Added: Marella Dale - Date: 18.10.2021 13:41 - Views: 49101 - Clicks: 4777
Lysergic acid diethylamide LSD is a potent hallucinogenic substance that was extensively investigated by psychiatrists during the s and s. Researchers were interested in the unique effects induced by this substance, some of which resemble symptoms seen in schizophrenia.
Moreover, during that period LSD was studied and used for the treatment of several mental disorders such as depression, anxiety, addiction and personality disorders. Despite this long history of research, how LSD induces its specific effects on a neuronal level has been relatively unclear.
In recent years there has been a revival of research in hallucinogenic drugs and their possible clinical applications. These contemporary studies in the UK and Switzerland include neuroimaging studies using functional magnetic resonance imaging fMRI. In this review, we collect and interpret these recent neuroimaging findings. Overall, across studies indicate that LSD administration is associated with extensive alterations in functional brain connectivity, measuring the correlated activities between different brain regions.
The studies mostly reported increases in connectivity between regions and, more specifically, consistently found increased connectivity within the thalamocortical system. These latter observations are in agreement with models proposing that hallucinogenic drugs exert their effects by inhibiting cerebral filtering of external and internal data.
However, studies also face several limitations, including potential biases of neuroimaging measurements. Lysergic acid diethylamide LSD is a very potent hallucinogenic substance. After the discovery of LSD by the Swiss chemist Albert Hoffmann inthe drug was commercialised by the Basel-based pharmaceutical company Sandoz for the use in psychiatry [ 3 ].
The indications mentioned covered two areas: firstly, administration of LSD as an adjunct to psychotherapy and, secondly, self-administration by the psychiatrist in order to gain insight into the world of patients with mental disorders, particularly psychosis. At first glance it seems contradictory that a Side effects lsd should have such opposing effects.
However, both areas — LSD as a treatment option for mental disorders and as a model for psychosis — were extensively investigated during the next decades. This research led — among others — to one of the first hypotheses that mental disorders might be caused by brain chemistry, when the similarity between LSD and serotonin was discovered [ 4 ]. During the s and s, more than reports on LSD were published, thousands of patients with various mental disorders were treated with LSD and were often regarded as encouraging [ 4 ].
However, research stopped when LSD was prohibited in the s. In recent years, the research on hallucinogenic drugs has experienced a revival. In the UK and in Switzerland, the effects of LSD on healthy subjects were investigated by a of researchers [ 156 ]. Ina first study by the Swiss psychiatrist Side effects lsd Gasser investigated clinical effects of LSD as an anxiety treatment for patients with life-threatening diseases [ 7 ].
One of the most interesting questions in this field is how the typical effects of LSD are represented on a neuronal level. This question was recently addressed by three clinical trials, which used functional magnetic resonance imaging fMRI in healthy subjects. These studies were conducted by teams in London [ 5 ], Zurich [ 6 ] and by our research group in Basel [ 89 ]. In the present paper we will summarise the of these trials and provide an interpretation of how the observed neuronal effects might evoke the profound subjective effects related to this substance.
We will focus Side effects lsd studies investigating resting state activities participants did not engage in any task during the functional magnetic resonance imaging [fMRI] scan of the brain and will not refer to task-related fMRI studies e. In addition, because of these restrictions, this article focuses exclusively on functional connectivity, measurement of the correlation of brain activity between different regions. This concept and related terms used in this article are summarised in figure 1.
In humans these moderate doses are expected to induce all typical effects associated with this drug [ 14 ]. All studies described below were conducted in healthy subjects and sample sizes were rather small range 15—24 subjects. Details on the included studies are shown in table 1 below. Table 1. Characteristic of the studies included in this review. The first published fMRI study on LSD focused on changes in functional connectivity within and between resting state networks [ 5 ].
Resting state networks are sets of specific brain regions which exhibit synchronised activity without further behavioural tasks or activity. Several brain connectivity networks have been described, such as the default mode network or different visual networks [ 17 ].
Carhart-Harris et al.
They found decreased connectivity within several networks, but increased connectivity between the networks. In other words, these findings indicated that the synchronised activity normally seen within the respective network was less synchronised, but different networks were more synchronised with each other. It was concluded, that these brain states show typical drug effects induced by LSD. Details on the networks showing decreased connectivity after LSD are shown in table 2 and details on alterations in between-network connectivity are shown in figure 2.
Table 2. LSD-induced alterations in functional connectivity within resting state networks compared between studies. Our team attempted to replicate these findings in a consecutive study [ 16 ]. We could confirm the findings regarding connectivity within networks and we also observed increased connectivity between networks please see table 2figs 2 and 3 for more details. However, consistency between studies was limited as connectivity between specific networks varied widely across studies.
With regard to within-network connectivity, we noted that very similar alterations were observed in another study after the administration of a serotonin reuptake inhibitor [ 19 ]. The authors found that within-network connectivity within the default mode network, the visual networks 1—3, the sensorimotor network and the auditory network were decreased compared with placebo.
As this drug is not associated with any subjective effects typical of a hallucinogenic drug, the observed alterations might not be specific to LSD or rather be an epiphenomenon of a nonspecific serotonergic stimulation. Functional connectivity of the whole brain after LSD administration has been investigated by three studies so far [ 28915 ]. These studies used a measure called global functional connectivitywhich is the mean correlation of a given region to all other regions.
An advantage of this measure is that it is data-driven, meaning that no a priori hypotheses, such as which region or network might or might not be affected by LSD, are needed. Tagliazucchi et al. In more detail, the authors described increased global connectivity in precuneus and thalamus, but no details were reported for other regions [ 15 ].
Compared with that, our group found increases in global connectivity that were limited to thalamic regions and part of the basal ganglia [ 89 ] please see fig. The fact that alterations were spatially less widespread in our sample might be explained by slight methodological differences global connectivity was calculated based on voxels compared to region of interest resulting in a stricter statistical threshold.
Subsequently, Preller et al. Preller et al. With global al regression, the authors reported increased global connectivity primarily in occipital and temporal regions and in the postcentral gyrus and precuneus, whereas other Side effects lsd, parietal and subcortical Side effects lsd showed decreased connectivity.
The authors also repeated their analysis without global al regression. Findings changed ificantly, including decreased connectivity in the right insula and increased connectivity in the cerebellum and parts of the basal ganglia and thalamus.
Psilocybin is a hallucinogenic drug naturally occurring in certain mushroom species. Like LSD, psilocybin primarily acts as a serotonin 2A -receptor agonist [ 22 ]. Presumably, its subjective effects are very similar to those of LSD [ 2324 ]. It is therefore likely that psilocybin induces neural alterations very similar to those of LSD. However, reliable data have yet to be found. Compared with LSD, psilocybin has been examined by means of neuroimaging for some time, the first human study having been undertaken in the s [ 25 ].
The group from London, who also conducted one of the LSD studies mentioned above, investigated comparable aspects of functional connectivity changes after psilocybin 2 Side effects lsd intravenously in 15 healthy subjects [ 1518 ]. The first study investigated connectivity between several resting state networks and reported widespread increases across several networks, in general accordance with findings obtained after LSD administration [ 18 ]; please see fig.
However, as we have already pointed out elsewhere [ 16 ], agreements between these findings after psilocybin and alterations seen after LSD administration [ 516 ] were quite limited. This raises the question about the specificity of the observed alterations for hallucinogenic drug effects. The second study investigated changes in global functional connectivity and found increased global Side effects lsd in several regions, including the precuneus and the thalamus [ 15 ].
Therefore, these latter findings are in relatively good agreement with alterations seen after LSD administration [ 1516 ]. Several studies have indicated that substances such as LSD and psilocybin might have therapeutic effects in various mental disorders such as anxiety, depression and addiction [ 726 — 28 ]. The question of how a single mechanism of action can exert positive effects in heterogeneous diseases is an interesting one. A recent model proposed that alterations in functional connectivity, as seen in the neuroimaging described above, might explain potential therapeutic effects of hallucinogenic drugs [ 29 ].
Nichols et al. According to this model, pathological connectivity patterns associated with diverse mental diseases are acutely modified through destabilisation of hub functions with subsequent changes in functional connectivity between various brain regions. According to the authors, these events somehow give rise to the development of new connectivity patterns, which are stabilised after the acute effects have subsided, possibly through anti-inflammatory effects [ 29 ].
Some experimental fMRI findings pointed to lasting functional connectivity changes after the administration of a hallucinogenic drug [ 31 ], which might support these hypotheses. The concept that LSD induces its subjective effects mainly via increases in functional connectivity between brain regions is tempting. For example, this concept provides a straightforward idea as to how LSD might induce effects like synaesthesia e. As described above, several findings suggest that LSD profoundly alters functional connectivity within the thalamocortical system.
Our research specifically focused on this area and we will briefly summarise some theoretical aspects of these findings. It has been proposed that the thalamus is an important site of action for hallucinogenic drugs [ 4 ]. An important model proposed by Vollenweider and Geyer [ 33 ] suggested that hallucinogenic drugs work by disrupting thalamic gating of external and internal als, leading to an increased information passage across the cortex.
The thalamus shows widespread connections to other brain regions [ 3435 ] and is an important brain hub [ 36 ]. Together, cortex and thalamus form a complex system of extensive and reciprocal connections. These thalamocortical pathways are thought to serve integration and transfer of information between cortical regions, possibly via synchronisation [ 37 ]. The concept that hallucinogens might act by affecting functioning of the thalamocortical system seems plausible, as the proposed neuronal model directly reflects core aspects of the subjective drug experience.
Phenomenologically, the alterations induced by hallucinogenic drugs have often been described as a state of increased awareness, that is, conscious perception of aspects of the internal and external world that are normally Side effects lsd.
For example, after his self-experiment with mescaline a hallucinogen very similar to LSDAldous Huxley speculated that this substance induces its effects by impairing these filter mechanisms [ 39 ].
A similar concept was formulated by the psychiatrist Stanislav Grof during his clinical studies with LSD in the s. According to Grof, LSD acts as a nonspecific amplifier of brain function [ 40 ]. Ultimately, the neuronal basis of these empirical observations might be found in increased connectivity within the thalamocortical system, which facilitates increased conscious awareness of information flow.
It is intuitively appealing that the altered state of consciousness induced by LSD might be caused by widespread increases in functional connectivity. However, so far it has not been possible to reliably link these alterations to subjectively experienced drug effects.Side effects lsd
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