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 extend to a number of sites including the cerebellum, thalamus, hypothalamus, cerebral cortex, and hippocampus. A single LC neuron can effect a large target area. Stimulation of LC neurons results in a number of different effects depending on the post-synaptic cell. For example, stimulation of hippocampal pyramidal cells with norepinephrine results in an increase in post-synaptic activity. The LC is part of the ascending reticular activating system which is known to be involved in the regulation of attention, arousal, and the sleep-wake cycle. Electrical stimulation of the LC in rats results in hyper-responsive reactions to stimuli (visual, auditory, tactile, etc.)5 LSD has been found to enhance the reactivity of the LC to sensory stimulations. However, LSD was not found to enhance the 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 the effects of LSD can be described by its effects on the LC, it is apparent that LSD’s effects on the LC are indirect.4 While norepinephrine activity throughout the brain is mainly mediated by the LC, the majority of serotonergic neurons are located in the Raphe Nuclei (RN). The RN is located in the middle of the brainstem from the midbrain to the medulla. It innervates the spinal cord where it is involved in the 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 the reticular system; perhaps protecting the brain from sensory overload. Post-synaptic 5-HT receptors in the visual areas are also believed to be inhibitory. Thus, it is apparent that an interruption of 5-HT activity would result in disinhibition, and therefore excitation, of various sensory modalities. Current thought is that the mechanism of LSD is related to the regulation of 5-HT activity in the RN. However, the RN is also influenced by GABAergic, catecholamergic, and histamergic neurons.
LSD has been shown to also have affinities for many of these receptors. Thus it is possible that some of its effects may be mediated through other pathways. Current research however has focused on the effects of LSD on 5-HT activity. Before specific mechanisms and theories are discussed, a brief discussion of the principles of synaptic transmission will be given. Overview of Synaptic Transmission There are two types of synapses between neurons: chemical and electrical.
Chemical synapses are more common and are the type discussed in this paper. When an action potential (AP) travels down 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 be terminated through reuptake of the neurotransmitter to the pre-synaptic cell, the presence of enzymes which inactivate the transmitter (metabolism), or simple diffusion. A pre-synaptic neuron can act on the post-synaptic neuron through direct or indirect pathways. In a direct pathway, the post-synaptic receptor is also an ion channel.
The binding of a neurotransmitter to its receptor on the post-synaptic cell directly modifies the activity of the channel. Neurotransmitters can have excitatory or inhibitory effects. If a neurotransmitter is excitatory, it binds to a ligand activated channel in the post-synaptic cell resulting in a change in membrane permeability to ions such as Na+ or K+ resulting in a depolarization which therefore brings the post-synaptic cell closer to threshold. Inhibitory neurotransmitters can work post-synaptically by modifying the membrane permeability of the post-synaptic cell to anions such as 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 secondary messenger system. Many indirect receptors such as muscarinic, Ach, and 5-HT involve the use of G proteins.5 Indirect mechanisms often will alter the behavior of a neuron without effecting its resting potential. For example, norepinephrine blocks slow Ca activated K channels in the rat hippocampal pyramidal cells.
Normally, Ca influx eventually causes the K channels to open. This causes a prolonged after hyperpolarization which extends the refractory period of the neuron. Therefore, by blocking the K channels, the prolonged after hyperpolarization is inhibited which results in the neuron firing more APs for a given excitatory input.5 Other indirect means of neuromodulation include interfering with pre-synaptic neurotransmitter synthesis, 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 of effects on both pre and post-synaptic cells. Pre-synaptic receptors are sometimes involved in self regulation 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 these neuroreceptors.
Molecules that excite a receptor are referred to as agonists while those that interfere with receptor binding are called antagonists. For example, 5-HT often acts as an inhibitory neurotransmitter. A 5-HT receptor antagonist could interfere with the activation of post-synaptic 5-HT receptors causing them to be less responsive to inhibition. This disinhibition would make the post-synaptic cell more responsive to neural inputs, most likely resulting in an excitatory response. Theory: LSD Pre-synaptically Inhibits 5-HT Neurons Raphe 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 neural firing 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. This firing pattern however is susceptible to neuromodulation by a number of transmitters.7 In 1968, Aghajanian and colleagues observed that systemic administration of LSD inhibited spontaneous firing of these autoreactive serotonergic neurons in the RN. Serotonergic neurons are known to have a negative feedback pathway through autoreceptors (receptors on the pre-synaptic cell that respond to the neurotransmitter released by the cell). This means that an increase in 5-HT levels causes a decrease in the activity of serotonergic neurons. Serotonergic neurons are also known to make synaptic connections with other RN neurons. This could have the result of spreading out the effects of negative feedback to other RN neurons. This led to the theory that LSD causes a d …