Lsd - Lysergic Acid Diethylamide

LSD

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 for analytic psychotherapy. It was thought that the administration of LSD could aid the patient in releasing repressed material. It was also suggested that psychiatrists themselves might develop more insight into the pathology of a diseased mind through self experimentation. 1,2 During the late 60s, LSD became popular as a recreational drug. While it has been suggested that recreational use of the drug has dropped, a recent report on CNN claimed that 4.4% of 8th graders have tried it. LSD is considered to be one of, if not the, most potent hallucinogenic drug known. Small doses of LSD (1/2 - 2 ug/kg body weight) result in a number of system wide effects that could be classified into somatic, psychological, cognitive, and perceptual categories. These effects can last between 5 and 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" brachycardia The study of hallucinogens such as LSD is fundamental to the neurosciences. Science thrives on mystery and contradiction; indeed without these it stagnates. The pronounced effects that hallucinogens have throughout the nervous system have served as potent demonstrations of difficult to explain behavior. The attempts to unravel the mechanisms of hallucinogens are closely tied 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 activity and behavior. It will then discuss some of the neural populations and neurotransmitters that are believed to by effected by LSD. The paper will conclude with a more detailed discussion of possible ways that LSD can effect the neurotransmitter receptors which are probably ultimately responsible for its LSD. A Brief Foray Into Philosophy and the Cognitive Sciences Modern physics is divided by two descriptions of the universe: the theory of relativity and quantum mechanics. Many physicists have faith that at some point a "Grand Unified Theory" will be developed which will provide a unified description of the universe from subatomic particles to the movement of the planets. Like in physics, the cognitive sciences can describe the brain at different levels of abstraction. For example, neurobiologists study brain function at the level of neurons while psychologists look for the laws describing behavior and cognitive mechanisms. Also like in physics, many in these fields believe that it is possible that one day we will be able to understand complicated behaviors in terms of neuronal mechanisms. Others believe that this unification isn't possible even in theory because there is some metaphysical quality to consciousness that transcends neural firing patterns. Even if consciousness can't be described by a "Grand Unified Theory" of the cognitive sciences, it is apparent that many of our cognitive mechanisms and behaviors can. While research on the level of neurons and psychological mechanisms is fairly well developed, the area in between these is rather murky. Some progress has been made however. Cognitive scientists have been able to associate mechanisms with areas of the brain and have also been able to describe the effects on these systems by various neurotransmitters. For example, disruption of hippocampal activity has been found to result in a deficiency in consolidating short term to long term memory. Cognitive disorders such as Parkinson's disease can be traced to problems in dopaminergic pathways. Serotonin has been implicated in the etiology of various CNS disorders including depression, obsessive-compulsive behavior, schizophrenia, and nausea. It is also known to effect the cardiovascular and thermoregulatory systems as well as cognitive abilities such as learning and memory. The lack of knowledge in the middle ground between neurobiology and psychology makes a description of the mechanisms of hallucinogens necessarily coarse. The following section will explore the possible mechanisms of LSD in a holistic yet coarse manner. Ensuing sections will concentrate on the more developed studies of the mechanisms on a neuronal level. The Suspects Researchers have attempted to identify the mechanism of LSD through three different approaches: comparing the effects of LSD with the behavioral interactions already identified with neuotransmitters, chemically determining which neurotransmitters and receptors LSD interacts with, and identifying regions of the brain that could be responsible for the wide variety of effects listed in Table 1. Initial research found that LSD structurally resembled serotonin (5-HT). As described in the previous section, 5-HT is implicated in the regulation of many systems known to be effected by LSD. This evidence indicates that many of the effects of LSD are through serotonin mediated pathways. Subsequent research revealed that LSD not only has affinities for 5-HT receptors but also for receptors of histamine, ACh, dopamine, and the catecholines: epinephrine and norepinephrine.3 Only a relative handful of neurons (numbering in the 1000s) are serotonergic (i.e. release 5-HT). Most of these neurons are clustered in the brainstem. Some parts of the brainstem have the interesting property of containing relatively few neurons that function as the predominant provider of a particular neurotransmitter to most of the brain. For example, while there are only a few thousand serotonergic cells in the Raphe Nuclei, they make up the majority of serotonergic cells in the brain. Their axons innervate almost all areas of the brain. The possibility for small neuron populations to have such systemic effects makes the brain stem a likely site for hallucinogenic mechanisms. Two areas of the brainstem that are thought to be involved in LSD's pathway are the Locus Coeruleus (LC) and the Raphe Nuclei. The LC is a small cluster of norepinephrine containing neurons in the pons beneath the 4th ventricle. The LC is responsible for the majority of norepinephrine neuronal input in most brain regions.4 It has axons which