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lsd

lsd LSD is one of the most potent psychoactive drugs known to mankind, and its history is actually a rather curious one. It was synthesized by Dr. Albert Hofmann in the Sandoz Laboratories in Basel, in 1938, while Hofmann was working on a series of compounds derived from ergot alkaloids that had as their basic structure lysergic acid (Horowitz, 1976). But it wasn’t until 1943, however, that Hofmann took his first ‘trip’ on this drug when it was accidentally absorbed through the skin of his fingers while he was working with it (Horowitz, 1976). Since then, it has made its entrance into the world of biochemical psychiatry and was at different times used by psychiatrists and physicians to “access the unconscious mind,” to make the psychiatric patients “tell the truth,” to treat alcoholics, and to help terminally ill patients come to grips with the fact that they are going to die (Hordern, 1978). It finally surfaced in public as a recreational drug in 1960’s, and quickly brought about a tremendous amounts of attention and controversy Indeed, the effects that the hallucinogens such as LSD have throughout the nervous system serve as potent demonstrators of difficult to explain behavior - LSD’s effects have been classified into somatic (mydriasis, hyperglycemia, hyperthermia, piloerection, vomiting, lachrymation, hypotension, brachycardia); psychological (hallucinations, depersonalization, mood swings, euphoria, megalomania); cognitive (disturbed thought processes, difficulty expressing thoughts, impairment of reasoning); and perceptual (increased stimulus from environment, changes in shape/color, synaesthesia, disturbed perception of time) categories (Sankar, 1975). The study of such hallucinogens is, therefore, fundamental to neurosciences, since the mechanisms by which they work are closely tied to basic research in the physiology of neuroreceptors, neurotransmitters, neural structures, and their relation to behavior. This paper will attempt to uncover some of the effects that LSD has on various brain structures and explain how those effects come D-lysergic acid diethylamide, which is what an abbreviation ‘LSD’ stands for, is the most potent (only 0.05 mg are needed for LSD to be active, and in some people a dose of 0.03 is effective (Ray & Ksir, 1996)) and notorious of the hallucinogens. It is usually classified as an indole hallucinogen of the phantastica family, that is, it contains the structure known as the indole nucleus, which is also the basic structure of the neurotransmitter serotonin; and it is capable of altering perceptions while allowing the person to remain in communication with the present world, meaning that somebody under the influence of this drug will often be aware of both the “fantasy” world and the “real” world at the same time (hence the category ‘phantastica’) (Ray & Ksir, 1996). The drug molecules of LSD have their action by acting on serotonin systems (initial research found that LSD structurally resembled serotonin (5-HT), (Ashton, 1987)), thus LSD primarily affects only those brain systems that depend on serotonin. The LSD molecules that reach other types of receptors have no particular effect of which one can be aware (Ashton, 1987). Only a handful of neurons, however, are serotonergic (i.e. release 5-HT). In fact, the number of serotonergic neurons have been estimated to be numbering in the 1000’s, and most of these neurons are clustered in the brainstem (Leysen, 1985). Logically, then, LSD affects primarily brain stem A seeming contradiction that arises, however, is the disagreement between the described-above specificity with which LSD affects only certain parts of the brain (those that depend on serotonin, primarily) and another known fact that many more brain structures are also involved, with the involvement of the brainstem structures being only the begining - “specifically LSD affects the oldest parts of the brain first - upper end of the spinal chord, medulla oblongata, cerebrum, pineal gland, and hypothalamus region, but then the immediate back brain (occipital lobe) comes into play, along with the area of hearing, the cerebellum, other sense interpretive centers, and the motor areas” (Leysen, 1985). What accounts, then, for this spread of the effects if only certain brain structures that are serotonergic are The answer lies in a very curious fact that some parts of the brainstem have an 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 (an area of the brainstem), they make up the majority of serotonergic cells in the brain, and their axons innervate almost all of its areas” (Nicholas, Martin, and Wallace, 1992). The Raphe Nuclei is one of the two primary areas of the brainstem that are thought to be involved in LSD’s pathway, with the Locus Ceruleus being the second one (Green & Locus Ceruleus is a small cluster of norepinephrine-containing neurons in the pons beneath the 4th ventricle, it has axons which extend to a number of sites including the cerebellum, thalamus, hypothalamus, cerebral cortex, and hippocampus, and an ability to effect a large target area with a single neuron. (Nicholas, Martin, and Wallace, 1992). It is a part of the ascending reticular activating system, which is known to be involved in the regulation of attention, arousal, and the sleep-wake cycle. Raphe Nuclei is also a part of the ascending reticular activating system, and, as already mentioned above, is the location of the majority of serotonergic neurons. It is located in the middle of the brainstem from the midbrain to the medulla, and it innervates the spinal chord, where it is involved in the regulation of pain (Nicholas, Martin, and Wallace, 1992). Like the Locus Ceruleus, the Raphe Nuclei innervates wide areas of the Thus, it becomes apparent that even though the drug itself may target only certain areas of the brain, those may be the key areas for certain processes the results of which are required for the activity of many more brain centers. It is, then, through these key areas that LSD affects the rest of the brain. LSD was found to enhance the reactivity of Locus Ceruleus to sensory stimulations, so that many of the effects of LSD can be described by its effects on LC (Aghajanian, 1980). On the Raphe Nuclei LSD acts as an interruptor of 5-HT (serotonin) activity, which results in disinhibition, and, therefore, excitation of various sensory modalities, since 5-HT inhibits ascending traffic in the reticular system (perhaps protecting the brain from sensory overload), and inhibits the visual areas by its post-synaptic 5-HT receptors (Nicholas, Martin, and Wallace, 1992). Because, as mentioned above, LSD works through serotonin centers, and because among serotonin effects on human behavior are such things as mood, memory, and appetite control (Moeller, 1998) some of the brain centers that LSD affects “indirectly” include such areas as hyppocampus (responsible for memory), hypothalamus (responsible for appetite) and some parts of the lymbic system and frontal lobe (responsible for mood) (Banich, 1997). The are affected, however, only due to the connection with the brainstem structures that are targeted by LSD, and the mechanisms by which Moreover, the lack of knowledge in the middle ground between neurobiology and psychology makes a description of the mechanisms of hallucinogens neceserraly coarse and broad, without the definitive hundred-percent identified causes. The described-above causes are very strongly supported theories, but without further research in this field “dark areas” are guaranteed to persist. Moeller F. Serotonin, Microsoft Encarta Encyclopedia, 1998. Nicholas J, Martin R, Wallace B, From Neuron to Brain: Accelular and Molecular Approach to the Function of the Nervous System, 1992. Aghajanian G.K, Mescaline and LSD Facilitate the Activation of Locus Ceruleus Neurons by Peripheral Stimulation, Brain Res 186: 492-496, 1980. Green R, Heal D, The Effects of Drugs on Serotonin Mediated Behavioral Models, Neuropharmacology of Serotonin, 1985. Laysen J Characterization of Serotonin Receptor Binding Sites, Neuropharmacology of Serotonin, 1985. Ashton H, Brain Systems Disorders and Psychoactive Drugs, 1987 Ray O, Ksir C, Drugs, Society, and Human Behavior, 1996 Horrowitz M, Interview with Albert Hofmann, High Times, 24-81, 1976 Horden A, Psychopharmacology: Some Historical Considerations 1968 Sankar, LSD: A Total Study, 1975 Bibliography:

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