Johns Hopkins Scientists Give Psychedelics the Serious Treatment

A 2015 clinical trial evaluated the value of psilocybin in 10 participants with alcohol dependence. The results suggested that the drug reduced cravings for alcohol and increased abstinence. Psychedelics have certain effects, such as mystical experiences, that make them attractive for recreational use. Limited research suggests that they may also have medical uses, such as reducing depression and anxiety, as well as promoting abstinence from smoking and alcohol.

G. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Amygdala

Gatch et al. (2009) trained male Sprague-Dawley rats under an FR10 food-reinforced paradigm to discriminate DMT (5 mg/kg) from saline and then tested the ability of LSD, R-(−)-DOM, (+)-methamphetamine, and racemic MDMA to substitute in these rats. DMT also was evaluated for drug-appropriate responding in rats trained to discriminate LSD, DOM, MDMA, or (+)-methamphetamine from saline. LSD, DOM, and MDMA all fully substituted in DMT-trained rats, but (+)-methamphetamine failed to substitute. In rats trained to discriminate LSD from saline, only DOM fully substituted, and DMT and MDMA only partially substituted.

Can This Psychedelic Help Cure Opioid Addiction?

Most often, Miner et al. (2003) observed that 5-HT2A receptors were restricted to a particular area of the dendrite, usually extrasynaptic regions apposed to unlabeled dendrites. They reported that 73% of the immunopositive sites were postsynaptic, and 58% of those were on dendritic shafts, with 42% expressed in dendritic spines. A postsynaptic localization is also consistent with the reports by Xia et al. (2003a,b), who demonstrated that 5-HT2A receptors interact with PSD-95, the major protein of postsynaptic densities in asymmetric synapses.

Is psilocybin addictive? Do people experience psilocybin-related withdrawal?

Addiction suffers the highest levels of unmet medical needs of all mental health conditions (178), with the current armamentarium providing modest impact on patients’ lives and failing to address remarkably high rates of treatment resistance, relapse and mortality (179). In this review, we have summarized the past, present, and future of research investigating psychedelic therapies for addiction. Approaching nearly a century since its introduction into Western addiction medicine, psychedelic therapy has demonstrated clinical success across a range of settings from the real world to controlled clinical research, and more recently double-blind randomized controlled clinical trials.

Pregnant People

Griffiths et al. (1979) concluded that the reinforcing effects of PCP are most likely unrelated to its hallucinogenic properties, and that the lack of self-administration in animals agrees with the finding that people use psychedelics at a very low level and that most discontinue use spontaneously. In support of this early work, a recent study in three baboons showed that, under daily schedules, they self-administered very low amounts of LSD, considerably less than cocaine. This did increase in two of these non-human primates under intermittent schedules, although still at a much lower level than cocaine (Goodwin, 2016).

They note that when KO mice were trained to discriminate a visual stimulus, 85% of the mice exhibited operant behavior, whereas 100% of the WT mice reached criterion. Elevated synaptic levels of serotonin occur in the SERT KO mice, which would be expected to lead to receptor downregulation. Indeed, Li et al. (2000) showed that SERT KO mice have reduced densities of 5-HT1A receptors, and Rioux et al. (1999) demonstrated reduced 5-HT2A receptors in SERT KO mice. Interestingly, in a later study, Li et al. (2003) reported that 5-HT2A receptor density was reduced only in the claustrum and ventral striatum of SERT KO mice, whereas Rioux et al. (1999) reported decreased expression of 5-HT2A receptors also in the cortex. Obviously, it is impossible to model the complexity of the psychopharmacology induced by psychedelics in humans with any nonhuman animal model. As far as we know, animals administered a psychedelic do not “hallucinate” or have the same sorts of sensory and cognitive effects that occur in humans.

How many young students use hallucinogens**?

Eight recent double-blind, placebo-controlled studies of psilocybin in healthy volunteers, with follow-up between 8 and 16 months, reported “no subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long term impairment of functioning” [20]. And two other recent clinical trials of psilocybin in 54 healthy volunteers found no evidence of lasting adverse effects [8], [9]. With that in mind, if the positive therapeutic effects of psychedelics continue to be validated by additional well designed clinical studies, it opens up a whole new dimension of medical research.

III. Mechanism of Action

Researchers are also investigating other drugs sometimes classified as psychedelic and dissociative drugs, such as MDMA, and the way they work in the brain. Scherf and Angenstein (2015) simultaneously measured generated field EPSPs and BOLD response in the CA1 region of the rat hippocampus during electrical stimulation of the contralateral CA3 region. Consecutive stimulations with low-intensity stimulation trains resulted in clear postsynaptic responses of CA1 pyramidal cells, but no significant BOLD response. No positive correlation was found between the electrophysiologic parameters of CA1 pyramidal cell activity and the BOLD response.

• The vast majority of hallucinogen users do not transition to hallucinogen dependence (Stone et al., 2006).
• Although DOI is quite potent, it likely never became popular as a street drug because of its very prolonged duration of action, so it had never been placed into Schedule I of the Controlled Substances Act (although as of November 2015, there are congressional moves afoot to change that).
• 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.
• This substance would then diffuse out from the postsynaptic membrane and block K+ channels on presynaptic glutamate terminals, leading to glutamate release.

LSD and Mental Health: Research & Future Treatments

• Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale and a mental imagery test.
• There is also extensive evidence for the interaction of glutamate systems in serotonin 5-HT2A receptor–mediated behaviors.
• Similarly, effects of LSD were not influenced by sex or body weight in a pooled study of 81 healthy subjects.
• 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.

Bohn and Schmid (2010) reviewed functional selectivity of the 5-HT2A receptor and the role of arrestin as one of the signaling pathways. To disrupt the function of the signaling complex in vivo, the HTR in normal C57BL/6J mice was assessed after intracerebroventricular administration of inhibitors of PI3K, Src, and Akt prior to treatment with 5-HTP. By contrast, pretreatment of β-arrestin-2 KO mice with PI3K, Src, or Akt inhibitors prior to 5-HTP did not reduce the HTR, suggesting that the HTR in β-arrestin-2 mice is independent of these signaling are psychedelics addictive components. Schmid and Bohn (2010) suggested that the HTR induced by high doses of 5-HTP or serotonin in WT mice could reflect activity of both serotonin and its N-methylated derivatives. Thus, when WT mice were pretreated with the Akt inhibitor together with an N-methyltransferase inhibitor prior to 5-HTP, the HTR was nearly abolished. In a follow-up study, Strachan et al. (2009) carried out a more detailed examination of RSK2 and its relationship to 5-HT2A receptor signaling, finding that RSK2 phosphorylates a conserved Ser314 within i3.

Fears of psychedelics leading to psychosis date back to the move to ban LSD, emphasising cases of ‘acid casualties’, which had a powerful impact on society’s representations of psychedelics, although these instances are rare, especially in clinical use (see Table 2). First synthesised by Albert Hofmann in 1938, LSD is a semi-synthetic tryptamine derived from the naturally occurring ergot alkaloid ergotamine (Nichols, 2004). It acts primarily as a serotonergic receptor agonist and also acts at dopaminergic and adrenergic receptor sites (Nichols, 2004). Having been described as a ‘problem child’ (Hofmann, 1979), LSD became a major focus of negative public perceptions, many of which still prevail today. Biden administration preparing for potential FDA approval of MDMA-assisted therapy for PTSD. Right now — except for ketamine — psychedelics can only be used as part of a research study.