LSD, due to its monoamine-like structure, primarily acts as an agonist of serotonin (5-HT) receptor proteins. More specifically, the psychedelic effects of LSD are attributed to it’s ability to activate the g-protein coupled (metabotropic) 5-HT-2A/2C receptors. Activation of these receptors results in the release of α, β, and δ g-protein subunits resulting from a conformational change in the receptor, which results in an exchange of GDP for GTP. Once activated, the g-proteins are able to activate adenylyl cyclase, resulting in the downstream phosphorylation of various proteins, and in some cases, the direct activation of ion channels for potassium (K+), sodium (Na+), and calcium (Ca2+).
Additionally, LSD acts as an agonist at a slew of other 5-HT receptors (5-HT-1A/1B/1D, 5-HT-2A/2C, 5-HT-5A, 5-HT-6 and 5-HT-7) as well as the D1 & D2 Dopamine (DA) receptors, and the α1 and α2-adrenergic receptors. This great variety of receptors may account for the variable nature of LSD’s activity, as many of these receptors exist in peripheral tissues, and when considered together, in nearly every region of the brain. Serotonin in particular is an immensely widespread neurotransmitter, participating in everything from the management of slow-pain mechanisms to vision, mood, appetite, memory, cognition and more. Disruptions in serotonergic tone are the most likely cause of LSD’s ability to produce alterations in all of these areas of consciousness, awareness, and general mental function, though activity at some of the non-serotonergic receptors likely mediates this activity in one way or another.
In the pre-frontal cortex (PFC), 5-HT-2A receptors are primarily localized in deep layer IV and layer V dendritic spines of pyramidal cells and interneurons, areas which have been implicated in the management of attention and consciousness. Throughout the PFC, LSD results in the release of glutamate, the primary excitatory neurotransmitter of the brain, which leads to increased excitatory post-synaptic potentials. Again, the PFC is implicated in many cognitive functions- including but not limited to- decision-making, situational interpretation and perception, and cognitive awareness. Increased activity in the PFC likely accounts for many of the cognitive and perceptual effects of LSD. A marked presence of these receptors in the thalamus, a center for nearly all sensory integration in the mammalian brain, likely accounts for alterations in responses to sensory and peripheral stimuli.
Due to the variable nature of 5-HT receptors, and the ability of LSD to act at many of these receptors, the activity of LSD is greatly varied depending on the neurological substrates under consideration. For instance, the 5-HT-1A receptor is an autoreceptor (usually located on the soma of the neuron) which exists as a feedback mechanism designed to limit the amount of serotonin released by a given neuron. LSD acts as an agonist at these receptors, thus decreasing serotonergic activity. In areas where these receptors are in high density, LSD is likely to decrease the overall flow of serotonin. One such area is the dorsal raphe nuclei, which shows a serotonergic inhibitory response in the presence of LSD. Before the differentiation of 5-HT receptor subtypes, it was thought that LSD, though acting as an agonist, simply decreased serotonin activity. It has recently been shown however, that the 5-HT-1A receptor likely has little bearing on the psychedelic activity of LSD, since phenethylamine psychedelics with similar activity lack any affinity for the receptor.
Through the use of selective 5-HT antagonists, which block the activity of LSD, it was eventually determined that LSD exerts its primary effects through the post-synaptic receptors of the 5-HT-2 subtypes. Administration of ketanserin and pirenperone, both of which act as competitive antagonists at the 5-HT-2A receptor, prevented discrimination of LSD from saline in animal studies, providing significant evidence for the primary activity of LSD as occurring at this receptor. Studies with humans, using the subjective subscales of Dittrich’s ASC questionnaire, also showed a significant reduction in reported effects following 5-HT-2A/C antagonist pretreatment in volunteers receiving psilocybin, which acts in a nature similar to LSD. The use of competitive DA antagonists however only reduced ratings on a single subset of the questionnaire, suggesting that although DA is involved in psychedelic activity, it plays a minor role compared to serotonin. There has also been shown to be a distinct correlation between the potency of psychedelic compounds and their affinity for the 5-HT-2 receptor family, further supporting the receptors’ involvement in the activity of these psychedelic entities.
The locus ceruleus (LC), an area of the brain located in the pons, is considered a sensory novelty detector in the brain. With a high density of 5-HT receptors, this area is a primary target of LSD, and likely accounts for much of the visual activity of the drug. By activating GABAa inputs in the LC, LSD decreases spontaneous firing. However, by activating excitatory NMDA receptors in the LC, responses to sensory stimulation are increased. Interneuron firing in response to novel stimuli is markedly increased in the presence of LSD, leading to this increased activation and perception of sensory stimulation. This means that a lower threshold of activity exists under these conditions, resulting in detectable activity from stimuli that would normally be “filtered out,” or determined as insignificant.
*Dopaminergic activity has no effect on the visual illusions or hallucinations elicited by LSD, as shown by their continued presence following pretreatment with the D¬2 antagonist haloperidol (Haldol), which blunted or diminished several of the other effects of the drug, but had no effect on visual activity.*
In response to LSD administration, several cortical areas of the brain show increases in dopaminergic activation. Areas thought to be involved in reward detection or discrimination, such as the ventral tegmental area (VTA) and the nucleus accumbens, do not show dopaminergic activation as the result of LSD administration, accounting for the lack of addictive properties in the drug. The activation of 5-HT-2A receptors has been shown to have a modulatory effect at dopaminergic neurons, increasing release and thereby increasing extracellular levels of the neurotransmitter. Antagonist binding to DA receptors is decreased in the presence of LSD, suggesting that extracellular levels of DA are increased, resulting in the displacement of any non-competitive antagonist or agonist.
Additionally, LSD has a high affinity for the D1 and D2 DA receptors. The degree of affinity for these receptors suggests that they may be activated at the low doses at which LSD shows psychedelic activity. In support of a relationship that implies potentiation of LSD activity by DA stimulation, it has been found that rats pre-treated with D2 agonists show discrimination for LSD at significantly lower doses.
In subjective human studies of the effects of LSD, DA antagonists attenuated ratings on only a single subset of the psychedelic questionnaire, supporting the notion that DA plays a minor role in the general psychedelic activity of the drug.
See * under Visual for information on DA’s role in LSD’s visual activity.
SSRIs and 5-HTP
Anecdotal and clinical evidence has shown that SSRI administration results in blunted or diminished effects when applied prior to LSD. A probable explanation for this antagonism of LSD activity is the effect of serotonin at 5-HT-1A receptors as discussed earlier. 5-HT concentrations in the synaptic cleft are increased by SSRIs, which prevent the reuptake of 5-HT by antagonizing SERT, the serotonin reuptake transporter. This excess 5-HT may stimulate autoreceptors in the short-term, resulting in temporarily decreased serotonin release. Following this line of logic, pre-administration of 5-HTP, as is common amongst users of recreational hallucinogens, may similarly antagonize LSD activity by activating 5-HT-1A receptors. In the long-term, excess serotonin in the synaptic cleft results in the downregulation of 5-HT receptors at the postsynaptic neuron, accounting for the delayed antidepressant effects of SSRI administration. This downregulation of 5-HT receptors likely accounts for the blunted effects of LSD following long-term administration of SSRIs.
Serotonin's immensely widespread role as a neurotransmitter throughout the central and peripheral nervous system, and its concurent status as a target of change under the conditions of LSD, likely explains the drug's ability to elicit side effects (though, considering the variable nature of the psychedelic experience, side effects is subject to relatively subjective interpretation) ranging from anorexia and muscle cramps, to sweating and dilated pupils.
A few examples (to be expanded upon soon):
*Hyperthermia and hypophagia have also been shown to be mediated by the 5-HT-2A receptor, as their presence is abolished if the LSD-receiving party is pretreated with a selective 5-HT-2A receptor antagonist.
* LSD administration has been shown to increase levels of adreonocorticoptropic releasing hormone, a hormone primarily associated with high levels of stress, possibly accounting for some of the anxiogenic effects of the drug.
Interestingly, LSD has a similar affinity for the 5-HT-2A/C receptors as some of the other psychedelic compounds of the tryptamine and phenethylamine families, yet its potency is at least one order of magnitude greater than all of them. This observation suggests that the potency of LSD may not be entirely mediated by its actions at the 5-HT-2A receptor. One possible explanation for this is LSD’s affinity for the alpha-adrenergic receptor. Though it’s affinity for this receptor is modest, it has been shown that non-LSD induced stimulation of the receptor potentiates the activity of subsequently administered LSD, providing some evidence that LSD’s adrenergic activity may mediate its psychedelic activity, partially accounting for its potency outside of it’s 5-HT-2A affinity.
It is also possible that the potency of LSD is the responsibility of a yet undiscovered pathway at which LSD shows activity. An undiscovered or undetermined receptor or pathway may modulate the effects of LSD through any number of mechanisms, such as the enhancement of g-protein activity either directly or through the enhancement of adenylyl cyclase activity, or potentially via the phosphorylation of primary proteins. Considering the history of discovery and interpretation, this is not an unlikely hypothesis, and is certainly one that will be examined in future studies.
Though the neural mechanisms of synesthesia have yet to be conclusively determined, one possible theory involving the decreased inhibition of neural feedback mechanisms may explain the ability of LSD and other psychedelic drugs to increase the prevalence or occurrence of this phenomenon. Feedback mechanisms responsible for the regulation of fiber pathways connecting various areas of the brain are maintained by a delicate balance of excitation and inhibition by the neurotransmitters glutamate and GABA, both of which have been shown to be mediated by LSD. LSD’s ability to alter the frequency and intensity of excitation and inhibition signals may disturb the functions of such pathways. In such a model, late mechanisms for sensory integration may influence areas of sensory stimuli detection such as those in the LC mentioned earlier. Due however to the yet undefined nature of synesthesia, LSD’s role in inducing this phenomenon is one of the remaining mysteries of it’s activity.
Please suggest areas on which expansion would be useful and I will do my best to fill in the gaps.
Excellent! You totally outdid yourself. I've been waiting for something like this for ages and I'm sure it took a lot of work to turn all those pages into an outline like this!
So now we have the how; I'm currently working on the what: variations in the LSD experience. I've decided to break it up into 4 categories of dose: Threshold (50-120ug), Psychedelic (120ug-300ug), "Cosmic" (300ug-700ug), and Ineffable (700ug+). If anyone can think of better labels than "Cosmic" or "Ineffable" then please suggest. After dividing them into 4 categories of dose I then basically divide the experience into sub-groups: The Senses (Open/Closed eyes, hearing, etc.), Mental Experience, Bodily Sensations and Other. Each sub-group has positive/neutral/negative effects lists much like Erowid. Unlike Erowid, SWIM is going to try to write quite extensive reports concerning variations in the LSD experience that can be produced. The primary point will be to try to help forum users figure out if what their SWIM took could've been LSD, which should hopefully eliminate a great many recurring questions; I hope, however, that it will also serve as a general guide for novices or newbies to the experience as to what to expect from different dosages.
Since it's all subjective and the SWIM writing it is only available to tap the resources that have been made available to him, he's going to try to collect as many strange effects of trips that have gone unreported as is possible (mainly using the forum search engine and erowid).
Anyway, major props! Just wanted to give you the run-down on what i'm trying to do (suggestions would be welcome on this end as well)!