LSD as a therapeutic treatment – Alcohol and Drug Foundation
As the counter-culture drug of choice, the now infamous experimental use of LSD during the 1960s led to a moral panic about its effects on individuals and on society as a whole. Today, media outlets continue to report LSD as a drug that makes people dangerous, psychotic, and in some cases homicidal, further entrenching public fears about it.
In this, the second in our series looking at potential new uses for some of society's most controversial drugs, we take another look at LSD.
Studies reporting the possibility of using LSD as a therapeutic treatment for various mental health conditions were published from the 1950s. But following the USA’s criminalisation of LSD in 1966, clinical research was abandoned and its potential forgotten for decades.1
Now, emerging research is beginning to change the perception of LSD from a drug that can negatively affect mental health and wellbeing, to one that can alleviate the symptoms of anxiety and depression. Its benefits are also being studied in relation to helping individuals who are trying to overcome drug dependency.2
LSD (Lysergic acid diethylamide) is a part of a group of drugs known as psychedelics. It is also considered to be an empathogen, that is a drug that enhances feelings of empathy and connectedness.3 It is a synthetic chemical derived from a fungus that commonly infects rye.4
LSD is also described as a ‘psychedelic’ (or mind-manifesting) drug because of the changes experienced to perception, mood and thought. When taken in high doses it reportedly distorts experiences of time and space in addition to producing visual hallucinations. 5
The recreational use of LSD may result in an individual having an extremely negative experience, or ‘bad trip’. These can be very frightening.
But research in to the administration of LSD in a safe, therapeutic setting, involving a controlled dose, is being found to positively change people’s perspective and alleviate fears and anxieties.
LSD as a treatment
Recent findings indicate that psychedelic drugs can affect the function and structure of the brain and promote neuron growth.6 Exactly how LSD affects the brain is complicated, but it seems to interact with multiple receptors, such as serotonin and dopamine.7
Research is exploring the potential of LSD to encourage new ways of thinking and ‘reset’ the brain’s habitual patterns of thought.
The resurgent interest in LSD is building on studies conducted 40 years ago: primarily focusing on treating depression, post-traumatic stress disorder, drug dependency, and reducing anxiety in patients with a life-threatening disease.8 The role of LSD in improving mental health seems to be linked to a weakening or ‘dissolution’ of the ego, helping individuals see the ‘bigger picture’ beyond their personal problems.9
For therapeutic treatment LSD is administered under supervision in a safe environment, such as a psychologist’s office.
The psychologist or medical professional provides guidance and reassurance as the patient experiences the effects of the drug, and hopefully addresses the issue that brought them to seek treatment. Although the patient’s consciousness is dramatically altered, they maintain a clear recollection of their experience. 10
While LSD is not considered to pose a risk for dependency, and there haven’t been any deaths recorded from an overdose, some people do experience anxiety and confusion and there have been rare cases of self-harm outside of a therapeutic context.
11 There are many reports also indicating that individuals can have powerfully confronting experiences under the influence of the drug, which is why administering it in a controlled environment where the participant is informed, supported and monitored, is important.12
While we are seeing positive progress in LSD-assisted therapy, the research into its potential therapeutic benefits has a long way to go before we can really understand its impact on the brain.
A 2016 study London demonstrated that LSD has the potential to change entrenched patterns of thought – and again flagged its potential as a treatment for depression and anxiety.13 In this study, a single dose of LSD was administered to individuals who did not have a history of mental illness, and found it enhanced their feelings of openness, optimism, and mood for around two weeks.14
Research on LSD as a therapeutic treatment for alcohol dependency has demonstrated similar results – with individuals experiencing improved levels of optimism and positivity, as well as an increased capacity to face their problems.15
One of the more promising trials has picked up from much earlier research on the administration of LSD to patients facing a life-threating disease, where it helped to reduce anxiety associated with the anticipation of death.16 Here, patients also demonstrated an improved sense of self-assurance, relaxation, and mental strength, with the results lasting around 12 months.17
In contrast with existing therapies for depression and some other mental health conditions, which may take years to create change, the results of LSD-assisted therapy seem to manifest quite quickly.
One question that remains however is how often the therapy must be re-visited to maintain an individual’s progress.18 So too, the viability of it as a treatment for people living with a number of other mental health conditions also remains unknown.
As research continues to answer these questions, and explore the full impact and medical potential of this drug, what is clear is that LSD offers a fascinating glimpse into the functioning of the human mind, and that we need to look beyond the often sensationalist headlines when making an assessment of any drug.
Acute effects of lysergic acid diethylamide (LSD) on resting brain function
Müller Felix, Borgwardt Stefan
University of Basel, Department of Psychiatry (UPK), Basel, Switzerland
Lysergic acid diethylamide (LSD) is a potent hallucinogenic substance that was extensively investigated by psychiatrists during the 1950s and 1960s. 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, previous results 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.
Keywords: lysergic acid diethylamide (LSD), fMRI, brain connectivity
Lysergic acid diethylamide (LSD) is a very potent hallucinogenic substance. Even small doses such as 100 µg can trigger profound changes in various mental domains.
Among others, common effects are visual alterations, emotional and cognitive alterations, synaesthesia, derealisation and dissolution of the ego boundaries , all of which depend on LSD’s agonism at the serotonin2A-receptor .
After the discovery of LSD by the Swiss chemist Albert Hoffmann in 1943, the drug was commercialised by the Basel-based pharmaceutical company Sandoz for the use in psychiatry .
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 drug 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 .
During the 1950s and 1960s, more than 1000 reports on LSD were published, thousands of patients with various mental disorders were treated with LSD and results were often regarded as encouraging . However, research stopped when LSD was prohibited in the 1970s.
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 number of researchers [1, 5, 6].
In 2015, a first study by the Swiss psychiatrist Peter Gasser investigated clinical effects of LSD as an anxiety treatment for patients with life-threatening diseases . 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 , Zurich  and by our research group in Basel [8, 9].
In the present paper we will summarise the results 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 on 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.g. [8–11]).
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. The studies discussed in this review used moderate orally administered doses of 100 µg LSD [2, 8, 9] and 75 µg LSD intravenously . In humans these moderate doses are expected to induce all typical effects associated with this drug . 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.
fullscreenFigure 1 Key concepts of this article. Figures reproduced from Tahedi et al., 2018  and Collin et al. 2011 .
Characteristic of the studies included in this review.
|Carhart-Harris et al., 2016 ||London||15 (healthy)||75 µg LSD intravenously||Healthy, not hallucinogen-naïve||Yes||Within- and between-network functional connectivity|
|Tagliazucchi et al., 2016 ||Global functional connectivity|
|Müller et al., 2018 ||Basel||20 (healthy)||100 µg orally||Healthy, mostly hallucinogen-naïve||Yes||Within- and between-network functional connectivity|
|Müller et al., 2017 [8, 9]||Global functional connectivity|
|Preller et al., 2018 ||Zurich||24 (healthy)||100 µg orally||Healthy, mostly hallucinogen-naïve||Yes||Global functional connectivity|
The first published fMRI study on LSD focused on changes in functional connectivity within and between resting state networks . 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 . Carhart-Harris et al. investigated activity within several networks (connectivity between brain regions belonging to the same network) as well as connectivity between them .
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.
This finding was interpreted as altered “integration and segregation”, that is, that LSD induces a state in which compartmentalisation between networks is blurred while the integrity of the individual networks is “breaking down”. It was concluded, that these brain states show typical drug effects induced by LSD.
In line with this, the authors reported a significant correlation between decreased connectivity within the default mode network and a subjective drug effect “ego dissolution” (a state of temporary loss of the sense of a self) .
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.
LSD-induced alterations in functional connectivity within resting state networks compared between studies.
|Visual network 1||↓||↓|
|Visual network 2||↓||→|
|Visual network 3||↓||↓|
|Parietal cortex network||↓||Not investigated|
|Right frontopariatel network||↓||Not investigated|
|Default mode network||↓||↓|
fullscreenFigure 2 Significant increases in between-network functional connectivity after administration of LSD and psilocybin compared with placebo. Findings from Roseman et al., 2014  are shown in green, findings from Carhart-Harris et al., 2016  are shown in blue, Findings from Müller et al., 2018  are shown in red. Black indicates networks which were not investigated by Carhart-Harris et al. Figure reprinted from: Müller F, Dolder PC, Schmidt A et al. Altered network hub connectivity after acute LSD administration. NeuroImage Clin. 2018;18:694-701 , with permission from Elsevier.
Our team attempted to replicate these findings in a consecutive study . We could confirm the findings regarding connectivity within networks and we also observed increased connectivity between networks (please see table 2, figs 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 .
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.
Moreover, we were not able to confirm associations between the observed neuronal alterations and the phenomenon of “ego dissolution” that were reported by the initial study and we did nor find any other associations .
fullscreenFigure 3 Decreased functional connectivity (shown in green-blue) within several resting state networks (shown in yellow) after LSD administration. Images are thresholded at p