This paper is an excerpt from my 2019 undergraduate research. This paper reviews and critiques the scientific methods used to examine the effects of LSD on the brain.
LSD, Lysergic acid diethylamide is a serotonergic hallucinogen and psychedelic drug. It is famously known for inducing visual hallucinations commonly known as “tripping” (Rapport, 1949). LSD works by affecting multiple neurotransmitters and brain receptors such as dopamine, adrenergic and glutamate receptors yet most commonly the serotonin receptor 5-HT2A (Rapport, 1949). This receptor’s function concentrates on the regulation and creation of the feeling of well-being and happiness and is involved in “modulating cognition, reward, learning, memory, and numerous physiological processes” (Rapport, 1949). It is also important to the function of blood clotting (Ludwig and Schmidt, 1868). Studies have shown it has the ability to alter consciousness by increasing the speed of neural connectivity within the brain as well as reducing the filters present in the Default-Mode Network (DMN) (Nutt et al, 2016). The chemical composition of LSD mimics almost exactly the composition of the serotonin receptor 5-HT2A (Nutt et al, 2016) enhancing the power of the serotonin by basically acting as more receptors, which increases the levels of serotonin in the brain, which is why people using the drug report extreme emotional experiences and feelings of a meditative state.
For this paper, I will be looking at two studies specifically; “Neural correlates of the LSD experience revealed by multimodal neuroimaging” (Nutt et al, 2016) and “Animal Models of Serotonergic Psychedelics” (Hanks & Gonzalez-Maeso, 2013). Both studies were focused on studying the effects of LSD on the brain; both anatomically, functionally and behaviorally.
The first study, “Neural correlates of the LSD experience revealed by multimodal neuroimaging” (Nutt et al, 2016), used a three-fold experimental technique using; arterial spin labelling, resting state MRI and magnetoencephalography (MEG). These techniques were used in order to acquire more accurate conclusions as previous studies had only collected data via electroencephalography (EEG). The data, therefore, was more conclusive as it measured “blood flow, functional connections within and between brain networks, and brainwaves in the volunteers on and off the drug” (Nutt et al, 2016). Twenty ‘mentally-healthy’ people participated in a two-day experiment, where on the first day they were given 75 micrograms of LSD, and on the following day, a placebo. They were measured during “eye-closed, task-free, “resting state” conditions.” (Nutt et al, 2016).
The resulting data found an increase in overall neural connectivity illustrated by increased blood flow and electrical activity across neural networks when using LSD. Under LSD, new networks emerged that were not previously communicating under the placebo. The MRI and MEG visually illustrate these increased connections showing “brains on LSD ablaze with activity and connection compared to brains without it” (Love, 2018). These pathways predominantly enhanced the visual networks resulting in participants experiencing enhance visualisations in the form of hallucinations even within the “eyes-closed resting state” (Nutt et al, 2016). However, under LSD some previous connections were broken such as within the parahippocampus and the retrosplenial cortex (RSC), which functions in visuospatial processing and episodic memory processing, suggesting a reason for the loss of memory and spatial awareness experienced by some participants (Nutt et al, 2016).
Figure 2: Scans showing images of the participants’ brains under LSD compared to the placebo. [3]
Another important network that lost connectivity was the DMN. The disintegration of the DMN resulted in a loss of sense of self or ‘ego-depletion’ (Nutt et al, 2016). The results of the study suggests that the DMN can act as a filter on communication among brain networks so this dissolution is what increased the overall network connectivity and speed, yet this dissolution also dissolves our able to filter out what is reality and what is not, which when coupled with the hallucinations, can sometimes result in increased anxiety when using LSD (Nutt et al, 2016). The results also suggest “the magnitude of this effect is directly correlated to the strength of the subjective experience of ‘ego-dissolution’ and feeling of oneness and unity” (Nutt et al, 2016) and that the decreased connectivity between the DMN, the parahippocampus and RSC strengthens the theory of this network’s involvement in the processing of reality and the sense of self (Nutt et al, 2016).
The second study, “Animal Models of Serotonergic Psychedelics” (Hanks & Gonzalez-Maeso, 2013), was a behavioural rodent-study analysing predictive analogous behaviour in humans. The study illustrated that LSD “produces abnormal behavior” (Hanks & Gonzalez-Maeso, 2013) in mice such as tremors and “rapid and violent” head-twitching (Hanks & Gonzalez-Maeso, 2013) induced by increased levels of the serotonin precursor 5-hydroxytryptophan (5-HTP) (Hanks & Gonzalez-Maeso, 2013). This particular dosage of 5-HTP has not been replicated on humans so it is unknown if the “head twitching” behavioural effect is transferable to humans yet the study claims to be “predictive of psychedelic potential in humans with a high degree of reliability” (Hanks & Gonzalez-Maeso, 2013). Additionally, the study also conducted a reinforcement experiment to measure behaviour. In the experiment, the rats were trained to receive a food reward after pressing a lever 40 times (Hanks & Gonzalez-Maeso, 2013). The results found that rats on psychedelics had increased pauses between presses on the lever, which was not found on the other rats in the control group. This, again, has not been tested on humans, so is unknown whether this finding is transferable (Hanks & Gonzalez-Maeso, 2013). Overall, this method of using animal models can provide insight, such as the resulting information that “the serotonin 5-HT2A receptor is the primary target responsible for psychedelic effects” (Hanks & Gonzalez-Maeso, 2013) yet as explained above is not the most applicable to humans. Therefore, it can be concluded that this model individually is less effective than the previous MEG method.
The first study was more effective at providing insight into how LSD affects the brain as it used a three-fold model of complementary neuroimaging techniques (Nutt et al, 2016). They found that there was increased blood flow in the visual cortex, which led to the increased functional connectivity between the visual cortex and other areas of the brain (Nutt et al, 2016). This coupled with the deactivation in the DMN illustrates the visual hallucinations that people on LSD describe (Nutt et al, 2016) due to the decrease in executive power reducing the ability to distinguish reality from fiction. The strong correlational relationship that was found between these different measures with a high significance (Nutt et al, 2016) means that the resulting conclusions were better backed and valid. This made the data is more reliable, enabling stronger evidential inferences to be made. The use of MEG scans also shows the brain activating and ‘lighting up’ across many cortices which emphasises how many connections are increased with the use of LSD. Comparing the placebo and MEG brain scans the conclusions is made visually apparent, which is very helpful for those wanting to understand the research findings. MEG was an appropriate method to use here as MEG measures electromagnetic activity in the brain (the connections that were found were found via measuring the electromagnetic activity). It is also a non-invasive method which is safer for those who are experiencing hallucinations.
The second study was used for more invasive study and to analyse behavioural responses to LSD. The serotonergic processes such as emotional responses and hallucinations seem to be uniquely human processes which question the need for animal models for LSD, a serotonergic hallucinogen and psychedelic drug (Geyer, 1998). Additionally, the behavioural effects needing to be studied and investigated, such as ego dissolution, loss of reality perception, hallucinations, and happiness levels, cannot be measured as they require verbal description which cannot be given by humans (Geyer, 1998). As much as the results are difficult to generalise about humans from, they do provide insight into the effects of using psychedelics and is much more ethically acceptable to use ie. if a rodent dies from using LSD this is much more ethically acceptable than if a human does. However, the question of the extent of animal rights and whether they should be protected still persists. Rodent studies were also involved in the discovery that LSD acted not as a serotonin antagonist, tranquillising and inhibiting serotonin in the brain, but instead, as a serotonin activator, strengthen the levels of serotonin in the brain by mimicking the chemical structure of the serotonin receptor 5-HT2A (Geyer, 1998) as discussed above, a discovery which can lead to reducing the effects of psychosis (Geyer, 1998), ending the suffering of some humans, which is an argument to use animal models despite the animal rights violations. Without using these rodent studies, this discovery would never have been made as the method is too invasive to use on humans.
To conclude, combining the above study with the animal model study could be beneficial as it highlights both the neurological and behavioural study, however, it would be arguably more substantial to do a behavioural study on humans to see direct effects rather than having to make surface-level analogies comparing a rodent’s brain to a human’s brain which as explained above is difficult to compare. However, there are many ethical considerations to take into account, both in the use of animal models and in using humans for testing a drug which effects haven't been fully investigated. This is why animal models have been used in the past even if the comparison is considered weak. The use of fMRI arguably is another more dynamic method that could be used to measure the effects of LSD on the brain by measuring changes in cerebral blood flow, which is present and important in the visual cortex, to understand activation of different brain areas anatomically.
REFERENCES
Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy,
K., . . . Nutt, D. J. (2016). Neural correlates of the LSD experience revealed by multimodal
neuroimaging. Proceedings of the National Academy of Sciences,113(17), 4853-4858. doi:10.1073/pnas.1518377113
Gavin, M. (2014). What You Need to Know About Drugs: LSD. Retrieved March 16th, 2019, from
Geyer, M. (1998). Behavioral Studies of Hallucinogenic Drugs in Animals: Implications for
Schizophrenia Research [Abstract]. Pharmacopsychiatry,31(S 2), 73-79. doi:10.1055/s-2007-979350
Hanks, J. B., & González-Maeso, J. (2013). Animal Models of Serotonergic Psychedelics. ACS
Chemical Neuroscience,4(1), 33-42. doi:10.1021/cn300138m
Love, S. (2018, March 02). LSD Brings Your Brain to the Edge of Chaos. Retrieved March 18, 2019,
Rapport MM (1949). Serum vasoconstrictor (serotonin) the presence of creatinine in the complex; a proposed structure of the vasoconstrictor principle. J. Biol. Chem. 180:961-969.
The Beckley Foundation. (2017, May 19). The World's First Images of the Brain on LSD. Retrieved
March 18, 2019, from https://beckleyfoundation.org/event/lsd-revealed/
Footnotes
[2] Source: Gavin, M. (2014). What You Need to Know About Drugs: LSD. Retrieved May 28, 2015, from http://kidshealth.org/kid/grow/drugs_alcohol/know_drugs_lsd.html
[3] Source: Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., . . . Nutt, D. J. (2016). Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences,113(17), 4853-4858. doi:10.1073/pnas.1518377113
Appendix
Reflection:
I explained how LSD affects the brain on the chemical level; how LSD works by mimicking the chemical composition of the serotonin receptor 5-HT2A enhancing the power of the serotonin by basically acting as more receptors, which increases the levels of serotonin in the brain. I explained how LSD affects the brain on the anatomical and physiological levels; by examining and explaining how the electrical connectivity increases as blood flow increases which expands the network across the brain, making it work faster and develop new connections which didn’t previously exist, especially in connection with the visual cortex. I explained how by having more cerebral blood flow and electrical activity in the visual cortex, whilst having a deactivation of the DMN, which is responsible for the sense of self and executive control, lead to ego dissolution and visual hallucinations as the participant is unable to distinguish visual reality from fiction. I discussed how MEG was an appropriate method to use as electromagnetic activity is important to measure here, and how fMRI could have been used as the increase/decrease of blood flow is also important to understand the areas of the brain active/inactive on LSD. I explained this in the context of how this is produced by LSD and how LSD affects the brain, which was the main research question in this paper.
I critiqued both the MEG study and the animal models study, compared the strengths and weaknesses of both, then concluded which was more effective with regards to my aim of understanding more about how LSD affects the brain. I also suggested further methods that could have made the experimental design better such as the inclusion of fMRI and explained why in terms of the constraints of human rights, animal models may have to be used even if less effective.
I identified how LSD affects cognitive processes such as distinguishing reality from fiction, visual perception, the sense of self and executive control. I explained how biologically and chemically this happens, as explained above, focusing especially on the increased activity in the visual cortex and the decrease of activity in/inhibition of the DMN which results in the increase/decrease of these cognitive processes, as well as explaining how the increase in electrical activity produces increased connectivity which leads to faster cognitive processing through networks that were not previously established which is also why the brain activates almost completely shown in Figure 2 above.
Throughout this paper, I examined and evaluated the strengths and weaknesses of the use of animal models to study the effect on LSD on the brain and how the drug affects cognitive processes, such as executive control and the visual hallucinations produced. The strengths I outlined include; providing insight into the effects of using psychedelics, much more ethically acceptable to use, can use more invasive and dangerous methods and have been involved in the discovery of previous relevant serotonin discoveries. The weaknesses I outlined include; animal rights issue, studying cognitive processes unique to humans on rodents, lack of transferable/representative findings, inability to produce verbal responses to describe cognitive processes such as ego dissolution, loss of reality perception, hallucinations, and happiness levels. I compared this to the strengths and weaknesses of the MEG study and concluded that the MEG was significantly stronger due to the use of multiple complementary approaches for the given context of understanding the effect of LSD on the brain.
