Eight recent are psychedelics addictive 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. The fMRI studies and their various analyses and reanalyses by Carhart-Harris and colleagues are at odds with the earlier SPECT and PET imaging studies and may reflect different methodologies. In particular, psilocybin is not typically administered to humans by injection, nor are Psilocybe mushrooms generally taken in routes other than by mouth. In the Hermle et al. (1992), Vollenweider et al. (1997a,b), and Gouzoulis-Mayfrank et al. (1999) studies cited earlier, the drug was administered orally, but psilocybin was administered intravenously in the studies by Carhart-Harris et al.
Minimal Physical Dependence
Although evidence and human rights arguments led to exemptions for specific indigenous groups, the laws and biases against peyote remained in place and were then extended to other psychedelics. This narrative review examines the evidence for potential harms of the classic psychedelics by separating anecdotes and misinformation from systematic research. Yes, when used in a controlled, intentional setting, such as under the guidance of a trained therapist or spiritual leader, psychedelics can be used safely for spiritual or therapeutic purposes. It’s important to approach their use cautiously, set clear intentions, and ensure the environment is supportive and safe. For those who feel that their spiritual practice is becoming overly reliant on psychedelics, it may be helpful to take a break from use and explore other forms of spiritual or personal development. This might involve practices such as meditation, prayer, journaling, or therapy, which can help to integrate the insights gained from psychedelics and to address any underlying issues that may be contributing to dependency.
Are Psychedelic Drugs Addictive?
Subsequently, Health Canada granted exemption to 16 healthcare professionals to take psilocybin themselves for personal training (Dubinski, 2020), which is indicative of a rapidly growing infrastructure for psilocybin-assisted therapy in Canada. “Set” refers to the user’s mindset, including their thoughts, emotions, and expectations, while “setting” refers to the physical and social environment in which the substance is used. Together, set and setting play a crucial role in shaping the nature of the psychedelic experience and its potential risks. A positive set and setting can reduce the risk of negative experiences, including addiction. Moreover, the social acceptance of psychedelics in these scenes can make it difficult for individuals to recognize when their use has become problematic. In a culture that celebrates and promotes psychedelic experiences, individuals may feel encouraged to use more frequently or in higher doses, increasing the risk of psychological dependence and other negative consequences.
- Thus, psilocybin may modulate default mode functions by decreasing ongoing lower frequency oscillations within this network.
- Our programs address both the psychological aspects of addiction and any co-occurring mental health conditions.
- They indicated that it was easily observed, that independent observers could reliably detect the behavior, and that this HTR in mice “provided a suitable tool for the behavioral studies” (Keller and Umbreit, 1956).
- This name has been popular among the lay public for more than 5 decades, but it has generally been frowned upon by the scientific community because it implies that these substances have useful properties.
- Looking at psilocybin, Gable (1993) concluded that it carries a lower dependence risk than caffeine, and being among the lowest risks of death of all major substance abuse categories.
Therapeutic effects
The six phenethylamines had very weak uptake inhibition properties, with IC50 values ranging from 30 to 80 μM. DPT had IC50 values for reuptake inhibition of dopamine, 5-HT, and NE of 23 μM, 2.9 μM, and 9.1 μM, respectively, somewhat less potent than those found by Cozzi et al. (2009) using human platelets. The ability of the compounds to induce release of stored monoamines from rat brain synaptosomes also was studied. The six phenethylamines were virtually inactive, as was DPT, having no effect at 10−4 M of the drug. These results seem to suggest that, in general, effects of psychedelics on monoamine reuptake and release may not be relevant and that direct receptor actions remain most important.
Kometer et al. (2013) used a similar experimental approach to assess the effects of psilocybin on both α oscillations that regulate cortical excitability and early visual P1 and N170 potentials in 17 healthy humans. They also tested whether these effects were related to the formation of visual hallucinations. Parieto-occipital α oscillations are crucial for modulation of visual network excitability and strongly influence visual perception (see references in Kometer et al., 2013). The authors hypothesized that activating 5-HT2A receptors with psilocybin might modulate α oscillations, leading to an altered excitability that would promote visual hallucination formation. 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).
Adverse effects of psychedelics: From anecdotes and misinformation to systematic science
Since then, virtually nothing has been reported to suggest that psychedelics might have specific efficacy against endogenous depression. Nonetheless, studies cited in the previous section concerning treatment of anxiety and depression secondary to a cancer diagnosis do indicate that psychedelics may be effective in treating depression. A small, open-label study of ayahuasca in relieving depression reported by Osorio et al. (2015) is also suggestive. In subsequent studies, the Nichols group used a more receptor-selective psychedelic, DOI, to probe the role of the 5-HT2 receptor in fly behavior (Nichols, 2006; Johnson et al., 2009, 2011).
Psychedelics and Mental Health: A Population Study
5-HT, AMS, and DOI elicited significantly greater maximal increases in IP accumulation, Ca2+ release, and ERK1/2 phosphorylation in RSK2 KO mouse embryonic fibroblasts (MEFs). The relative efficacies of quipazine, 5-MeO-DMT, lisuride, and meta-chlorophenylpiperazine (m-CPP) were significantly increased at all three effector readouts in RSK2 KO MEFs. In contrast with effects on maximal signaling, relative agonist potencies were not potentiated, with few exceptions. The ratios of the Emax responses for RSK2 KO MEFs and WT MEFs differed for each agonist and response, with the greatest changes seen for IP accumulation and ERK1/2 phosphorylation. Strachan et al. (2010) compared responses in WT and KO MEFs for a variety of agonists and partial agonists, with a detailed discussion of the effects; overall, their data suggested that 5-HT2A agonists were differentially responsive to RSK2 deletion.
Classic psychedelics that have been extensively studied include LSD, shown earlier, mescaline, psilocybin, and N,N-dimethyltryptamine (DMT) (Fig. 2). Important examples of these substances include a substance used in ancient India known as Soma, which was highly revered and is frequently mentioned in the Rigveda, with numerous Vedic hymns written in praise of Soma (Wasson and Ingalls, 1971). In the ancient village of Eleusis, outside Athens, for more than 2000 years there was an annual all-night secret ceremony that is believed to have involved ingestion of a hallucinogenic brew known as κψκεον (Wasson et al., 1978).
The lower density of 5-HT2A receptors correlates with changes in hallucinogen-like behavioral and cellular responses that require expression of the 5-HT2A receptor in the mouse brain cortex. Thus, chronic treatment with LY decreases LSD-dependent head-twitch behavior as well as LSD-dependent induction of expression of c-fos, egr-1, and egr-2 in the mouse somatosensory cortex. In conclusion, data from Moreno et al. (2013) support the hypothesis that chronic blockade of mGlu2 receptor–dependent signaling downregulates 5-HT2A receptor binding in the mouse somatosensory cortex drug addiction and its hallucinogen-like cellular signaling and behavioral effects. Given that mGlu2 receptors are located presynaptically, their blockade would lead to excessive glutamate release, potentially resulting in feedback downregulation of 5-HT2A receptors expressed on the pyramidal apical dendrites. LSD and DOB induce a ketanserin-sensitive increase in shaking behavior in mice and rats, which includes both head twitches and wet dog shakes. Substantial evidence suggests that shaking behavior primarily results from metabotropic glutamate mGlu2/3-sensitive glutamate release downstream of frontocortical 5-HT2A activation (this review).
This interaction is explored more fully in the section in this review on the use of animal models. Research over the past 2 decades has clearly shown that psychedelics enhance glutamatergic transmission in the cortex at the neuronal level and also in behavioral responses. The effect was completely blocked by M and also by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate antagonist LY (3S,4aR,6R,8aR)-6-2-(2H-tetrazol-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid. These data provided the first evidence that psilocybin-induced effects in humans were due to 5-HT2A receptor activation. Subsequently, Vollenweider and colleagues have carried out several additional clinical studies, discussed later, of various aspects of the action of psilocybin and have shown that ketanserin can block most of those effects.
- In rats trained to discriminate (+)-methamphetamine from saline, only MDMA fully substituted.
- Schmid et al. (2008) tested whether 5-HT2A receptor regulation by β-arrestins contributes to serotonergic responsiveness in vivo by comparing WT mice with mice that lack β-arrestin-2.
- VS activation to this task has also been used to assess the functional effects of drugs being developed as potential addiction medicines, including dopamine D3 receptor (DRD3) antagonists (87) and already licensed drugs such as naltrexone (88) and nalmefene (89).
Psychedelic drugs such as psilocybin and LSD, are generally considered to have low addiction potential, although it is possible for people to develop a hallucinogen-related substance use disorder. Psychedelics differ significantly from other substances in terms of addiction potential. Understanding these differences can clarify why psychedelics generally don’t lead to physical dependence. Yes, further research is needed to fully understand the addictive potential of psychedelic mushrooms.