The psychedelic effects of d-Lysergic Acid Diethyl Essay

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LSD

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 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
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