Although the majority of studies point to a major site of action for psychedelics in the frontal cortex, perhaps with important involvement of the thalamus, psychedelics also have a potent effect on the LC. This finding is very intriguing because the LC is a point of convergence for widely ranging somatosensory and visceral sensory inputs from all regions of the body. The LC has been likened to a “novelty detector” for salient external stimuli (Cedarbaum and Aghajanian, 1978; Aston-Jones and Bloom, 1981). The LC sends NE projections diffusely to all parts of the neuraxis, including the cerebral cortex (Aghajanian and Marek, 1999a). Within the cortex, 5-HT2A and α1-adrenergic receptors share a similar regional and laminar distribution, with heaviest concentrations in layer Va (see Marek and Aghajanian, 1999, and references therein).
- Furrer et al. (2011) 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.
- 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.
- These individuals all became comatose, with hyperthermia, vomiting, light gastric bleeding, and respiratory problems.
- A decrease in Clinician-Administered PTSD Scale scores from baseline was significantly greater for the MDMA group than for the placebo group.
- To determine whether these metabolites might be formed and relevant, mice were pretreated with the MAO-A–elective inhibitor clorgyline.
Johns Hopkins University is too far away from me. Is there anywhere else I can receive psilocybin-assisted therapy?
Intracortical, but not intrahippocampal, infusion of DOI significantly enhanced the release of ACh in the cortex. During the very early years, when LSD was considered to be somewhat of a miracle drug, the possibility was investigated that psychedelics might be useful in ameliorating the symptoms of autistic spectrum disorders. Between 1959 and 1974, a number of studies were reported on the use of LSD to treat children with autism. Typically, after the drug was administered, the children were simply observed and their reactions were recorded in a narrative format.
Head Twitch Response.
- In a double-blind procedure, subjects were given either an oral dose of 30 mg psilocybin, or a 200-mg placebo dose of nicotinic acid, administered in identical capsules.
- Only the psychedelics DOI and LSD induced increased expression of egr-1, egr-2, and period-1 transcripts and were activated by changes in cortical signaling that appear to be specific effects of the two psychedelics, which correlate with the generation of the mouse HTR.
- Finally, the authors compared the IP accumulation and intracellular Ca2+ release signaling pathways in both WT and 5-HT2A–S314A expressed in intact cells.
- Subsequently, Ripoll et al. (2005) assessed the ability of the four-plates to distinguish the anxiolytic effect of DOI from diazepam, alprazolam, paroxetine, and venlafaxine.
- In the mouse head-twitch assay, 25I-NBOMe and a related analog were extremely potent in inducing this behavior, which was blocked by preadministration of the selective 5-HT2A antagonist M (R)-(+)-a-(2,3-dimethoxyphenyl)-1-2-(4-fluorophenyl)ethyl-4-pipidinemethanol (Halberstadt and Geyer, 2014).
- Thus, psilocybin may modulate default mode functions by decreasing ongoing lower frequency oscillations within this network.
The rate of clinical response in the active treatment groups was 85% compared with 25% in the placebo group. It is the most severe type of headache, characterized by unilateral orbital or periorbital pain, accompanied by ipsilateral autonomic features in the nose, eyes, and face, with attacks lasting on average about 90 minutes. Recent evidence, however, has indicated that psychedelics may be more effective therapies for aborting acute attacks than conventional treatments.
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This transcript was stably transfected into HEK-293 cells to generate what the authors designated as an SB1 cell population. Serotonin, dopamine, DOI, and clozapine all produced robust internalization, whereas the 5-HT2A antagonist ketanserin did not. PKC activation by a phorbol ester (PMA) was sufficient to cause endocytosis in the absence of any agonist. In an earlier study, the authors had shown that PKC activation was required for internalization by 5-HT, but not by dopamine. Sphingosine, an inhibitor of PKC activation, almost completely prevented 5-HT– or DOI–mediated receptor internalization but did not affect dopamine-mediated internalization.
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Surprisingly, a challenge dose of DOI 48 hours later showed a significant 51% increase in the number of HTR. This supersensitivity persisted for up to 6 days after the first DOI injection but decreased over time, so that the HTR response had returned to control levels 8 days after the initial DOI injection. Chronic DOI administration also was examined by giving mice daily injections of 2.5 mg/kg DOI for 13 days. Daily HTR responses to DOI injections were reduced from 24 hours after the first injection, through day 5, when they returned to the value observed on day 1. Halberstadt and Geyer (2010) also characterized the effect of LSD on the PPI in rats and compared it with the nonhallucinogenic ergoline lisuride.
One of the common subjectively perceived effects of psychedelics is a strongly altered experience of time (reviewed in Heimann, 1994). For example, one LSD user indicated that he had watched the big bang and the evolution of the universe all in the space of only a few minutes. Animal studies of johns hopkins scientists give psychedelics the serious treatment effects of psychedelics on time perception have been reported, a few of which will be briefly discussed here.
Johns Hopkins experts discuss the promise and pitfalls in studying the healing power of psychedelics
The marked decrease in lower frequency oscillations observed in this study may indicate that psilocybin induces a shift of the resting excitation/inhibition balance toward excitation, which would be expected to disrupt the ordinary temporal structure of neuronal processes within the extended DMN. Lerner and Lyvers (2006) compared users of psychedelic drugs with users of nonpsychedelic drugs and nonillicit drug–using social drinkers. Compared with the other two groups, psychedelic drug users scored significantly higher on mystical beliefs (e.g., oneness with God and the universe), life values of spirituality, and concern for others, and scored lower on the value of financial prosperity, irrespective of culture of origin.
They used a double-blind, placebo-controlled randomized design, in which subjects received pretreatments of placebo or ketanserin (50 mg, p.o.) and treatments of placebo or psilocybin (215 μg/kg). Stimuli were Kanizsa figures that induce the perception of an illusory triangle, or non-Kanizsa figures in which the figure alignment no longer induces that perception. EEG data were recorded and the P1 and N170 amplitudes were quantified, with a time frame from 80–120 milliseconds for the P1 and 150–190 milliseconds for the N170 amplitude.
“There is the misconception that if we’re studying something, it must work, which is almost never the case in toto,” Barrett said. Armed with these promising results, Griffiths and his colleagues turned their attention to other clinical applications. They decided to investigate tobacco addiction—in part because it is much easier to quantify than emotional or spiritual outcomes. Johns Hopkins researcher Matthew Johnson led a small pilot study in 2014 to see whether psilocybin could help people quit smoking. May et al. (2006) discovered indazole-based 5-HT2A agonists with poor CNS activity and solution stability superior to conventional tryptamine-based 5-HT2 agonists such as serotonin and AMS.
Theirs was the first study to systematically assess the effect of psilocybin on timing performance on standardized measures of temporal processing. They used a placebo-controlled, double-blind design in 12 healthy volunteers, administering placebo, a medium psilocybin dose of 115 μg/kg, or a high psilocybin dose of 250 μg/kg. The standardized measures of temporal processing included the temporal reproduction, sensorimotor synchronization, and tapping speed (personal and maximal).
Midbrain raphe cells send serotonergic projections throughout the forebrain and are the source of serotonin afferents in the PFC (Moore et al., 1978). Raphe cells fire at a characteristic regular rate that is generally correlated with a mammalian organism’s level of vigilance or attention. When the organism is awake, the cells fire at a characteristic slow regular rate; as the organism grows drowsy, the rate of firing slows. Most recently, Mengod et al. (2015) reviewed the cartography of 5-HT1A and 5-HT2A receptor subtypes in the PFC and its projections. They conclude that in the rat PFC, 5-HT2A receptors are expressed in pyramidal tract neurons that project to the dorsal raphe nucleus, VTA, and nucleus accumbens.
The authors concluded that psychedelic use may promote alcohol and other drug abstinence as well as prosocial behavior in a population with high rates of recidivism. These investigators carried out an open-label proof-of-concept trial of psilocybin treatment in a sample of 10 volunteers with a DSM-IV diagnosis of alcohol dependence (Bogenschutz et al., 2014). Treatment consisted of psychosocial treatment only, psychosocial treatment coupled with psilocybin, and post-treatment follow-up.
Do you have any studies for “healthy” volunteers?
Wood et al. (2012) compared the effect of DOI with amphetamine and MK-801 on PFC neuronal activity in freely moving rats. Their study was the first to investigate the effects of a psychedelic on cortical neurophysiology in awake animals. They analyzed neuronal population activity, LFP power, and correlations between spike-discharge power and LFP power.
Radioligand binding studies in the first cohort found that chronic MDL11939 led to a significant 88% increase in receptor density with no change in Kd. In the second group, quantitative autoradiography revealed that animals chronically treated with MDL11939 had a significant 232% increase in receptor density in the CA1 field and a significant 231% increase in the dentate gyrus, compared with vehicle-injected controls. In the third group, after chronic MDL11939 administration, DOB was directly infused into the dorsal hippocampus 24 hours after the last MDL11939 injection.
As noted above, DOI-induced head twitches in mice were inhibited in a dose-dependent manner by the selective mGlu2/3 agonists LY and LY (Kłodzinska et al., 2002). This action is presumably due to a presynaptic effect on glutamate neurons, in which mGlu2/3 agonists suppress glutamate release and antagonists block the presynaptic autoreceptor agonist effect of endogenously released glutamate (Conn and Pin, 1997). They coadministered DOI along with GABAA and GABAB receptor agonists and antagonists, and investigated effects on the four-plates test of anxiety in mice. Low doses of DOI that had no effect alone in the four-plates test were significantly potentiated by alprazolam and diazepam, but not by flumazenil.