The promise of psychedelic medicine in psychiatry

In that study, nearly all of the compounds studied had greater potency in inducing AA release than in stimulating PI turnover. Some of these differences are noteworthy; for example, in psilocin, the potency for activating AA release was nearly 30-fold greater than for stimulating PI turnover. Buchborn et al. (2015) concluded that the differential receptor adaptations observed for DOB and LSD, respectively, indicate that tolerance to serotonergic hallucinogens can arise at two levels.

A. Evidence for Agonist or Partial Agonist Action at Serotonin 5-Hydroxytryptamine 2A Receptors

Importantly, however, the sEPSC increases for both types of cells recovered after agonist removal, something that would not be expected in cells with irreversible signal production by GTPγS. These experiments were very strong evidence that 5-HT2A receptor signaling was not generating a retrograde messenger. 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).

C. Functional Selectivity at the Serotonin 5-Hydroxytryptamine 2A Receptor

On the basis of their results as well as other data, Miner et al. (2003) proposed that cortical 5-HT innervation is primarily nonjunctional and that the entire cortical volume may be reached by serotonin. They suggest that some of the cortical actions of 5-HT may be constantly exerted, with more or less efficacy at the various 5-HT receptors, thus providing widespread global and/or sustained influence in the neocortex. Autoradiography in the rat brain using R-(−)-125IDOI revealed highest binding in the claustrum and the frontal cortex (McKenna and Saavedra, 1987). Other autoradiographic and in situ hybridization studies have observed high densities of 5-HT2A receptors and transcripts in the cortex (Blue johns hopkins scientists give psychedelics the serious treatment et al., 1988; Mengod et al., 1990; Wright et al., 1995). Two weeks after ending the 3-month 0.16 mg/kg LSD treatment, rats had significantly elevated locomotor activity compared with saline-injected controls, which was not blocked by M but was blocked by haloperidol and olanzapine. One month after cessation of 0.16 mg/kg LSD treatment, rats also had significantly altered social behavior, with reduced sniffing, grooming, and following and markedly enhanced aggressive (boxing, kicking, wrestling) and exploratory (sniffing, rearing, hole poking) behaviors.

Arvanian et al. (2006) carried out a study in which rats received a staggered double hemisection (DH) at postnatal day two (P2) of the left hemicord at T11 and the right hemicord at T12. A second group had a complete transection at T11 (CT), with a third group serving as a sham-operated control. Drugs were administered intrathecally above the lesion during surgery and again subcutaneously at P4, P6, P8, and P10. The frequency of rearing in an open field test and hindlimb kicks during swimming were then used to assess motor function, and both DH and CT rats showed severe impairment.

These findings suggest that serotonin and 5-MeO-DMT have different abilities to activate Akt, and that serotonin requires β-arrestin-2, whereas 5-MeO-DMT does not. The 5-HT2A receptor was then immunoprecipitated from the frontal cortex of both WT and β-arrestin-2 KO mice after drug treatment. A dose of 5-HTP in WT that stimulates Akt phosphorylation in the cortex revealed a depletion of protein PSD-95 from the complex and recruitment of β-arrestin-2, Src, and Akt. In the cortex of β-arrestin-2 KO mice, however, no depletion of PSD-95 or recruitment of Src or Akt was observed in response to 5-HTP.

IV. Where Is the Serotonin 5-Hydroxytryptamine 2A Receptor Expressed?

The investigators suggested that the upregulation of 5-HT2A receptors in OCD patients may be a compensatory mechanism for a lack of serotonin in the feedback loop between the thalamus and OFC, the caudate nuclei, and the globus pallidus. It is known that serotonergic psychedelics cause rapid downregulation of 5-HT2A receptors, which might have an effect similar to SSRI treatment with respect to 5-HT2A receptors. Following up on these reports, the effect of varying of doses of oral psilocybin (100, 200, or 300 μg/kg) was tested in a small proof-of-concept pilot study of nine subjects who suffered from OCD (Moreno et al., 2006).

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They identified one compound, 1-((S)-2-aminopropyl)-1H-indazol-6-ol), with an EC50 of 43 nM and Emax of 89% that lowered intraocular pressure by 33% in conscious ocular hypertensive monkeys. Since the introduction of LSD into popular culture, there has been a great deal of speculation as to whether psychedelics might acutely improve creativity. Sessa (2008) wrote an essay about much of the thinking and reported on creativity from that early period of time. In addition to these reports of LSD treatment, anecdotal accounts of OCD symptom reduction by consumption of Psilocybe mushrooms have also been published (Leonard and Rapoport, 1987; Moreno and Delgado, 1997).

Effects on Locomotor Activity.

Grob et al. (2011) reported nonsignificant trends for benefits of psilocybin compared with placebo on measures of depression and anxiety. Compared with pretreatment baseline, however, the patients’ Spielberger State-Trait Anxiety Inventory (STAI) trait anxiety subscale scores revealed a significant reduction in anxiety at 1 and 3 months after treatment. Similarly, the patients’ Beck Depression Inventory (BDI) scores showed an improvement of mood that reached significance at 6 months compared with baseline. In a subsequent study, Kyzar et al. (2012) studied the effect of mescaline (5–20 mg/l) on zebrafish behavior in the novel tank test, open field, and shoaling tests.

Halberstadt and Geyer (2013b) recently reviewed the topic of serotonergic hallucinogens as translational models relevant to schizophrenia. In their review, they note the many early groups that studied the effects of LSD, mescaline, and psilocybin, who concluded that these drugs produced mental states that resembled the earliest phases of schizophrenia. The four widely used animal behavioral models are startle habituation, PPI, HTRs in rodents, and deficits in temporal processing (interval timing).

• It remains to be determined whether the effects of R-DOI on these immune cells, and on its ability to prevent the development of asthma, involves blockade of TNF-α signaling.
• Although very rare, there have been reports of rhabdomyolysis after ingestion of LSD (Berrens et al., 2010).
• They employed Chinese hamster ovary (CHO)-FA4 cells stably expressing the human 5-HT2A receptor that had similar maximal responses for inositol phosphate (IP) accumulation and AA release in response to serotonin.
• Finally, in healthy human volunteers, PET has been used to study a possible role for dopamine in the effects of psilocybin.

Psychedelics are a class of drug that cannot be fully understood without reference to a number of other fields of research, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others. This review will focus mostly on pharmacology, both preclinical and clinical, but on occasion reference will be made to aspects of some of those other areas. Lykos paired MDMA with intensive therapy sessions, which raised questions about how much of the benefit stemmed from the drug versus from the psychotherapy package.

• Another possibility, not considered by the investigators, is that these tryptamines might be taken up into serotonin neuron terminals and might displace stored intraneuronal serotonin, in a mechanism similar to a 5-HT releasing agent such as MDMA.
• 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.
• Culturing WT MEFs transfected with a yellow fluorescent protein (YFP) C-terminally tagged 5-HT2A receptor in complete media (containing 10% fetal bovine serum) revealed that the majority of the 5-HT2A–YFP was internalized in WT MEFs.
• The amygdala receives substantial serotoninergic innervation originating mainly from the dorsal raphe nucleus and, to a lesser extent, from the median raphe nucleus (Pralong et al., 2002; Hensler, 2006; Asan et al., 2013).
• Again, using mouse RSK2−/− fibroblasts, they ectopically expressed WT RSK2, N-terminal kinase-dead RSK2 (K100A), or C-terminal kinase-dead RSK2 (K451A) constructs.
• Third, during this time range, the decrease in activation over the right-lateralized extrastriate and posterior parietal cortex was correlated with the reported intensity of visual hallucinations.

B. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Thalamus and Reticular Nucleus

WT flies with red eyes, however, did not demonstrate any overt impairment of coordination or activity even after ingesting comparatively large amounts of LSD. The white gene encodes the protein for the tryptophan transporter (tryptophan is the biosynthetic precursor for serotonin) and it was later demonstrated by another group that white mutant flies have low levels of serotonin (Borycz et al., 2008). Therefore, it seems likely there is a compensatory upregulation of serotonin receptors in these flies that results from abnormally low levels of serotonin that confers the observed supersensitivity of w1118 flies to LSD. The head twitch in mice is operationally defined as a rapid rhythmic paroxysmal side-to-side rotational head movement that occurs after administration of serotonergic hallucinogens (Halberstadt and Geyer, 2011).

Their data are consistent with the notion of functionally antagonistic interactions between 5-HT2A and mGlu2/3 receptors that might regulate sensorimotor gating mechanisms. Using double in situ hybridization, Santana et al. (2013) performed a quantitative study of the expression of α1A, α1B, and α1D adrenergic receptors in pyramidal vesicular glutamate transporter 1–positive and GABAergic (GAD65/67–positive) cells of rat PFC. Given the common signaling pathways shared by 5-HT2A and α1 adrenergic receptors, they examined the coexpression of both receptors in the rat PFC using double in situ hybridization histochemistry. They found that virtually all subdivisions of the PFC contained cells expressing one or more α1 adrenergic receptors. 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 (agranular insular) PFC and the claustrum, as well as in ventral areas such as the orbital and piriform cortices and the tenia tecta.

At the 30-minute mark, there was more than twice as much of this metabolite present in plasma as there was of the parent compound. This metabolite was definitively identified as the 5-O-glucuronide using liquid chromatography/mass spectrometry and chemical synthesis. Evidently, the highly hydrophobic nature of the N-benzyl phenethylamines readily targets them to the mixed function oxidases in the endoplasmic reticulum, where they are efficiently 5-O-demethylated and then very quickly glucuronidated. They identified a major metabolite of the compound in the urine that had a concentration 80-fold higher than the parent drug. The subject’s urine was treated with β-glucuronidase and then analyzed using ultraperformance liquid chromatography electrospray ionization plus tandem mass spectrometry to identify a major metabolite with a mass that was one methyl group lower than the parent compound.

Although LSD was most widely used and therefore has led to the greatest number of HPPD cases, it is clear that other hallucinogens also can evoke the syndrome. For example, Espiard et al. (2005) reported HPPD in an 18-year-old man after mixed intoxication with psilocybin and cannabis. Ikeda et al. (2005) reported flashbacks after use of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) by a 35-year-old man without a previous psychiatric history. He had used the substance six or seven times over 5 months but discontinued it after he had a bad trip, with anxiety, palpitations, auditory oversensitiveness, and visual distortions. Although treatment with antidepressants and risperidone did not ameliorate her symptoms, treatment with the antiseizure drug lamotrigine almost completely abolished her visual disturbances (Hermle et al., 2012). Andreasen et al. (2009) reported a fatality involving the potent synthetic psychedelic phenethylamine compound 1-(8-bromobenzo1,2-b; 4,5-b′difuran-4-yl)-2-aminopropane, known commonly as Bromo-Dragonfly.

Hanes (1996) reported on a 27-year-old male patient with body dysmorphic disorder who spent up to 4 hours every day checking his appearance in the mirror. The intensity of his somatic distress markedly improved on occasions when he had ingested psilocybin mushrooms, noting that at those times, when he looked in the mirror, he no longer appeared deformed. On the basis of the effect sizes, there is no currently available treatment that can produce such long-lasting and high therapeutic efficacy. Large-scale, multisite trials now need to be implemented to determine whether these results can be repeated in a larger cohort of patients.