the 5-HT2A receptor also can lead to different downstream gene expression patterns. González-Maeso et al. quantified concentration-dependent gene changes in response to various agonists in HEK-293 cells expressing the human 5-HT2A receptor, followed by examination of the in vivo gene expression responses in the mouse somatosensory cortex.

Unexpectedly, however, these lesions led to increased density of cortical 5-HT2A receptors, a finding that would not be entirely consistent with presynaptic 5-HT2A receptor localization. Shi et al. examined agonist-induced desensitization of 5-HT2A receptors in the rat hypothalamic paraventricular nucleus with 1 mg/kg R-(−)-DOI. Treatment with R-(−)-DOI for either 4 or 7 days caused a significant approximately 50% decrease in high-affinity 5-HT2A binding, compared with saline-treated controls. Oxytocin and acetylcholine release induced by 5-HT2A receptor activation were also suppressed in a dose-dependent manner after treatment with DOI.

Administration of LSD to rats (0.5 mg/kg, i.p.) led to a significant increase in fos-like immunoreactivity in the rat PFC and ACC that was completely blocked by systemic pretreatment with the specific 5-HT2A antagonist MDL (Gresch et al., 2002). Double staining for both fos immunoreactivity and the 5-HT2A receptor Psychedelic revealed that LSD did not induce fos in pyramidal cells expressing 5-HT2A receptors in either the PFC or parietal cortex. Increased fos expression was induced in cortical cells in layers III and IV, with only rare occurrence of a doubly labeled pyramidal cell, suggesting fos induction by some indirect mechanism.

Brandrup and Vanggaard report on the outcome of LSD treatment of a 30-year-old man suffering from a completely disabling OCD. The treatment took place over 15 months, and surprisingly, without any other therapy provided. While under the influence of LSD, the patient was simply left alone except for brief visits by the doctor or the nurse. At 3 years, the patient was completely symptom free and remained so at 12-year follow-up, the point at which the therapists published the case report. It has been recognized for some time that psychedelics (i.e., 5-HT2A agonists) increase levels of cortical glutamate (Aghajanian and Marek, 1997, 1999b; Béïque et al., 2007; also see the earlier section on glutamate in this review). Vollenweider and Kometer suggested that indirect activation of glutamate networks by classic psychedelics may enhance neuroplasticity through stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors and subsequent increase in the level of BDNF.

Intracerebroventricular administration of either ketanserin or xylamidine significantly attenuated DOI-elicited head bobs but had no effect on DOI-elicited body shakes. These data were interpreted to mean that head bob behavior was mediated by central 5-HT2A receptors, whereas body shakes were mediated by 5-HT2C receptors located either peripherally, or else in brain areas not accessible to infusions of DOI into the lateral ventricle. By contrast, Kłodzinska et al. showed that 30-minute pretreatment of mice with the mGlu2/3 agonists LY and LY significantly decreased (by 64%–70%) head twitches induced by 2.5 mg/kg DOI intraperitoneally. Activation of mGlu2/3 receptors, which are localized presynaptically and serve as autoreceptors, would therefore be expected to suppress glutamate release from terminals.

Edelman emphasized that consciousness concerns the rapid integration of signals from a great variety of modalities and submodalities to create a unified, coherent scene or idea. When one considers all of the key brain areas noted in this review that either express or are directly affected by 5-HT2A agonist interactions, it should be no surprise that the psychopharmacology of psychedelics is so complex. Furrer et al. also observed significantly lower portal blood flow at baseline in old compared with young mice, and DOI improved portal flow and increased microperfusion in old livers. Electron microscopy studies demonstrated deficient platelet adhesion in old livers after hepatectomy, which was improved by DOI administration. Mechanistic studies revealed that DOI increased interleukin -6 at 48 hours after hepatectomy, but the strongest effect of DOI was to increase serum levels of vascular endothelial growth factor . Thus, application of anti-VEGF antibodies blunted the proliferative effect of DOI, and administering exogenous VEGF enhanced liver regeneration to levels seen in DOI-treated mice.

Eight days of DOI treatment led to a 41% reduction in Bmax for 5-HT2A receptors, with a slight but nonsignificant increase in Kd. Neither 4 nor 8 days of chronic treatment with MDL11939 had any significant effect on 5-HT2A density or function. Mice showed tolerance to the behavioral effects of DOI that began 24 hours after the first dose of DOI and persisted to the end of the experiment.

The authors suggest that their results warrant future studies using a traditional blinded, randomized, placebo-controlled trial to explore the efficacy and duration of effect from a more prolonged exposure to repeated doses of psilocybin in OCD patients. Obsessive-compulsive disorder is a debilitating medical condition that is very difficult to treat and for which conventional therapies, such as selective serotonin reuptake inhibitors , are not highly efficacious. It has long been believed that serotonin systems are involved in OCD (Benkelfat et al., 1989), and the apparent efficacy of serotonergic psychedelics would point more specifically to involvement of the 5-HT2A receptor. The earliest indication of efficacy for a psychedelic in treatment of OCD was reported by Jackson , in which a patient suffering from depression and violent obsessive sexual thoughts experienced dramatic and permanent improvement after only two doses of LSD.

The various α1 adrenergic receptor transcripts showed an almost nonoverlapping regional distribution within the mPFC that was particularly evident for α1A and α1D adrenergic receptors. The former transcript was densely expressed in deep layers VIa and VIb of the medial, dorsal, and lateral PFC and the claustrum, as well as in ventral areas such as the orbital and piriform cortices and the tenia tecta. By contrast, the α1D adrenergic receptor transcript was especially abundant in layers II to III, and outer layer V in medial and dorsolateral aspects of the PFC. All three types of α1 adrenergic receptors were observed to be present in pyramidal (vesicular glutamate transporter 1–positive) and GABAergic (GAD65/67–positive) neurons. Pyramidal neurons expressing α1A adrenergic receptors were more abundantly localized in deep layers V to VI in the three mPFC subdivisions.

After application of DOI, a mixed 5-HT2A/2C agonist that lacks 5-HT1A effects, the late component was evoked by every stimulus in all tested cells. The authors note that their data with Ca2+ and Sr2+ point to a presynaptic 5-HT2A action, although 5-HT2A receptors are known to be expressed primarily postsynaptically on pyramidal cell apical dendrites. Martí-Solano et al. compared relative signaling bias of several putative 5-HT2A agonists in both the PI hydrolysis and AA release pathways. They relied on extensive molecular dynamics to generate binding poses for the ligands in the receptor and then considered how the ligand poses could potentially engage different residues within the receptor to explain observed signaling bias.