Harman et al. recruited 27 male participants who were in various professional occupations, including engineers, physicists, mathematicians, architects, a furniture designer, and a commercial artist. A number of subjects had worked for weeks or months on their chosen projects without being able to find a satisfactory solution. Various psychologic tests and tests of creativity were administered before and after the drug sessions, which involved administration of 200 mg mescaline. Participants were prepared by presession interviews and instructions regarding how to approach the drug sessions. Although lacking detailed specifics as well as a follow-up, this early report does suggest that psychedelics might acutely improve creativity. More recently, Hasselbalch et al. (2008) used 18Faltanserin PET to assess cerebral 5-HT2A receptor density in 16 patients with mild cognitive impairment of the amnestic type, compared with 17 age and sex-matched controls.
How Do Psychedelics Work in the Brain?
Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action.
Law enforcement seizures of psilocybin mushrooms rose dramatically between 2017-2022
The recent resurgence of interest in the clinical uses of psychedelics led Johnson et al. (2008) to propose appropriate procedures for using them in clinical practice. The guidelines they outline have certain parallels with ritual uses of hallucinogens by older indigenous cultures. In particular, Johnson et al. (2008) cite the need for structured use (expressed as ritual in indigenous use) and restrictions on use, including the need for guidance and appreciation of the powerful psychologic effects of hallucinogens (expressed as reverence in indigenous use).
Are psychedelic and dissociative drugs addictive? Can people experience withdrawal?
Cohen (1967) and Jaffe (1985) have both stated that death due to direct LSD toxicity is unknown. For example, eight individuals who believed they had cocaine accidentally insufflated an extremely high dose of LSD. Their plasma LSD levels were reported as between 1000 and 7000 μg/100 ml (recall that a typical total oral dose of LSD might be 100–200 μg). These individuals all became comatose, with hyperthermia, vomiting, light gastric bleeding, and respiratory problems. With hospital treatment, however, all eight survived and without apparent residual effects (Klock et al., 1974).
- Between 1950 and the mid-1960s there were more than a thousand clinical papers discussing 40,000 patients, several dozen books, and six international conferences on psychedelic drug therapy.
- Moreover, a limited number of (pre)clinical studies that investigated the relationship between biological and behavioral adaptations showed that the stimulation of molecular and neuronal was accompanied by increased learning behavior.
- They first analyzed the kinematics of head twitches using high-speed video recordings, reporting that the HTR was highly rhythmic, occurring within a specific frequency range (mean head movement frequency of 90.3 Hz).
- Finally, the authors compared the IP accumulation and intracellular Ca2+ release signaling pathways in both WT and 5-HT2A–S314A expressed in intact cells.
- The proliferating cells that survive the elimination via apoptotic cell death migrate and mature into newborn granule cells and fully integrate into the hippocampal network (23–25).
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 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.
Dissociative Drugs
The changes were more than 3 times greater than those caused by a control compound, methylphenidate (a stimulant used to treat attention deficit hyperactivity disorder). Alternatively, enhanced neuroplasticity can be attributed to differences in receptor affinity, given that psychedelics are psychedelics addictive are not pure 5-HT2AR agonists, which could explain the different effects on neuroplasticity between psychedelics. DMT exhibits, besides the 5-HT2AR, also high affinity for the S1R, which is highly expressed in the hippocampus and is a stimulator of synaptic plasticity (99–101). Activation of S1R by DMT has been suggested to stimulate synaptic plasticity in addition to 5-HT2AR-induced modulation and is likely responsible for ayahuasca’s antidepressant effects (64, 102). Moreover, LSD was shown to stimulate S1R indirectly via activation of the neurosteroid dehydroepiandrosterone (DHEA), which stimulated synaptic plasticity and neurogenesis (103, 104).
How is NIDA advancing research on psychedelic and dissociative drugs?
For example, using 18Ffludeoxyglucose (FDG) PET, it was found that schizophrenia subjects with predominantly negative symptoms have a lower glucose metabolic rate than subjects with predominantly positive symptoms, particularly in frontal, temporal, and cerebellar circuitry (Potkin et al., 2002). By contrast, schizophrenia patients with positive symptomatology have increased frontal metabolic rate of glucose. Soyka et al. (2005) used 18FFDG PET in 10 unmedicated schizophrenia patients with vivid positive symptoms. Schizophrenia https://ecosoberhouse.com/ patients had higher, but nonsignificant, regional metabolic rates of glucose in almost all quantified regions compared with controls, but the right/left frontal-occipital metabolic ratio was significantly higher for the schizophrenia patients, indicating a hypermetabolic pattern. It has been known for some time that several serotonin receptor types are expressed in ocular tissues of the human eye (Martin et al., 1992), and May et al. (2003) demonstrated that 5-HT2 receptors were involved in local control of intraocular pressure (IOP) in cynomolgus monkeys. The nonselective 5-HT2A/2C agonist R-DOI also was shown to have a dose-dependent reducing effect on IOP in the cynomolgus monkey (May et al., 2003).
How do psychedelics work? This brain region may explain their effects
- In mice trained at the lower dose of LSD (0.17 mg/kg), stimulus control was present for at least 30 minutes but then rapidly declined over the following 30 minutes.
- Sharif and Senchyna (2006) used RT-PCR to demonstrate that human ocular tissues expressed mRNA for the 5-HT2A and 5-HT2B receptors, with greatest abundance in the retina, ciliary body, ciliary epithelium, choroid, conjunctiva, and iris.
- They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of LSD, psilocybin, or mescaline.
- In a second phase looking at relapse, the animal models are weaned off of the opioid for a period of time.
In contrast with most other G protein–coupled receptors (GPCRs), the 5-HT2A receptor undergoes downregulation in response either to agonist or antagonist treatment (Gray and Roth, 2001). Two nonconserved residues in the 5-HT2A receptor, S421 in the C terminus, and S188 in intracellular loop 2, have been reported to be essential for agonist-induced desensitization in cloned receptors expressed in human embryonic kidney 293 (HEK-293) cells (Gray et al., 2003). When either residue was mutated to alanine, 5-HT–induced desensitization was markedly attenuated. Hasler et al. (2004) studied eight subjects given either placebo or 45, 115, 215, or 315 μg/kg psilocybin (a very low, low medium, or high dose, respectively). Instruments used to assess psilocybin effects included the 5D-ASC, the Frankfurt Attention Inventory (FAIR), and the Adjective Mood Rating Scale (AMRS). The only scores that were increased on the AMRS were “general inactivation,” “emotional excitability,” and “dreaminess.” Hasler et al. (2004) found no evidence that psilocybin is hazardous with respect to somatic health.
Flies carrying a mutation in the white gene (w1118) demonstrated a progressive loss of activity and coordination over about 15 minutes after LSD administration, followed by a recovery beginning at about 60 minutes. The more severely affected flies became completely paralyzed at about 15–20 minutes after feeding. Ketanserin blocked the LSD-induced decrease in locomotor activity observed in the mutant fly strain. 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).
Psilocybin eases existential anxiety in people with life
Furthermore, it has been shown that medication-free depressed patients with high pessimistic attitudes have increased 5-HT2A receptor binding in the PFC compared with healthy control subjects (Meyer et al., 2003; Bhagwagar et al., 2006; Meyer, 2012). Although nonhuman primates might be the best animals to model the actions of psychedelics in humans, almost nothing has been published in the past decade using monkeys. Fantegrossi et al. (2004) reported on transient reinforcing effects of phenylisopropylamine and indoleamine psychedelics in rhesus monkeys. They investigated the capacity of several psychedelics to maintain self-administration in four rhesus monkeys with a history of MDMA self-administration. No dose of either DMT or psilocybin engendered significantly higher mean response rates than did contingent saline, although one monkey did exhibit transitory reinforcing effects after DMT and psilocybin.