HaCKeRz Kr0nlcKLeZ 1/HaCKeRz Kr0nlcKLeZ.iso/anarchy/essays/term/lsd.txt

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Table of Contents

Introduction
     Table 1:Effects of LSD
A Brief Foray Into Philosophy and the Cognitive Sciences
The Suspects
     Figure 1: Structure of LSD
Overview of Synaptic Transmission
Theory: LSD Pre-synaptically Inhibits 5-HT Neurons
Theory: LSD Post-synaptically Antagonizes 5-HT2 Receptors
     Figure 2: LSD Binding at 5-HT2 Receptor
Theory: LSD Post-synaptically Partially Agonizes 5-HT2 Receptors
Theory: LSD Post-synaptically Agonizes 5-HT1 Receptors
Conclusion
References

Introduction

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.


References

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