FREE ESSAY ON LSD

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 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 depletion of 5-HT through negative feedback in pre-synaptic
autoreceptors.7 The depletion of 5-HT was thought to be responsible for the effects on
the previously described systems innervated by the serotonergic neurons. A number of
subsequent observations 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.9 While LSD does cause a decrease in the autoreactive firing of RN neurons, this
appears to be an effect and not the cause. These observations are considered however to
be compatible with a post-synaptic model. Subsequent research found that LSD and other
hallucinogens have a high affinity for post-synaptic 5-HT1 and 5-HT2 receptors. In fact
there is significant correlation between the affinity of a hallucinogen for these
receptors and its human potency. While it seems logical that 5-HT activity is modulated
at 5-HT receptor sites, it is possible that LSD could be affecting 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 it appears that 5-HT
activity is indeed modified by 5-HT receptors.10 While evidence indicates that LSD is a
5-HT1 agonist, it is debated whether the effects on 5-HT2 receptors is agonistic or
antagonistic.11 Theory: LSD Post-synaptically Antagonizes 5-HT2 Receptors Initial
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
doubt some of the evidence presented as being compatible with agonist activity. The
primary evidence for agonistic behavior comes from observations that the effects of LSD
are inhibited by 5-HT2 antagonists. P&P pointed out that this is not always the case. For
example, some 5-HT2 antagonists such as spiperone do not block LSD behavior. In addition,
radioligand binding studies have shown that the affinity of 5-HT2 receptor agonists is pH
dependent while the affinity of 5-HT2 receptor antagonists and LSD are pH independent.9
5-HT2 receptors are connected to a phosphatidylinositol (PI) second messenger system. PI
turnover has been found to be stimulated by 5-HT and antagonized by 5-HT2 antagonists.
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 inhibited the
stimulatory effect of 10M 5-HT. The ability of LSD to inhibit a concentration 1000x
greater is consistent with it being a 5-HT2 antagonist P&P also point out that the
excitatory effects of 5-HT on CNS neurons appears to be caused by a decrease in K+
conductance attributable to activation of 5-HT2 receptors. P&P found that LSD inhibits
this effect in rat somatosensory pyramidal neurons. This also is evidence that LSD acts
in an antagonistic role.9 The final line of evidence presented by P&P was from smooth
muscle studies. The guinea pig trachea contracts when M concentrations of 5-HT are
present. The ability of 5-HT antagonists to inhibit this effect correlates with the
antagonists affinity for the 5-HT2 binding site. Thus it appears that this muscle
contraction is 5-HT2 mediated. It was found that nM concentrations of LSD did not cause
muscle contraction and inhibited the agonistic effects of M concentrations of 5-HT. This
also is compatible with the actions of an antagonist. Theory: LSD Post-synaptically
Partially Agonizes 5-HT Receptors Many of the apparent contradictions in evidence in the
debate over whether LSD acts as a 5-HT2 agonist 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 research and 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 the interactions between LSD and 5-HT was
drug discrimination training in rats. Rats were trained to discriminate
1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline. Training with DOM
stimuli generalized to many indolealkylamine and phenalkylamine hallucinogens. DOM was
chosen instead of LSD as a training drug because of concern that LSD had a number of
pharmacological effects. It was thought that if the rat was trained with LSD, it might
makes discriminations based on one of the pharmacological effects of LSD other than its
effects on 5-HT. With this tool, Glennon demonstrated that a number of 5-HT2 antagonists
inhibited the ability 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 do not have this effect. However, spiperone and a few other
similar antagonists appear to only be about 40% effective in inhibiting 5-HT2 sites due
to its relative nonselectivity.13 As discussed in the previous section, PI turnover has
been found to be stimulated by 5-HT and is antagonized by 5-HT2 antagonists. In another
study of the effects of LSD on PI turnover, it was found that LSD acted as a partial
agonist (it produces approximately 25% of the effect caused by 5-HT). The apparent
difference between this second study and P&P's is that the second study tested the
effects at a variety of doses. From this it was concluded that while LSD has a higher
affinity for 5-HT receptors than 5-HT does, it has a lower efficacy. This is compatible
with P&P's observation that nM concentrations of LSD inhibited the stimulatory effects of
uM 5-HT. If LSD acted as a partial agonist with low efficacy, it could compete with 5-HT
in binding to 5-HT2 receptors. Since 5-HT is a more potent agonist than the LSD, the
effects of LSD would appear antagonistic. Glennon argued that the guinea pig trachea may
not be a good example since 5-HT does not work through a PI mechanism in this case. In
the rat aorta, however, 5-HT does hydrolize PI and the contractile effects of 5-HT are
antagonized by ketanserin (a 5-HT2 antagonist). While LSD was not tested, another
hallucinogen, DOB, was found to have an agonistic effect that could be antagonized by
ketanserin. This suggests that LSD acts agonistically in the rat aorta. Glennon points
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.
Hallucinogens such as LSD have been shown to behave agonistically and in the case of
platelets, to be antagonized by 5-HT2 antagonists such as ketanserin.11 LSD 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 been
found 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. This biphasic behavior can also be explained if LSD behaves as a partial
agonist.11 In summary, this theory claims that: LSD is a high-affinity, low efficacy,
nonselective 5-HT agonist; in the absence of another agonist it may function as an
agonist, whereas in the presence of a high efficacy agonist, it will function as an
antagonist. 11 Theory: LSD Post-synaptically Agonizes 5-HT1 Receptors Glennon also gave
another possible explanation for the antagonistic activity of LSD. There is some evidence
that 5-HT1 receptors have an antagonistic relationship with 5-HT2 receptors. As discussed
in the previous section, head twitch behavior is believed to be 5-HT2 mediated. DOI acts
as a 5-HT2 agonist and elicits head twitch. 5-OMe DMT also is a 5-HT agonist but has less
efficacy than DOI. If the subject is pretreated with 5-OMe DMT, the effects of DOI are
attenuated (because many of the receptors are filled with the lower efficacy 5-OMe DMT
molecules.) It has been found that A 5-HT1 agonist (8-OH DPAT) can also cause DOI
attenuation. Other studies have also demonstrated that 5-HT1 agonists can behave
functionally as 5-HT2 antagonists.11 Glennon argued that this theory is lent extra
credence from the observation that 5-HT2 and 5-HT1c have similar relationships with
various hallucinogens. A number of these hallucinogens have been shown to be 5-HT1c
agonists. Like 5-HT2 sites, the affinity of hallucinogens for 5-HT1c sites correlates
with their hallucinogenic potency in humans. Thus another explanation of the biphasic
behavior of LSD is that increasingly higher doses of LSD cause increased antagonism of
the 5HT2 receptor through agonism of 5HT1 receptors. Although, the pre-synaptic theory
seems to be fairly well discredited, it is interesting to note that there 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 are also
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 of norepinephrine.13 As discussed previously, the majority of norepinephrine
neurons are located in the LC which also has system wide innervation. Recent research on
5-HT receptors calls the theory that 5-HT1 agonism results in 5-HT2 antagonism into
question. Since Glennon's paper, the 5-HT1c receptor has been reclassified as 5-HT2c.
Since the 5-HT2 receptors discussed in this paper belong to the same family as what was
called the 5-HT1c receptor, these have been reclassified as 5-HT2a.14 Since 5-HT1c is a
member 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 an antagonistic effect on the other, it seems likely that the evidence
for this may need to be re-evaluated in terms of recent findings. Conclusion The lack of
understanding about the mechanisms of LSD is indicative of the problems involved in the
bridging of the worlds of psychology and neurobiology. As more is learned about the roles
and interactions of various neurotransmitters, receptors, and on a larger scale: portions
of the brain, the mystery will be further unraveled. With this caveat emptor firmly in
mind, it seems that the best explanation of LSD's effects is that it behaves as a high
affinity partial 5-HT agonist. Depending on the presence of other molecules and its own
concentration, LSD can have either agonistic or antagonistic effects on post-synaptic
5-HT2 family receptors. This modulation of 5-HT behavior is probably responsible for many
of the effects attributable to LSD. LSD also has an affinity for other 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 to these
transmitters through its activity on 5-HT1 receptors. Both the Locus Coeruleus and the
Raphe Nuclei are part of the ascending reticular activating system which is implicated in
the sensory modalities. The inhibition of 5-HT in the RN and release of norepinephrine
from LC neurons results in a flood of information from the sensory system reaching the
brain. Some of the cognitive effects of LSD could be attributed to the effects of brain
stem innervation to areas of the brain such as the cerebral cortex and the hippocampus. 
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