Browsing by Subject "psychedelics"

Kiinnostus käyttää psykedeelejä, kuten lysergihapon dietyyliamidia (LSD) ja psilosybiiniä, erinäisten psykiatristen sairauksien hoidossa ei ole jättänyt huomiotta päihteiden väärinkäyttöä. Tutkimukset ovat osoittaneet alustavia positiivisia vaikutuksia LSD:n käyttämisessä erinäisten addiktioiden, kuten kokaiini-, nikotiini- ja alkoholiriippuvuuksien hoidossa. LSD:n on raportoitu auttaneen joitain alkoholismista kärsiviä pysymään raittiina jopa 6-12 kuukautta yksittäisen LSD annoksen jälkeen. Valitettavasti näitä tuloksia on hankala tulkita, ja vaikutusten taustalla olevat mekanismit tunnetaan huonosti. Tutkimme hiirimallimme avulla, kuinka yksittäinen LSD annos vaikuttaa ahmimiskäyttäytymiseen. Käytimme sukroosiliuosta ahmivaa eläinmallia palkkionottamiskäyttäytymisen mallintamiseen, mikä on yksi addiktioihin liittyvän käyttäytymisen tunnusmerkeistä. Tutkimuksemme tavoitteena oli selvittää vaikuttaako LSD palkkionottamiskäyttäytymiseen, ja siten mahdollisesti aivojen palkkiojärjestelmään. LSD -annostelu (0,05 ja 0,1 mg/kg, i.p.) vähensi akuutisti sukroosiliuoksen ahmimiskäyttäytymistä, mutta vaikutus loppui viikon kuluessa. Tästä havaitusta akuutista vaikutuksesta huolimatta erot ryhmien välillä eivät olleet tilastollisesti merkittäviä. Täten oletettiin, että nettovaikutukset aivojen palkkiojärjestelmään ovat epätodennäköisiä. Kuitenkin pelkän i.p. injektion (10 ml/kg) havaittiin vaikuttavan veden juomiseen. Havaitsimme merkittävän piikin veden juonnissa injektointipäivänä, mikä palautui normaalitasolle jo seuraavaan päivään mennessä. Nämä tulokset johtivat jatkotutkimukseemme, jossa osoitettiin injektion aiheuttavan piikin vedenjuontiin riippumatta siitä, injektoidaanko saliinia vai LSD:tä. Tätä vaikutusta ei enää havaittu, mikäli injektioita annettiin perättäisinä päivinä, mutta jopa yhden tai kahden päivän väli injektioiden välillä riitti palauttamaan injektion aiheuttaman piikin vedenjuontiin. Koska onnistuimme poistamaan vedenjuontiin aiheutuneen vaikutuksen toistetuilla saliini-injektioilla, eikä vaikutus palautunut injektoitaessa LSD:tä, voimme todeta, että vaikutus liittyi injektiotoimenpiteeseen. Keskeisin havaintomme tässä tutkimuksessa oli, ettei LSD:llä ole merkittävää akuuttia vaikutusta sukroosiliuoksen ahmimiskäyttäytymiseen tässä hiirimallissa.

In recent years, psychedelics have shown promise in the treatment of conditions like depression and addiction. The therapeutic effects of psychedelics have been linked to their ability to increase plasticity in the brain, an effect that has also been seen for antidepressants. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which has an important role in the development of the nervous system, as well as promotion of neuronal survival and differentiation during adulthood. BDNF, through its receptor TrkB, has been implicated in antidepressant action, and BDNF-TrkB signalling is involved in many aspects of plasticity. Recently, antidepressants have been reported to bind directly to TrkB, and through this binding mediate their plasticity-enhancing, as well as behavioural effects. Psychedelics have been shown to increase structural and functional plasticity, but the mechanisms behind these effects are not fully understood. For example, the serotonergic receptor 5-HT2A is known to be behind the acute hallucinogenic effects of psychedelics, but its role in plasticity is still debated. The aim of this study was to investigate the mechanisms of LSD-induced plasticity. The dimerization of TrkB was examined after LSD treatment in the protein-fragment complementation assay (PCA). Phosphorylation of TrkB signalling markers mTOR and ERK, which have known effects on plasticity, was assessed in Western blot, and the total expression of BDNF was examined with the enzyme-linked immunosorbent assay (ELISA). The timeline of the effects was investigated, and the involvement of 5-HT2A in TrkB dimerization and the phosphorylation of ERK was assessed by combining LSD treatment with the 5-HT2A antagonist M100907. Dimerization was also assessed in a TrkB mutant (Y433F) that has previously been shown to disrupt antidepressant effects on plasticity. These experiments showed that LSD treatment increased TrkB dimerization as well as phosphorylation of mTOR and ERK. The Y433F mutation interfered with LSD-induced TrkB dimerization, but the effects of LSD on TrkB dimerization or ERK phosphorylation were not blocked by M100907. Together, these data suggest that 5-HT2A is not involved in LSD-induced promotion of TrkB dimerization or ERK phosphorylation. The increases in phosphorylation and dimerization were found to be most robust after a 1 h LSD treatment, however an increase in BDNF expression was seen in cortical neuron cultures only after a 24 h treatment with LSD. The results reported in this study support the view that 5-HT2A might not be needed for the plasticity-inducing effects of psychedelics. If this is true, the development of treatments that target plasticity without hallucinatory effects could be possible. Overall, this research provides insight into the mechanisms of LSD-induced plasticity and offers new and interesting directions for future research in the field.

Among the clients of social work, the people who have traumatic experiences are more common than in the general population. In the recent years MDMA, also known by its street name ecstasy, has been studied for treating posttraumatic stress disorder, with promising results. As the research goes on, it is possible that some people turn to MDMA for the purpose of treating their own traumas by themselves. Social workers should be able to evaluate realistically the risks and potential benefits of such behavior, and also think about the problems of the current prohibition and punishment-based drug laws in terms of human rights. If MDMA-assisted therapies become a legal treatment option, social workers should know how to assist and guide their clients in case they wish to engage in such treatment. The US Food and Drug Administration (FDA) has granted a breakthrough status to psilocybin (a psychedelic compound found in some mushroom species) and MDMA-assisted psychotherapies. This means that the preliminary results have been so promising it is possible to make these treatments available faster, in case the further research provides results as good as the previous research. Currently phase 3 studies are ongoing. Lately there have also been discussions about whether these substances are dangerous or even beneficial outside the clinical context. Multiple studies have been done on psychedelics regarding this matter, and the researchers have found out that lifetime use of psychedelics is associated with reduced risk for mental health problems and suicidality instead of increased risk. A similar investigation has not yet been done to the same extent on MDMA. The purpose of this analysis is to fill the void in the research regarding MDMA and find out whether MDMA use is linked to increased likelihood of past month psychological distress, measured by K6 scale, and past year suicidality, defined as suicidal thoughts, suicide plans and suicide attempts. The dataset used for this study is National Survey on Drug Use and Health (NSDUH) from the years 2016–2019. The data of NSDUH is collected via randomized selection of a representative population of the US. The main method of the analysis is multivariate logistic regression. Among the lifetime use of MDMA and other drugs, also the effects of recency have been investigated. The weighted odds ratios were compared to the odds ratios of other drug use groups. Based on the results of this analysis, MDMA use was not associated with increased likelihoods of past month psychological distress or past year suicidality, after adjusting for sociodemographic factors, risk-taking tendency and other illicit/non-medical drug use. Instead, lifetime use of MDMA was associated in most of the models to decreased likelihood of the predicted variables. The odds ratios of MDMA groups were smaller than the odds ratios for other substances in almost every model. Among the other substances, the results of psilocybin were the closest to the results of MDMA. The study suggests that the increased risk for mental health problems and suicidality among the people who use MDMA is likely to be more linked to other drug use than specifically to MDMA use. This analysis does not suggest that MDMA would be an independent risk factor for psychological distress or suicidality.

The prevalence of major depressive disorder is increasing despite the increased standard of living. The prevailing hypothesis to explain depression is that there is an unbalance in information processing in relevant brain networks. Antidepressants (SSRIs, SNRIs) have been shown to induce a juvenile-like plasticity state (iPlasticity) in the brain that helps in rewiring the affected neuronal networks when combined with beneficial environmental stimuli (e.g. psychotherapy). However, it takes weeks to see the beneficial effects of conventional antidepressants on mood and they bring relief only to approximately two-thirds of the patients. There is an urgent need for more efficient and rapid-acting antidepressants. Preliminary data suggests that psychedelics may have potential to respond to this need. It is thought that the therapeutic effect of psychedelics rises from the molecular effects leading to structural and functional plasticity and behavioral changes. Molecular effects of psychedelics are believed to arise from the activation of serotonin 2A (5-HT2A) receptors. It is well established that serotonin 2A (5-HT2A) receptor activation lies behind the hallucinogenic effects of psychedelics, but its role in drug-induced plasticity is currently under debate. Signaling of brain-derived neurotrophic factor (BDNF) through its receptor TrkB has been proposed to underlie the plasticity-promoting effects of psychedelics. However, the mechanisms leading to increased BDNF/TrkB signaling after psychedelic administration are poorly understood. This thesis aimed to study the molecular mechanisms associated with psychedelic-induced plasticity in cortical neuronal cultures. The timeline of the effects of LSD was studied by analyzing the phosphorylation of neurotrophic signaling markers downstream of TrkB (mTOR and ERK) in primary neuronal cultures using Western blot. The role of the 5-HT2A receptor was assessed by combining 5-HT2A antagonist M100907 pretreatment with LSD treatment, followed by Western blot analyses of the same signaling markers mTOR and ERK. The degree of molecular effects of psychedelics was compared to the effects of classical antidepressant fluoxetine. Protein-fragment complementation assay (PCA) was used to evaluate the dimerization of the TrkB receptor in the presence of psychedelics and classical antidepressants. In this context, Western blot was also used to assess the phosphorylation of the plasticity-related BDNF signaling markers ERK and two tyrosines of TrkB receptor (Y515 and Y816) that mediate recruitment of neurotrophic signaling pathways. We found that psychedelic treatment promoted phosphorylation of mTOR and ERK significantly. These effects were not affected by pretreatment with M100907, indicating activation of BDNF/TrkB signaling by psychedelics is independent from 5-HT2A activation. Psychedelics were also shown to cause a significant increase in dimerization of TrkB whereas increase caused by fluoxetine was not significant. Lastly, psychedelics were shown to cause increase in phosphorylation of TrkB and ERK that were comparable to those induced by fluoxetine. These results highlight the potential of psychedelics to promote BDNF-mediated neurotrophic signaling associated with juvenile-like plasticity. Interestingly, the results show recruitment of BDNF/TrkB downstream signaling independently from 5-HT2A activation, which suggests that plasticity-promoting effects of psychedelics might be detached from their hallucinogenic effects.

Objectives. Renewed clinical research finds treatment effects from psychedelic (psilocybin or LSD)-assisted therapy sustained at 12 month follow-up. Population studies find the association between lifetime psychedelic use (even once, Yes/No) and current mental health absent or protective after adjusting for sociodemographics, risk-taking tendency, and non-medical use of other drugs. This study aimed to investigate whether the recency of psychedelic use (>12, 1–12, or <1 months ago) is associated with past month psychological distress, past year suicidality, or everyday impairment. This study also addressed a previously expressed concern that the previous results stem from overadjustment for non-medical use of other drugs, explored how such adjustments should be done, and compared use of psilocybin, LSD, and psilocybin and/or LSD. All code was published. Methods. The analysis was based on combined data of adult respondents of the National Survey on Drug Use and Health (NSDUH) years 2008–2014 randomly selected to be representative of the population of the United States. Comparison groups by the psychedelic used and its recency of use were inferred from the data. Weighted odds ratios were calculated adjusting for sociodemographics, risk-taking tendency, and non-medical use of other drugs. Adjustments for other drug use were compared between a minimally adjusted model, a lifetime use-adjusting model, and a recency of use-adjusting model. Mirroring adjustments were made in order to see whether crack cocaine and heroin use recency would associate to psychological distress in an unexpectedly protective way, indicating overadjustment in the psychedelic recency associations. Results. No independent association between any recency of any psychedelic use and increased likelihood of past month psychological distress, past year suicidality, or everyday impairment was found. A decreased likelihood for past year suicidal thinking was found among all groups that had last used psychedelics >12 months ago or psilocybin <1 month ago, as well as for past year suicide plans and past month serious psychological distress among those whose last psychedelic use was psilocybin >12 months ago. More recent crack cocaine or heroin use was still associated with a higher risk for past month serious psychological distress after adjusting for lifetime non-medical use of other drugs. LSD and psilocybin could not be properly intercompared due to surprisingly small LSD-only recency groups. Adjusting for non-medical use of other drugs made a big difference, but adjustments for their lifetime use or recency of use did not mutually differ. Conclusions. This study strongly supports the results of previous population studies, as no independent risk from psychedelic use was found even when considering their recency of use. The results are also consistent with research indicating that psychedelics may have long-lasting beneficial effects for anxiety, depression, neuroticism, substance dependence, cognitive flexibility, and meaningfulness, and do not lead to dependence.