The psychedelic effects of d-Lysergic Acid Diethyl Essay Example

neurotransmitter receptors responsible for its effects. Philosophy, cognitive sciences, neuroscience, and physics all contribute to understanding hallucinogens. Physicists and cognitive scientists both strive for a unified comprehension of their respective fields. Physicists aim to create a "Grand Unified Theory" encompassing subatomic particles and planetary movement, while cognitive scientists analyze the brain at different levels of abstraction. Neurobiologists study brain function through neurons, psychologists seek behavioral laws and cognitive mechanisms, with both aiming to understand complex behaviors solely via neural mechanisms. However, there are arguments that theoretical unification may not be achievable in cognitive sciences due to consciousness having metaphysical attributes beyond neural firing patterns. Although full comprehension of consciousness is unattainable in cognitive sciences, many aspects of cognition can still be explained.Progress has been made in understanding the relationship between neuronal and psychological mechanisms. Specific brain regions have been associated with cognitive functions, and the impact of neurotransmitters on these systems has been explored. For example, disrupting hippocampal activity affects memory consolidation. Disorders like Parkinson's disease are linked to issues in dopaminergic pathways. Serotonin is involved in various CNS disorders and also affects cardiovascular and thermoregulatory systems, as well as learning and memory. Due to the lack of understanding between neurobiology and psychology, a general description of hallucinogens' mechanisms is necessary. In this section, we will explore the potential mechanisms of LSD in a simplified manner. Further sections will provide more detailed studies on neuronal mechanisms. Researchers have used three approaches to uncovering LSD's mechanism: comparing its effects with known interactions of neurotransmitters, determining its chemical interaction with neurotransmitters and receptors, and identifying brain regions responsible for specific effects mentioned in Table 1. Initial research

shows that LSD is structurally similar to serotonin (5-HT).As previously discussed, the effects of LSD are believed to be mediated through serotonin pathways, as 5-HT regulates systems affected by LSD. Additional research has revealed that LSD also interacts with receptors for histamine, ACh, dopamine, epinephrine, and norepinephrine. The brainstem's Raphe Nuclei consists of a small number of serotonergic neurons that release 5-HT. Despite their limited numbers, these neurons have widespread innervation throughout the brain, suggesting that the brainstem may be involved in hallucinogenic mechanisms. Two specific areas in the brainstem associated with LSD's pathway are the Locus Coeruleus (LC) and Raphe Nuclei. The LC contains norepinephrine-containing neurons which send signals to various brain regions such as the cerebellum, thalamus, hypothalamus, cerebral cortex, and hippocampus. Stimulation of these neurons produces different effects depending on the type of post-synaptic cell. For example, stimulating norepinephrine increases activity in hippocampal pyramidal cells. As part of the ascending reticular activating system, the LC plays a role in regulating attention, arousal, and sleep-wake cycles. When rats' LC is electrically stimulated it leads to hyper-responsive reactions to stimuli from various senses. While LSD enhances reactivity of the LC to sensory stimulation without increasing sensitivity to acetylcholine or glutamate or substance P; applying LSD specifically to the LC does not result in spontaneous neural firing.
LSD's effects are believed to be influenced indirectly by its impact on the locus coeruleus (LC), which primarily mediates norepinephrine activity in the brain. However, most serotonergic neurons are located in the Raphe Nuclei (RN), which is centrally positioned within the midbrain to medulla region of the brainstem. The RN not only innervates significant parts of the brain like

the LC but also plays a role in pain regulation as it connects to the spinal cord.

The RN belongs to the ascending reticular activating system and inhibits information flow within this system. Therefore, disruptions in 5-HT (serotonin) activity would result in disinhibition and increased stimulation of various sensory modalities. It is currently believed that LSD's mechanism of action involves regulating 5-HT activity specifically in the RN.

However, other types of neurons such as GABAergic, catecholaminergic, and histaminergic neurons also have an influence on the RN. LSD has affinities for receptors associated with these neurons as well, suggesting that some effects may occur through alternative pathways.

Nevertheless, current research primarily focuses on understanding how LSD impacts 5-HT activity. Before delving into specific mechanisms and theories related to this, it is important to briefly understand synaptic transmission which involves two types of connections between neurons: chemical and electrical synapses.This paper examines chemical synapses, where neurotransmitter-filled vesicles are released into the synapse via exocytosis during the transmission of an action potential in a pre-synaptic cell. These neurotransmitters then interact with receptors on the post-synaptic cell. Synaptic activity can be terminated through reuptake, metabolism, or diffusion. A pre-synaptic neuron can impact a post-synaptic neuron directly or indirectly. In the direct pathway, the post-synaptic receptor functions as an ion channel that undergoes modification when a neurotransmitter binds to it. By altering ion permeability and inducing depolarization or hyperpolarization in the post-synaptic cell, neurotransmitters can have excitatory or inhibitory effects. Some neurotransmitters like epinephrine, norepinephrine, and 5-HT act indirectly by involving G proteins in secondary messenger systems. These indirect mechanisms do not affect resting potential but instead modify overall neuron behavior. For example,

norepinephrine can inhibit slow Ca-activated K channels in rat hippocampal pyramidal cells that typically open due to calcium influx. This inhibition prevents a prolonged after hyperpolarization that would normally extend the neuron's refractory period. Consequently, there is increased firing of action potentials for a given excitatory input. Other forms of neuromodulation involve interfering with neurotransmitter synthesis, storage, release or reuptake at pre-synaptic sites.
Inhibiting the reuptake of neurotransmitters can lead to an excitatory response. The effects of stimulating neurotransmitter receptors differ between pre- and post-synaptic cells. Pre-synaptic receptors regulate themselves, while post-synaptic receptors can either increase (excitation) or decrease (inhibition) the firing of action potentials in neurons. Neuromodulation can also occur through molecules that affect these neuroreceptors. Molecules that excite a receptor are called agonists, whereas those that interfere with receptor binding are known as antagonists. For example, 5-HT acts as an inhibitory neurotransmitter and blocking its post-synaptic receptors using a 5-HT antagonist would reduce responsiveness to inhibitions. This lack of inhibition would result in increased sensitivity in the post-synaptic cell towards neural inputs and potentially cause an excitatory response.

The theory proposes that LSD has a pre-synaptic inhibitory effect on 5-HT neurons in the Raphe Nuclei. These autoreactive neurons exhibit spontaneous firing independent of external action potentials, which was observed through experiments isolating the firing pattern from the forebrain or by blocking synaptic transmission via Ca++ ion removal. However, neuromodulation by various transmitters can influence this firing pattern. In 1968, Aghajanian and colleagues discovered that when LSD is administered systemically, it inhibits the spontaneous firing of serotonergic neurons in the Raphe Nuclei.These serotonergic neurons possess autoreceptors that are sensitive to neurotransmitters released by the cell, creating

a feedback pathway. This implies that an increase in 5-HT levels leads to a reduction in activity within these specific serotonergic neurons. Furthermore, synaptic connections exist between these particular serotonergic neurons and other Raphe Nuclei neurons. The theory proposes that LSD may deplete 5-HT by negatively impacting pre-synaptic autoreceptors, possibly extending the effects of negative feedback to other Raphe Nuclei neurons. Initially, it was believed that this depletion of 5-HT is responsible for observed effects on various systems innervated by serotonergic neurons. However, subsequent observations have raised doubts about this theory as even low doses of LSD affect behavior without suppressing firing in the Raphe Nuclei. Additionally, the behavioral effects of LSD persist even after changes in firing patterns have ceased. Repeated administration of LSD reduces behavioral modifications but does not influence Raphe Nuclei activity. Unlike R Neurons, other hallucinogens like mescaline and DOM do not impact them. Surprisingly, a depletion of 5-HT actually enhances the activity of LSD instead of eliminating its effectiveness. However, Mianserin - a receptor antagonist for 5-HT2 - blocks LSD behavior while leaving its depression on Raphe Nuclei neurons unaffected. The decrease in autoreactive firing caused by LSD in RN neurons appears to be an effect rather than a cause, supporting previous post-synaptic models and theoriesFurther research has uncovered that substances like LSD have a strong affinity for post-synaptic 5-HT1 and 5-HT2 receptors. The potency of hallucinogens in humans is closely linked to their affinity for these receptors. While it is reasonable to assume that regulation of 5-HT activity occurs at these receptor sites, there is a possibility that LSD may indirectly influence 5-HT receptor activity through adrenergic or dopaminergic

pathways. Blocking these receptors does not impact LSD's activity on the 5-HT receptors, suggesting that modification of 5-HT activity happens via these receptors. There is still ongoing debate about whether LSD acts as an agonist or antagonist on the 5-HT2 receptors. Initially believed to be an agonist, Pierce and Peroutka challenged this idea and questioned the evidence supporting agonistic behavior, noting inconsistent inhibition of LSD's effects by 5-HT2 antagonists. Certain 5-HT2 antagonists, such as spiperone, do not block LSD's behavior. Radioligand binding studies indicate that the pH dependence in affinity exists for 5-HT2 receptor agonists while both 5HT-2 receptor antagonists and LSD remain pH independent. These receptors are connected to a phosphatidylinositol (PI) second messenger system with stimulation observed with serotonin and its antagonism seen with specific serotonergic receptor blockers. It has been discovered that nM concentrations of LSD do not stimulate PI turnover indicating it does not act as a classic agonistFurthermore, the text states that nM concentrations of LSD have an inhibitory effect on the stimulatory action of 10M 5-HT, indicating its role as a 5-HT2 antagonist. Additionally, P discovered that the excitatory impacts of 5-HT on CNS neurons involve a reduction in K+ conductance caused by activation of 5-HT2 receptors. In rat somatosensory pyramidal neurons, LSD impedes this effect, further supporting its function as an antagonist. Moreover, P's research on smooth muscle revealed that the contraction of guinea pig trachea in the presence of M concentrations of -HT is inhibited by -HT antagonists with affinity for the -HT binding site. This suggests that muscle contraction is mediated by -HT receptors. Notably, at nM concentrations, LSD does not induce muscle contraction or impede

the agonistic effects of M concentrations of 5-HT; hence it acts as an antagonist. The theory proposes that LSD partially functions as a 5-HT2 agonist to reconcile conflicting evidence regarding its classification. Dr.Glennon supports this theory based on his study and previous research discussed by P&P. To investigate interactions between LSD and 5-HT, rats were subjected to drug discrimination training using DOM instead of LSD due to concerns about its various pharmacological effects. Through this training, Glennon demonstrated that several 5-HT2 antagonists impeded rats' ability to differentiate between LSD and saline.
Glennon did not explain why certain antagonists like spiperone do not have the same effect as LSD acting as a 5-HT2 agonist. Spiperone and similar antagonists inhibit 40% of 5-HT2 sites due to their lack of selectivity. Previous research has shown that 5-HT stimulates PI turnover and is inhibited by 5-HT2 antagonists. Another study on LSD's impact on PI turnover found that it acted as a partial agonist, producing about 25% of the effect caused by 5-HT. This study tested LSD effects at different doses, unlike P&P's observation. The findings indicate that LSD has a higher affinity for 5-HT receptors compared to 5-HT but lower efficacy. These results align with the observation that low concentrations of LSD inhibit the stimulatory effects of higher concentrations of 5-HT. If LSD acts as a low efficacy partial agonist, it can compete with 5-HT in binding to 5-HT2 receptors, resulting in antagonistic effects. Glennon argued against using guinea pig trachea as an example because in this case, 5-HT does not work through a PI mechanism. However, in the rat aorta, where ketanserin counteracts the contractile effects caused by 5-HT

and DOB, indicating that LSD acts as an agonist.
However, there are cases where the effects of LSD may be antagonistic due to its low efficacy for the receptor. Both hyperthermia and platelet aggregation are influenced by mechanisms related to 5-HT2. Hallucinogens like LSD act as agonists but can be countered by 5-HT2 antagonists such as ketanserin, especially in terms of platelets' behavior. Additionally, LSD exhibits a biphasic response, with low doses having opposite effects compared to higher doses. It is believed that the head twitch response in rodents is mediated through actions on 5HT2 receptors. At low doses, LSD induces a head-twitch response, while at higher doses it inhibits the response. The rat startle reflex is enhanced with low doses of LSD but reduced with higher doses. This behavior can be explained by the theory that LSD acts as a partial agonist, meaning it has high affinity and low efficacy as a nonselective 5-HT agonist. In the absence of another agonist, LSD may act as an agonist itself; however, in the presence of a high efficacy agonist, it functions as an antagonist. Glennon proposes an explanation for LSD's antagonistic activity: 5-HT1 receptors have been found to have an antagonistic relationship with 5-HT2 receptors responsible for mediating head twitch behavior.
DOI, an agonist of the 5-HT2 receptor, induces head twitching. On the other hand, 5-OMe DMT also acts as a 5-HT agonist but with lower efficacy compared to DOI. When subjects are pre-treated with 5-OMe DMT, the effects of DOI are diminished because many receptors are already occupied by the lower efficacy molecules of 5-OMe DMT. Additionally, studies show that pre-treatment with another receptor called 8-OH DPAT

can attenuate the effects of DOI. These receptors can functionally act as antagonists for hallucinogen-associated receptors such as those known to be 5-HT1c agonists. The credibility of this theory is supported by previous studies showing similar relationships between 5-HT2 and 5-HT1c receptors and hallucinogens. The potency of hallucinogens in humans correlates with their affinity for both 5-HT1c and 5-HT2 sites. It is possible that higher doses of LSD may lead to increased antagonism of the 5-HT2 receptor by activating the 5HT1 receptors, which could explain its biphasic behavior. Despite debate surrounding the presence of pre-synaptic serotonin autoreceptors (specifically belonging to the 5-HT1 type), this theory is discredited. There are also post-synaptic 5HT-1 receptors whose role in regulating norepinephrine remains unclear; however, they may be involved due to their widespread innervation in the LC where most norepinephrine neurons are located.
In recent studies, the belief that activation of 5-HT1 leads to antagonism at the 5-HT2 receptors has been challenged. As a result, the "5-HT1c" receptor has been reclassified as 5-HT2c, leading to the reclassification of the discussed "5-HT2" receptors as 5-HT2a since they belong to the same family. This is why LSD exhibits similar affinities for both "5-HT1c" and "5-Ht2" receptors. Although there have been reclassifications that do not discount one receptor antagonizing another, it is important to evaluate evidence supporting this theory based on recent findings.

The challenges in connecting psychology and neurobiology are evident when considering the mechanisms of LSD. As our knowledge expands regarding neurotransmitter interactions and brain regions, we can gain a better understanding of LSD. It's worth noting that LSD acts as a high affinity partial agonist for 5-HT receptors, meaning its effects

on post-synaptic 5-HT2 family receptors can be both agonistic and antagonistic depending on its concentration and other molecules present.

This modulation of 5-HT behavior likely contributes to the various effects associated with LSD. Additionally, LSD also has affinities for other neurotransmitter receptors such as norepinephrine, dopamine, and histamine. By modulating neural responses through its activity on 5-HT1 receptors, it may contribute to an overall impact.

Both the Locus Coeruleus (LC) and Raphe Nuclei are part of the ascending reticular activating system involved in sensory modalities.The influence of brain stem innervation on areas such as the cerebral cortex and hippocampus may explain the cognitive effects experienced with LSD. Various studies and publications have discussed the function and pharmacology of serotonin in the nervous system, including "From Neuron to Brain: A Cellular and Molecular Approach to the Function of the Nervous System" by Nicholls J, Martin R, Wallace B (1992), which provides a broad exploration of the topic. Another study titled "Mescaline and LSD Facilitate the Activation of Locus Coeruleus Neurons by Peripheral Stimulation" by Aghajanian GK (1980) investigates how hallucinogenic drugs affect locus coeruleus neurons. Jacobs, B (1985) provides an overview of brain serotonergic unit activity and its relevance to serotonin neuropharmacology. Additionally, Jacobs, B, Trulson M, Heym J (1981) conducted a study on freely moving cats to investigate dissociations between hallucinogenic drug effects on behavior and raphe unit activity. Pierce P, Peroutka S (1990) examine d-LSD's antagonist properties at 5-Hydroxytryptamine2 receptors while Moret C (1985) explores the pharmacology of serotonin autoreceptors.The text discusses research conducted by Glennon R (1990), which investigates whether classical hallucinogens function as 5-HT2 agonists or antagonists. The impact of drugs on serotonin-mediated

behavioral models is explored by Green R and Heal D (1985). Another study by Leysen J (1985) examines the characteristics of serotonin receptor binding sites. These findings are referenced from various sources including a newsgroup post titled "FAQ-LSD" (1995) in alt.drugs.psychedelics, Sankar's book "LSD: A Total Study" (1975), Ashton H's book "Brain Systems Disorders and Psychotropic Drugs" (1987), and Snyder's book "Drugs and the Brain" published by Sci Am Books Inc.