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Psychedelics paired with therapy could treat chronic mental health conditions Research and Innovation

Although a rationale for treating autism with LSD might seem obscure on the surface, there is a potential scientific basis for such treatment. Murphy et al. used single-photon emission computed tomography imaging with a 5-HT2A–selective antagonist -radioligand (123I-5-I- R91150) to compare cortical density of 5-HT2A receptors in 10 healthy adult subjects and 8 adults with Asperger’s syndrome. They found that the Asperger’s patients had a significant reduction in cortical 5-HT2A binding in the total, anterior, and posterior cingulate; bilaterally in the frontal and superior temporal lobes; and in the left parietal lobe. They reported that reduced receptor binding was significantly related to abnormal social communication.

I was delighted when the editors invited me to write a review on “psychedelics,” perhaps a watershed moment, representing a shift in opinion that has been developing for more than 3 decades with respect to research and understanding of Psychedelics. When I began my graduate studies in 1969, it was politically correct in scientific circles to refer to these substances only as psychotomimetics, a negative term suggesting that they fostered a mental state resembling psychosis . Later, as it was realized that these compounds did not provide very realistic models of psychosis or mental illness, it became more correct to refer to them as hallucinogens, again a pejorative term suggesting that they principally produce hallucinations.

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. After 5-MeO-DMT treatment, no recruitment of β-arrestin-2, Src, or Akt to the 5-HT2A receptor occurred in either genotype. These results demonstrate that β-arrestin-2 is essential for mediating serotonin-induced assembly of the 5-HT2A/Src/Akt complex, and that 5-MeO-DMT differs from serotonin by not recruiting this complex. One can readily envision that when an endogenous neurotransmitter (e.g., serotonin) binds within the orthosteric site of one of its receptors, the receptor protein will collapse around the ligand to generate a transient and distinct ligand-receptor ensemble.

Their results indicated that this heterodimeric complex enhanced Gαi activation by psychedelic 5-HT2A agonists, a signaling event proposed to be involved in hallucinogen-specific signaling (González-Maeso et al., 2007). Much of the work on neuronal effects of psychedelics has been obtained from single cell recordings from brain slices, which do not represent an intact and functioning cortex. The neocortex is constantly active in vivo, as cortical and subcortical networks generate rhythmic patterns of activity at a variety of frequencies (Steriade et al., 1993). The propagation and synchronization of slow cortical oscillations depends at least in part on corticocortical connections and is proposed to be generated by recurrent excitation among large networks of cortical neurons.

Using a variety of different techniques, Béïque et al. challenged the hypothesis that activation of 5-HT2A receptors led to the production of a retrograde transmitter, which resulted in release of glutamate from thalamocortical afferents. In one experiment, they transfected cortical pyramidal cells with a construct coding for the C-terminal portion of PLCβ1, which acts as a dominant negative to suppress Gαq/11 signaling. The 5-HT2A agonist AMS induced a small inward current in nontransfected cells, but not in neighboring neurons transfected with PLCβ-ct. The investigators reasoned that if postsynaptic 5-HT2A receptor signaling induces glutamate release from presynaptic terminals, then inhibition of postsynaptic 5-HT2A signaling should also inhibit the ability of the cells to increase sEPSCs. They found, however, that the ability of AMS to increase frequency of sEPSCs was no different between control cells and those transfected with PLCβ-ct.

These encouraging results in such a small study led to extension of this approach by two groups, one at Johns Hopkins University and the other at New York University , in studies that were recently completed. These are two reasonably large, well powered phase 2 trials of psilocybin-assisted psychotherapy in patients suffering from cancer-related psychosocial distress . These two studies represent the first well powered, properly designed, formal double-blind, placebo-controlled assessment of a psychedelic agent used for a medical treatment, using modern clinical approaches and assessment instruments. Perhaps even more importantly, these studies report remarkable results of efficacy that are unprecedented for CRPD with any available conventional therapies.

“It’s shocking how if you change just one or two atoms, you dramatically change the [psychedelic’s] activity,” she says. “It really teaches you that if you're working with the brain, you really should start small,” she says. April19 also collaborated with Enveric to evaluate the 500 compounds it had previously identified in a “psybrary” of potentials. Using AI enabled Enveric to substantially narrow down its drug candidates to the most promising ones, Tucker says.