Lsd(A) Essay, Research Paper

Introduction -The psychedelic effects of d-Lysergic Acid Diethylamide-25 (LSD) were discovered by Dr. Albert Hoffman by accident in 1938. In the 1950s and 1960s, LSD was used by psychiatrists foranalytic psychotherapy. It was thought that the administration of LSD could aid the patient inreleasing repressed material. It was also suggested that psychiatrists themselves might developmore insight into the pathology of a diseased mind through self experimentation. 1,2 During the late60s, LSD became popular as a recreational drug. While it has been suggested that recreationaluse of the drug has dropped, a recent report on CNN claimed that 4.4% of 8th graders have triedit. LSD is considered to be one of, if not the, most potent hallucinogenic drug known. Small doses ofLSD (1/2 – 2 ug/kg body weight) result in a number of system wide effects that could be classifiedinto somatic, psychological, cognitive, and perceptual categories. These effects can last between 5and 14 hours. Table 1: Effects of LSD 1, 2, 3 Somatic Psychological Cognitive Perceptual mydriasis hallucinations disturbed thought processes increased stimulus from environment hyperglycemia depersonalization difficulty expressing thoughts changes in shape/color hyperthermia reliving of repressed memories impairment of reasoning synaesthesia (running together of sensory modalities) piloerection mood swings (related to set and setting) impairment of memory – esp. integration of short -> long term disturbed perception of time vomiting euphoria lachrymation megalomania hypotension schizophrenic-like state respiratory effects are stimulated at low doses and depressed at higher doses reduced “defenses”, subject to “power of suggestion” brachycardiaThe study of hallucinogens such as LSD is fundamental to the neurosciences. Science thrives onmystery and contradiction; indeed without these it stagnates. The pronounced effects thathallucinogens have throughout the nervous system have served as potent demonstrations ofdifficult to explain behavior. The attempts to unravel the mechanisms of hallucinogens are closelytied to basic research in the physiology of neuroreceptors, neurotransmitters, neural structures,and their relation to behavior. This paper will first examine the relationship between neural activityand behavior. It will then discuss some of the neural populations and neurotransmitters that arebelieved to by effected by LSD. The paper will conclude with a more detailed discussion ofpossible ways that LSD can effect the neurotransmitter receptors which are probably ultimatelyresponsible for its LSD. A Brief Foray Into Philosophy and the Cognitive SciencesModern physics is divided by two descriptions of the universe: the theory of relativity and quantummechanics. Many physicists have faith that at some point a “Grand Unified Theory” will bedeveloped which will provide a unified description of the universe from subatomic particles to themovement of the planets. Like in physics, the cognitive sciences can describe the brain at differentlevels of abstraction. For example, neurobiologists study brain function at the level of neuronswhile psychologists look for the laws describing behavior and cognitive mechanisms. Also like inphysics, many in these fields believe that it is possible that one day we will be able to understandcomplicated behaviors in terms of neuronal mechanisms. Others believe that this unification isn’tpossible even in theory because there is some metaphysical quality to consciousness thattranscends neural firing patterns. Even if consciousness can’t be described by a “Grand UnifiedTheory” of the cognitive sciences, it is apparent that many of our cognitive mechanisms andbehaviors can.While research on the level of neurons and psychological mechanisms is fairly well developed, thearea in between these is rather murky. Some progress has been made however. Cognitivescientists have been able to associate mechanisms with areas of the brain and have also been ableto describe the effects on these systems by various neurotransmitters. For example, disruption ofhippocampal activity has been found to result in a deficiency in consolidating short term to longterm memory. Cognitive disorders such as Parkinson’s disease can be traced to problems indopaminergic pathways. Serotonin has been implicated in the etiology of various CNS disordersincluding depression, obsessive-compulsive behavior, schizophrenia, and nausea. It is also knownto effect the cardiovascular and thermoregulatory systems as well as cognitive abilities such aslearning and memory.The lack of knowledge in the middle ground between neurobiology and psychology makes adescription of the mechanisms of hallucinogens necessarily coarse. The following section willexplore the possible mechanisms of LSD in a holistic yet coarse manner. Ensuing sections willconcentrate on the more developed studies of the mechanisms on a neuronal level. The SuspectsResearchers have attempted to identify the mechanism of LSD through three different approaches:comparing the effects of LSD with the behavioral interactions already identified withneuotransmitters, chemically determining which neurotransmitters and receptors LSD interactswith, and identifying regions of the brain that could be responsible for the wide variety of effectslisted in Table 1. Initial research found that LSD structurally resembled serotonin (5-HT). As described in theprevious section, 5-HT is implicated in the regulation of many systems known to be effected byLSD. This evidence indicates that many of the effects of LSD are through serotonin mediatedpathways. Subsequent research revealed that LSDnot only has affinities for 5-HT receptors but also forreceptors of histamine, ACh, dopamine, and thecatecholines: epinephrine and norepinephrine.3Only a relative handful of neurons (numbering in the1000s) are serotonergic (i.e. release 5-HT). Most ofthese neurons are clustered in the brainstem. Someparts of the brainstem have the interesting propertyof containing relatively few neurons that function asthe predominant provider of a particularneurotransmitter to most of the brain. For example,while there are only a few thousand serotonergiccells in the Raphe Nuclei, they make up the majorityof serotonergic cells in the brain. Their axonsinnervate almost all areas of the brain. The possibilityfor small neuron populations to have such systemiceffects makes the brain stem a likely site forhallucinogenic mechanisms.Two areas of the brainstem that are thought to beinvolved in LSD’s pathway are the Locus Coeruleus(LC) and the Raphe Nuclei. The LC is a small cluster of norepinephrine containing neurons in thepons beneath the 4th ventricle. The LC is responsible for the majority of norepinephrine neuronalinput in most brain regions.4 It has axons which extend to a number of sites including thecerebellum, thalamus, hypothalamus, cerebral cortex, and hippocampus.A single LC neuron can effect a large target area. Stimulation of LC neurons results in a number ofdifferent effects depending on the post-synaptic cell. For example, stimulation of hippocampalpyramidal cells with norepinephrine results in an increase in post-synaptic activity. The LC is partof the ascending reticular activating system which is known to be involved in the regulation ofattention, arousal, and the sleep-wake cycle. Electrical stimulation of the LC in rats results inhyper-responsive reactions to stimuli (visual, auditory, tactile, etc.)5 LSD has been found toenhance the reactivity of the LC to sensory stimulations. However, LSD was not found to enhancethe sensitivity of LC neurons to acteylcholine, glutamate, or substance P.6 Furthermore,application of LSD to the LC does not by itself cause spontaneous neural firing. While many of theeffects of LSD can be described by its effects on the LC, it is apparent that LSD’s effects on theLC are indirect.4While norepinephrine activity throughout the brain is mainly mediated by the LC, the majority ofserotonergic neurons are located in the Raphe Nuclei (RN). The RN is located in the middle ofthe brainstem from the midbrain to the medulla. It innervates the spinal cord where it is involved inthe regulation of pain. Like the LC, the RN innervates wide areas of the brain. Along with the LC,the RN is part of the ascending reticular activating system. 5-HT inhibits ascending traffic in thereticular system; perhaps protecting the brain from sensory overload. Post-synaptic 5-HTreceptors in the visual areas are also believed to be inhibitory. Thus, it is apparent that aninterruption of 5-HT activity would result in disinhibition, and therefore excitation, of varioussensory modalities.Current thought is that the mechanism of LSD is related to the regulation of 5-HT activity in theRN. However, the RN is also influenced by GABAergic, catecholamergic, and histamergicneurons. LSD has been shown to also have affinities for many of these receptors. Thus it ispossible that some of its effects may be mediated through other pathways. Current researchhowever has focused on the effects of LSD on 5-HT activity. Before specific mechanisms andtheories are discussed, a brief discussion of the principles of synaptic transmission will be given. Overview of Synaptic TransmissionThere are two types of synapses between neurons: chemical and electrical. Chemical synapses aremore common and are the type discussed in this paper. When an action potential (AP) travelsdown a pre-synaptic cell, vesicles containing neurotransmitter are released into the synapse(exocytosis) where they effect receptors on the post synaptic cell. Synaptic activity can beterminated through reuptake of the neurotransmitter to the pre-synaptic cell, the presence ofenzymes which inactivate the transmitter (metabolism), or simple diffusion.A pre-synaptic neuron can act on the post-synaptic neuron through direct or indirect pathways. Ina direct pathway, the post-synaptic receptor is also an ion channel. The binding of aneurotransmitter to its receptor on the post-synaptic cell directly modifies the activity of thechannel. Neurotransmitters can have excitatory or inhibitory effects. If a neurotransmitter isexcitatory, it binds to a ligand activated channel in the post-synaptic cell resulting in a change inmembrane permeability to ions such as Na+ or K+ resulting in a depolarization which thereforebrings the post-synaptic cell closer to threshold. Inhibitory neurotransmitters can workpost-synaptically by modifying the membrane permeability of the post-synaptic cell to anions suchas Cl- which results in hyperpolarization.Many neurotransmitters that have system-wide effects such as epinephrine (adrenaline),norepinephrine (noradrenaline), and 5-HT work by an indirect pathway. In an indirect pathway,the post-synaptic receptor acts on an ion channel through indirect means such as a secondarymessenger system. Many indirect receptors such as muscarinic, Ach, and 5-HT involve the use ofG proteins.5 Indirect mechanisms often will alter the behavior of a neuron without effecting itsresting potential.For example, norepinephrine blocks slow Ca activated K channels in the rat hippocampalpyramidal cells. Normally, Ca influx eventually causes the K channels to open. This causes aprolonged after hyperpolarization which extends the refractory period of the neuron. Therefore, byblocking the K channels, the prolonged after hyperpolarization is inhibited which results in theneuron firing more APs for a given excitatory input.5Other indirect means of neuromodulation include interfering with pre-synaptic neurotransmittersynthesis, storage, release, or reuptake. Inhibiting the reuptake of a neurotransmitter, for example,can cause an excitatory response. Stimulation of neurotransmitter receptors can have a variety ofeffects on both pre and post-synaptic cells. Pre-synaptic receptors are sometimes involved in selfregulation while post-synaptic receptors can cause an increase (excitation) or decrease (inhibition)of AP firing in a neuron. A subtler method of neuromodulation involves molecules that effect theseneuroreceptors. Molecules that excite a receptor are referred to as agonists while those thatinterfere with receptor binding are called antagonists. For example, 5-HT often acts as aninhibitory neurotransmitter. A 5-HT receptor antagonist could interfere with the activation ofpost-synaptic 5-HT receptors causing them to be less responsive to inhibition. This disinhibitionwould make the post-synaptic cell more responsive to neural inputs, most likely resulting in anexcitatory response. Theory: LSD Pre-synaptically Inhibits 5-HT NeuronsRaphe Nuclei neurons are autoreactive; that is they exhibit a regular spontaneous firing rate that is

not triggered by an external AP. Evidence for this comes from the observation that RN neuralfiring is relatively unaffected by transections isolating it from the forebrain. Removal of Ca++ ions,which should block synaptic transmission, also has little effect on the rhythmic firing pattern. Thisfiring pattern however is susceptible to neuromodulation by a number of transmitters.7In 1968, Aghajanian and colleagues observed that systemic administration of LSD inhibitedspontaneous firing of these autoreactive serotonergic neurons in the RN. Serotonergic neurons areknown to have a negative feedback pathway through autoreceptors (receptors on thepre-synaptic cell that respond to the neurotransmitter released by the cell). This means that anincrease in 5-HT levels causes a decrease in the activity of serotonergic neurons. Serotonergicneurons are also known to make synaptic connections with other RN neurons. This could have theresult of spreading out the effects of negative feedback to other RN neurons. This led to thetheory that LSD causes a depletion of 5-HT through negative feedback in pre-synapticautoreceptors.7 The depletion of 5-HT was thought to be responsible for the effects on thepreviously described systems innervated by the serotonergic neurons. A number of subsequentobservations have called this theory into doubt however. Low doses of LSD effect behavior but do not depress firing in the RN.8 The behavioral effects of LSD outlast the modification of RNN firing.8 While repeated dosage of LSD results in a decrease of behavioral modifications (tolerance), its effects on the RN are unchanged.8 Other hallucinogens such as mescaline and DOM do not effect R neurons.8 Depletion of 5-HT does not eliminate the effectiveness of LSD. If LSD worked by inhibiting the 5-HT output of pre-synaptic 5-HT neurons, it should be ineffaceable if 5-HT is depleted. The opposite result was actually observed; depletion enhances LSD activity.9 Mianserin, a 5-HT2 receptor antagonist, blocks LSD behavior but does not block LSD’s depression of RN neurons.9While LSD does cause a decrease in the autoreactive firing of RN neurons, this appears to be aneffect and not the cause. These observations are considered however to be compatible with apost-synaptic model. Subsequent research found that LSD and other hallucinogens have a highaffinity for post-synaptic 5-HT1 and 5-HT2 receptors. In fact there is significant correlationbetween the affinity of a hallucinogen for these receptors and its human potency. While it seemslogical that 5-HT activity is modulated at 5-HT receptor sites, it is possible that LSD could beaffecting 5-HT receptor activity indirectly through adrenic or dopaminic pathways. However,blocking these receptors caused no change in LSD’s activity on the 5-HT receptors, thus itappears that 5-HT activity is indeed modified by 5-HT receptors.10 While evidence indicates thatLSD is a 5-HT1 agonist, it is debated whether the effects on 5-HT2 receptors is agonistic orantagonistic.11Theory: LSD Post-synaptically Antagonizes 5-HT2ReceptorsInitial post-synaptic theories postulated that LSD was a 5-HT2 agonist. Pierce and Peroutka(P&P), however, argued that LSD has a number of antagonistic properties and called into doubtsome of the evidence presented as being compatible with agonist activity. The primary evidencefor agonistic behavior comes from observations that the effects of LSD are inhibited by 5-HT2antagonists. P&P pointed out that this is not always the case. For example, some 5-HT2antagonists such as spiperonedo not block LSD behavior. In addition, radioligandbinding studies have shownthat the affinity of 5-HT2receptor agonists is pHdependent while the affinity of5-HT2 receptor antagonistsand LSD are pHindependent.95-HT2 receptors areconnected to aphosphatidylinositol (PI)second messenger system. PIturnover has been found to bestimulated by 5-HT andantagonized by 5-HT2antagonists. P&P found that nM concentrations of LSD do not stimulate PI turnover. Therefore,LSD does not act as a classic agonist. They also found that nM concentrations of LSD inhibitedthe stimulatory effect of 10M 5-HT. The ability of LSD to inhibit a concentration 1000x greater isconsistent with it being a 5-HT2 antagonistP&P also point out that the excitatory effects of 5-HT on CNS neurons appears to be caused bya decrease in K+ conductance attributable to activation of 5-HT2 receptors. P&P found that LSDinhibits this effect in rat somatosensory pyramidal neurons. This also is evidence that LSD acts inan antagonistic role.9The final line of evidence presented by P&P was from smooth muscle studies. The guinea pigtrachea contracts when M concentrations of 5-HT are present. The ability of 5-HT antagonists toinhibit this effect correlates with the antagonists affinity for the 5-HT2 binding site. Thus it appearsthat this muscle contraction is 5-HT2 mediated. It was found that nM concentrations of LSD didnot cause muscle contraction and inhibited the agonistic effects of M concentrations of 5-HT. Thisalso is compatible with the actions of an antagonist. Theory: LSD Post-synaptically Partially Agonizes 5-HTReceptorsMany of the apparent contradictions in evidence in the debate over whether LSD acts as a 5-HT2agonist or antagonist can be reconciled by the theory that LSD acts as a partial 5-HT2 agonist. Dr. Glennon presented a number of arguments for this theory including data from his own researchand from the studies discussed by P&P in the previous section.One of the primary tools used by Glennon to determine the effects of various chemicals on theinteractions between LSD and 5-HT was drug discrimination training in rats. Rats were trained todiscriminate 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline. Trainingwith DOM stimuli generalized to many indolealkylamine and phenalkylamine hallucinogens. DOMwas chosen instead of LSD as a training drug because of concern that LSD had a number ofpharmacological effects. It was thought that if the rat was trained with LSD, it might makesdiscriminations based on one of the pharmacological effects of LSD other than its effects on5-HT. With this tool, Glennon demonstrated that a number of 5-HT2 antagonists inhibited theability of rats to discriminate LSD from saline. This indicates that LSD acts as a 5-HT2 agonist. Glennon offered no explanation for P&P’s observation that some antagonists such as spiperone donot have this effect. However, spiperone and a few other similar antagonists appear to only beabout 40% effective in inhibiting 5-HT2 sites due to its relative nonselectivity.13As discussed in the previous section, PI turnover has been found to be stimulated by 5-HT and isantagonized by 5-HT2 antagonists. In another study of the effects of LSD on PI turnover, it wasfound that LSD acted as a partial agonist (it produces approximately 25% of the effect caused by5-HT). The apparent difference between this second study and P&P’s is that the second studytested the effects at a variety of doses. From this it was concluded that while LSD has a higheraffinity for 5-HT receptors than 5-HT does, it has a lower efficacy. This is compatible with P&P’sobservation that nM concentrations of LSD inhibited the stimulatory effects of uM 5-HT. If LSDacted as a partial agonist with low efficacy, it could compete with 5-HT in binding to 5-HT2receptors. Since 5-HT is a more potent agonist than the LSD, the effects of LSD would appearantagonistic.Glennon argued that the guinea pig trachea may not be a good example since 5-HT does notwork through a PI mechanism in this case. In the rat aorta, however, 5-HT does hydrolize PI andthe contractile effects of 5-HT are antagonized by ketanserin (a 5-HT2 antagonist). While LSDwas not tested, another hallucinogen, DOB, was found to have an agonistic effect that could beantagonized by ketanserin. This suggests that LSD acts agonistically in the rat aorta. Glennonpoints out that it may well be the case that in other cases, the effects may be antagonistic. However, these effects could be explained if LSD had a low efficacy for the receptor.Hyperthermia and platelet aggregation are both affected by 5-HT2 mechanisms. Hallucinogenssuch as LSD have been shown to behave agonistically and in the case of platelets, to beantagonized by 5-HT2 antagonists such as ketanserin.11LSD often has a biphasic response in which low doses have the opposite effects of higher doses. The head twitch response in rodents is believed to be 5-HT2 mediated. At low doses, it has beenfound that LSD elicits a head-twitch response while at higher doses it antagonizes the response. The rat startle reflex is amplified at low dosages of LSD while decreased at higher doses. Thisbiphasic behavior can also be explained if LSD behaves as a partial agonist.11In summary, this theory claims that: “LSD is a high-affinity, low efficacy, nonselective 5-HTagonist; in the absence of another agonist it may function as an agonist, whereas in the presence ofa high efficacy agonist, it will function as an antagonist.” 11Theory: LSD Post-synaptically Agonizes 5-HT1 ReceptorsGlennon also gave another possible explanation for the antagonistic activity of LSD. There is someevidence that 5-HT1 receptors have an antagonistic relationship with 5-HT2 receptors. Asdiscussed in the previous section, head twitch behavior is believed to be 5-HT2 mediated. DOIacts as a 5-HT2 agonist and elicits head twitch. 5-OMe DMT also is a 5-HT agonist but has lessefficacy than DOI. If the subject is pretreated with 5-OMe DMT, the effects of DOI areattenuated (because many of the receptors are filled with the lower efficacy 5-OMe DMTmolecules.) It has been found that A 5-HT1 agonist (8-OH DPAT) can also cause DOIattenuation. Other studies have also demonstrated that 5-HT1 agonists can behave functionally as5-HT2 antagonists.11Glennon argued that this theory is lent extra credence from the observation that 5-HT2 and5-HT1c have similar relationships with various hallucinogens. A number of these hallucinogenshave been shown to be 5-HT1c agonists. Like 5-HT2 sites, the affinity of hallucinogens for 5-HT1csites correlates with their hallucinogenic potency in humans. Thus another explanation of thebiphasic behavior of LSD is that increasingly higher doses of LSD cause increased antagonism ofthe 5HT2 receptor through agonism of 5HT1 receptors.Although, the pre-synaptic theory seems to be fairly well discredited, it is interesting to note thatthere is debate as to whether pre-synaptic serotonin autoreceptors are of the 5-HT1 type. Whether serotonergic autoreceptors are 5-HT1 or not, it has been demonstrated that there arealso post-synaptic 5HT-1 receptors.12 While the role of these receptors is not completely known,some researchers have hypothesized that 5-HT1 receptors may be involved in the regulation ofnorepinephrine.13 As discussed previously, the majority of norepinephrine neurons are located inthe LC which also has system wide innervation.Recent research on 5-HT receptors calls the theory that 5-HT1 agonism results in 5-HT2antagonism into question. Since Glennon’s paper, the 5-HT1c receptor has been reclassified as5-HT2c. Since the 5-HT2 receptors discussed in this paper belong to the same family as what wascalled the 5-HT1c receptor, these have been reclassified as 5-HT2a.14 Since “5-HT1c” is amember of the 5-HT2 family, it is not surprising the LSD affinities are similar for the two receptors. While these reclassifications do not necessarily discount the theory that one receptor has anantagonistic effect on the other, it seems likely that the evidence for this may need to bere-evaluated in terms of recent findings. ConclusionThe lack of understanding about the mechanisms of LSD is indicative of the problems involved inthe bridging of the worlds of psychology and neurobiology. As more is learned about the roles andinteractions of various neurotransmitters, receptors, and on a larger scale: portions of the brain, themystery will be further unraveled. With this caveat emptor firmly in mind, it seems that the bestexplanation of LSD’s effects is that it behaves as a high affinity partial 5-HT agonist. Depending onthe presence of other molecules and its own concentration, LSD can have either agonistic orantagonistic effects on post-synaptic 5-HT2 family receptors. This modulation of 5-HT behavior isprobably responsible for many of the effects attributable to LSD. LSD also has an affinity forother neurotransmitter receptors that play important roles in the brain stem such as norepinephrine,dopamine, and histamine. It is also hypothesized that LSD may modulate neural responses tothese transmitters through its activity on 5-HT1 receptors. Both the Locus Coeruleus and theRaphe Nuclei are part of the ascending reticular activating system which is implicated in thesensory modalities. The inhibition of 5-HT in the RN and release of norepinephrine from LCneurons results in a flood of information from the sensory system reaching the brain. Some of thecognitive effects of LSD could be attributed to the effects of brain stem innervation to areas of thebrain such as the cerebral cortex and the hippocampus.References 1.(1995): “FAQ-LSD” From internet newsgroup: alt.drugs.psychedelics 2.Sankar (1975): “LSD: A Total Study” 3.Ashton H (1987): “Brain Systems Disorders and Psychotropic Drugs” 4.Snyder (1986): “Drugs and the Brain” Sci Am Books Inc. From FAQ-LSD 5.Nicholls J, Martin R, Wallace B (1992): “From Neuron to Brain: Acellular andMolecular Approach to the Function of the Nervous System” 6.Aghajanian GK(1980): “Mescaline and LSD Facilitate the Activation of Locus Coeruleus Neurons by Peripheral Stimulation” Brain Res 186:492-496 7.Jacobs, B (1985): “An Overview of Brain Serotonergic Unit Activity and its Relevance to the Neuropharmacology of Serotonin.” From: Green, A: Neuropharmacology of Serotonin 8.Jacobs, B, Trulson M, Heym J, (1981): “Dissociations Between the Effects of Hallucinogenic Drugs on Behavior and Raphe Unit Activity in Freely Moving Cats” Brain Res 215:275-293 9.Pierce P, Peroutka S (1990): “Antagonist Properties of d-LSD at 5-Hydroxytryptamine2 Receptors”. Neuropsychopharmacolgy 3(5-6):509-517 10.Moret C (1985): “Pharmacology of the Serotonin Autoreceptor” From: Green, A: Neuropharmacology of Serotonin 11.Glennon R (1990): “Do Classical Hallucinogens Act as 5-HT2 Agonists or Antagonists?” Neuropsychopharmacolgy 3(5-6):509-517 12.Green R, Heal D (1985): “The Effects of Drugs on Serotonin Mediated Behavioral Models” From Green, A: Neuropharmacology of Serotonin 13.Leysen J (1985): “Characterization of serotonin receptor binding sites” From Green, A: Neuropharmacology of Serotonin 14.Borne R. (1994) “Serotonin: The Neurotransmitter for the 90 s” URL: http://www.fairlite.com/ocd/artiles/ser90.shtml. From: Drug Topics Oct, 10 1994:108