BIOLOGICAL BASIS OF BEHAVIOR
Psychology 321
Spring, 2005 HGH 225
Dr. John M. Morgan MWF, 8am to 9:00
Chemistry of LSD and Route of Access
By Kathryn E. Martinez
Classification
Pharmacologically, the commonly abused hallucinogenic substances
may be divided into two major groups. The indolealkylamines,
including d-lysergic acid diethylamide (LSD), psilocybin, and
dimethyltryptamine (DMT) bear a structural resemblance to the
neurotransmitter 5-hydroxytryptamine (serotonin). The
phenylethylamines, including mescaline and the
phenylisopropylamines such as 2, 5-dimethoxy-4-methylamphetamine
(DOM, "STP"), are structurally related to dopamine,
norepinephrine, and the amphetamines (Gelenberg, Bassuk,
Schoonover 1991).
Doses
Usual doses range from about 25 micrograms to more than 300
micrograms. LSD is known to posses a low level of toxicity; the
effective dose is about 50 micrograms while the lethal dose is
about 14,000 micrograms. These figures provide a therapeutic
ratio of 280, making the drug a remarkably nonlethal compound
(Julien 2001).
Pharmacology
d-Lysergic acid diethylamide is a synthetic hallucinogen derived
from an extract of the ergot fungus. The drug is colorless,
odorless, and tasteless. It is usually ingested as part of a
pill or dissolved on a piece of paper (Gelenberg, Bassuk,
Schoonover 1991).
LSD is often added to other substances, such as the back of
stamps, or sugar cubes, which can be handled more easily (Julien
2001).
Following oral administration, the drug is well absorbed from
the gastrointestinal tract and distributed to body tissues. Only
small amounts are detected in the brain, however (Gelenberg,
Bassuk, Schoonover 1991).
It also crosses the placenta. The largest amounts of LSD in the
body are found in the liver, where the drug is metabolized
before it is excreted. The usual duration of action is 6 to 8
hours (Julien 2001).
Although the mechanism of action is unclear, the drug inhibits
the activity of serotonergic neurons in the midbrain dorsal
raphe. The plasma half-life of LSD is 2 to 3 hrs. It is
metabolized into nonhallucinogenic substances, primarily by
conjugation of the liver (Gelenberg, Bassuk, Schoonover 1991).
Within the brain, the highest levels of LSD are in the visual
system, especially within a part called the lateral geniculate
nucleus, or LGN. LSD decreases the response of the LGN, which
acts a visual relay center. The LGN receives nerve impulses from
the retina and sends them to the occipital cortex of the brain,
an area also known as the visual cortex. LSD acts to decrease
the responsiveness of the LGN to signals from the retina. How
this effects the production of visual hallucinations is unclear
LSD is also concentrated highly in parts of the limbic system.
The limbic system is dedicated to regulating emotion,
aggression, docility, and memory.
Also, LSD concentrates in areas of the reticular formation. The
reticular formation mediates the level of arousal and alertness
in the brain. It begins in the medulla, and runs up through the
brain stem into the forebrain. The textbook authors call it "the
volume dial of consciousness" (Strang, 2004).
Because of its extreme potency, only minuscule amounts can be
detected in urine. Thus, conventional urine-screening tests are
inadequate to detect LSD. When the use of LSD is suspected,
urine is collected (up to 30 hours after ingestion) and an
ultrasensitive radioimmunoassay is performed to verify the
presence of the drug (Julien 2001).
Neurotransmitters affected
LSD is 'serotonergic' in action. This means it acts on the
neurotransmitter serotonin. In fact, LSD is one of the most
extreme serotonergic agonists. The chemical structure of LSD
resembles that of serotonin. LSD appears to work by blocking 5-
HT (the chemical name of serotonin) receptors at the synapse,
resulting in a rebound effect, which serotonin is overactive and
receptors are hypersensitive. Since the drug is metabolized
quickly, it takes up to two hours to produce a noticeable
effect, and has long duration of action; it seems that LSD works
to imbalance the brain's natural serotonin system (Strang,
2004).
Effects on subtypes of 5-HT receptors
LSD inhibits the activity of the 5-HT1a subtype of serotonin
receptor. Many of the 5-HT1a receptors are located in the raphe'
nucleus of the brain stem. However, this is probably not the
cause of the hallucinogenic effect, since other chemicals that
inhibit these receptors are not hallucinogenic. However, the
raphe' nuclei are known to have an important role in regulating
the autonomic nervous system, patterns of sleep and wakefulness,
and states of arousal.
LSD furthermore has an affinity for 5-HT2 receptors- an affinity
it shares with mescaline, an andrenergic hallucinogen. Many 5-
HT2 receptors are located in the cerebral cortex, and are linked
to the perceptual and mental effects of hallucinogens. The
cortex is the most advanced area of the brain, receiving
information from the thalamus and making higher-level processing
possible. LSD's effects on the 5-HT2 receptors are the likely
source of the hallucinogenic effects of the drug.
LSD in addition activates the NE neurons located in the locus
coeruleus of the brain. This is accomplished through a
modulating effect of LSD on the 5-HT neurons, which then affect
the NE neurons. The NE neurons receive sensory information from
the body and then direct the flow of that information-downward
to the reticular formation, and upward to the hippocampus,
hypothalamus, and amygdale. In animal studies, researchers have
shown that LSD increases the responsiveness of the locus
coeruleus to stimuli (Strang, 2004).
Acute Intoxication
The effects of LSD begin 20 to 60 minutes after ingestion,
depending on the amount ingested and the degree of tolerance
developed (Gelenberg, Bassuk, Schoonover 1991). Peak blood
levels are reached in about 3 hours (Julien 2001).
Lysergide + Selective serotonin re-uptake inhibitors (SSRI's)
Three patients with a history of lysergide (lysergic acid
diethylamide, LSD) abuse experienced the new onset or worsening
of the LSD flashback syndrome when given fluoxetine, paroxetine
or sertraline. Grand mal convulsions occurred in one patient on
LSD when given fluoxetine.
A girl of 18 with depression, panic and anxiety disorders and
with long history of illicit drug abuse experienced a 15-hour
LSD flashback within 2 days of starting to take sertraline
daily. Another flashback lasting a day occurred when the
sertraline was replaced by paroxetine. No further flashbacks
occurred when the SSRIs were stopped. A youth of 17 with
depression, also with a long history of illicit drug abuse
(including LSD), began to experience LSD flashbacks 2 weeks
after starting to take paroxetine. His father, a chronic drug
abuser, had been treated with both fluoxetine and paroxetine for
depression and had also reported new onset of a flashback
syndrome. An isolated report describes grand mal convulsions in
a patient while taking fluoxetine, tentatively attributed to the
concurrent abuse of LSD.
Not understood. Lysergic increases serotonin in the brain and
one suggestion is that when the serotonin re-uptake is blocked
in the brain, there is an increased stimulation of 5-HT1 and 5-
HT2 receptors.
Information is very limited indeed. The authors of the first
report suggested that patients who are given SSRIs should be
warned about the possibility of flashback or hallucinations if
they have a known history of LSD abuse. It might be better to
use other antidepressants that do not act through a 5-HT
mechanism (Stockley 2002).
Making LSD in the Laboratory
Attempts to prepare lysergic acid amides by the usual methods of
preparing amides, such as reacting an amine with lysergic acid
chloride or with ester of lysergic acid, have been unsuccessful.
United States Patents No. 2,090,429 and No.2, 090,430 describe
processes of preparing lysergic acid amides and, although these
processes are effective to accomplish the desired conversion of
lysergic acid to one of its amides, they are not without certain
disadvantages.
By the authors invention he provided a simple and convenient
method of preparing lysergic acid amides, which comprises
reacting lysergic acid with trifluoroacetic anhydride to produce
a mixed anhydride of lysergic and trifluoroacetic acids, and
when reacting the mixed anhydride with a nitrogenous base having
at least one hydrogen linked to nitrogen. The resulting amide of
lysergic acid is isolated from the reaction mixture by
conventional means.
The reaction of the lysergic and the trifluoroacetic anhydride
is a low temperature reaction, that is, it must be carried out
at a temperature below about 0 degrees C. The presently
preferred temperature range is about –15 C. to about –20 C. This
range is sufficiently high to permit the reaction to proceed at
a desirably fast rate, but yet provided an adequate safeguard
against a too rapid temperature and consequent excessive
decomposition of the mixed anhydride.
The reaction is carried out in a suitable dispersing agent, that
is, one that is inert with respect to the reactance. The
lysergic acid is relatively insoluble in dispersants suitable
for carrying out the reaction, so it is suspended in the
dispersant.
Two gallons of trifluoroacetic anhydride are required per mol.
of lysergic acid for the rapid and complete conversion of the
lysergic acid into the mixed anhydride. It appears that one
molecule of the anhydride associates with or favors an ionic
adduct with one molecule of the lysergic which contains a basic
nitrogen atom that it is the adduct which reacts with a second
molecule of trifluoroacetic anhydride to form the mixed
anhydride along with one molecule of trifluoroacetic acid. The
conversion of the lysergic acid in the mixed anhydride occurs
within a relatively short time, but to insure a complete
conversion the reaction is allowed to proceed for about one to
three hours.
The mixed anhydride of lysergic trifluoroacetic acids is
relatively unstable, especially at room temperature and above,
and must be stored at a low temperature. This temperature
instability of the mixed anhydride makes it desirable that it be
converted into a lysergic acid amide without unnecessary delay.
The mixed anhydride itself, since it contains a lysergic acid
group, also can exist in the reaction mixture in large [art as
an ionic adduct with trifluoroacetic anhydride or
trifluoroacetic acid. It is important for maximum yield of
product that the lysergic acid employed in the reaction by dry.
It is most convenient to dry the acid by heating it at about
105-110 degrees C. in a vacuum of about 1 mm of mercury or less
for a few hours, although any other customary means of drying
can be used.
The conversion of the mixed anhydride into an amide by reacting
the anhydride with the nitrogenous base, such as an amino
compound, can be carried out at room temperature or below. Most
conveniently the reaction is carried out by adding the cold
solution of the mixed anhydride to the amino compound or a
solution thereof, which is about room temperature. Because of
the acidic components present in the reaction mixture of the
mixed anhydride for maximal conversion of the mixed anhydride to
the amide. Preferably a slight excess over the five mols is
employed to insure complete utilization of the mixed anhydride.
If desired, a basic substance capable of neutralizing the acid
components present in the reaction mixture, but incapable of
interfering with the reaction, can be utilized. A strongly basic
tertiary amine is an example of such a substance. In such case,
about one equivalent of amino compound to be converted to a
lysergic acid amide, as well as any unconverted. Lysergic acid
can be removed from the reaction mixture and can be re-employed
in other conversions (Making LSD in the Laboratory, 2005).
References
Gelenberg, A.J., & Bassuk, E.L., & Schoonover, S.C. (1991). The
Practitioner's Guide to Psychoactive Drugs. 3rd. Ed. (pp. 288,
290). New York: Plenum Publishing Corporation.
Julien, R. M. (2001). A Primer of Drug Action. (p. 234). New
York: Worth Publishers.
Stockley. (2002). Stockley's Drug Interactions. (pp. 906-907).
Great Britain: The Bath Press.
Strang, M. (2004). LSD and Psilocybin- Serotonergic
Hallucinogens: Route of access, brain metabolism, and
neurochemical effects. February 24 2005, from The Shroomery.
http://www.shroomery.org/index/par/25277.
(2005). Making LSD in the Laboratory. February 28 2005, from
Temple of the Screaming Electron.
http://www.totse.com/en/drugs/psychedelics/lablsd.html
Synaptic Transmitters Involved in LSD Administration and the
Parts of the Neuron Affected
Katie Holley
The nearly concurrent discovery of serotonin (5-HT) and LSD-25
in the 1950 's encouraged a lot of research to be done on the
relationship between LSD and serotonin, which helped to develop
a greater understanding of the role serotonin plays as a
neurotransmitter in the brain (Nichols, 2004). Today it is
believed that LSD (and other hallucinogens) stimulate 5-HT2A
receptors (Kalat, 2004). Activation of these receptors causes
cortical glutamate levels to increase. This is presumed to be a
result of a "presynaptic receptor-mediated release" from neurons
in the thalumus (Nichols, 2004).
Early studies proposed that LSD antagonized the effects of
serotonin on peripheral tissues. It was later proposed that the
psychoactive properties of LSD may be a result of the blocking
of serotonin receptors in the central nervous system (Nichols,
2004). This theory was short-lived however when it was
discovered that a brominated derivative of LSD (BOL),a potent
serotonin antagonist in peripheral tissues, was found to have
essentially no LSD like effects. In 1961, Freedman found that
systematic use of LSD elevated serotonin content in the brain
(cited in Nichols, 2004). In a later study in 1967, Rosencrans,
et al. reported that LSD also reduced brain levels of acetic
acid (5-HIAA) (cited in Nichols, 2004). The combined findings of
these two studies demonstrated that LSD decreased serotonin
turnover in the brain.
It is now widely accepted that hallucinogen action is primarily
located on receptor 5-HT2A. In a study done in 1955, scientists
found that daily administration of LSD resulted in an almost
complete loss of sensitivity to the drug after 4 days. It is now
believed that this is a result of 5-HT2A receptor down-regulation
(cited in Nichols, 2004). In a later study published in 1985, it
was found that daily LSD administration selectively decreased 5-
HT2 receptor density in rat brains (Nichols, 2004).
Studies have shown that activation of 5-HT2A receptors increase
inhibitory post-synaptic potentials. However, when compared to
serotonin, the maximum effect produced by LSD is 30-50% of that
of serotonin. LSD is therefore a partial agonist, rather than an
antagonist (Nichols, 2004). Antagonists block the action of a
neurotransmitter, whereas agonists mimic or increase the effects
of a neurotransmitter (Kalat, 2004). Conversely, LSD is a weak
agonist when compared to less intoxicating compounds with
stronger behavioral influences. Therefore it is thought that LSD
must either activate another monoamine receptor that works with
the 5-HT2A receptor activation or the receptor may be coupled to
another signaling pathway which has yet to be
discovered(Nichols, 2004).
Numerous studies have found that 5-HT2A receptors are localized
on cortical pyramidal cells. This is supported by
electrophysiological data that suggests hallucinogens have
excitatory effects on neurons in the neocortex (Nichols, 2004).
The thalamus is probably the second most important site of
action for hallucinogens. In rat brains significant levels of 5-
HT2A are concentrated in parts of the thalamus. The thalamus,
along with the amygdala, represent the major source of glutamate
afferents within the neocortex. It processes somatosensory
inputs and receives afferents from the raphe nuclei and the
locus coeruleus (Nichols, 2004).
Although the majority of studies suggest that the frontal cortex
and thalamus are primarily responsible for the action of
hallucinogens, there is also evidence that the LC plays a part
in the effects of hallucinogens. The LC is the "point of
convergence for a variety of somatosensory and visceral sensory
inputs from all over the body" (Nichols, 2004). It sends
norepinephrine (NE) projections to all parts of the neuraxis,
including the cerebral cortex. Systematic administration of LSD
to anesthetized rats decreased activity of LC cells while at the
same time enhancing the activation of LC neurons which were
normally evoked by sensory stimuli (Nichols, 2004). As a result,
LSD alters all of the sensory processes. In addition, the LC is
often referred to as the "novelty detector" for salient external
stimuli. One would predict that sensory events that may not
ordinarily seem remarkable may be perceived as having "increased
novelty". This is indeed one of the effects commonly reported by
users of hallucinogens (Nichols, 2004).
It is widely accepted that hallucinogens enhance glutamatergic
transmission although debate still surrounds the mechanisms by
which hallucinogens do so. Although a great deal of research has
been done on the relationship between hallucinogens and
glutamate very little of it has been done using LSD, because of
its illegality and negative connotation. Even less research has
been conducted on the relationship between hallucinogens and
GABA, another important neurotransmitter in the prefrontal
cortex that plays an important role in the brain and behavior.
GABA acts by ionotropic means, opening chloride gates in a cell
(Kalat, 2004) It has been concluded that serotonin regulates
GABA interneurons (Nichols, 2004).
Studies have shown that serotonin both hyperpolarizes and
depolarizes layer V pyramidal neurons by acting the 5-HT1A and 5-
HT2A channels respectively (Nichols, 2004). Normal firing of
raphe cells in an animal whom is awake causes serotonin to be
released into cortical areas. Administration of hallucinogens
suppresses raphe cell firing either directly (through activation
of serotonin receptors) or indirectly (by stimulation of
inhibitory GABA neurons) (Nichols, 2004).
Hallucinogens also stimulate 5-HT2A receptors on glutamate axon
projections from the thalamus. This causes the cortical
pyramidal cells to become excited, while at the same time
releasing glutamate into cortical neuronal fields (Nichols,
2004). Normally, thalamic projections fire in response to
sensory information processed by the thalamus. Hallucinogens
cause glutamate to be released in the absence of appropriate
stimulus. As a result hallucinogens enhance
sensitivity/excitability of the cortical processing while at the
same time causing glutamate to be released from thalamic
afferents that normally signal incoming sensory information to
be processed (Nichols, 2004). As a result, hallucinogens lead to
an "overload" of the processing capacity of the cortex.
Evidence also suggests that LSD may directly activate dopamine
pathways as well. Although, contrary to most drugs which effect
dopamine channels LSD fails to produce a dependence, perhaps
because cortical areas receive dopamine activation, but areas in
the brain involved in reward mechanisms are not activated
(Nichols, 2004). This again is a area in which very little
research has been done.
In conclusion, it is impossible to pinpoint every possible
affect LSD has on the brain. Primarily, because the brain is
such a complex inter-connected system, the complete circuitry of
which remains elusive. It is further complicated by the limits
surrounding LSD research on humans. In essence, LSD affects all
mental functions associated with consciousness (cognition, self-
control, mood, perception, etc.). As we develop a better
understanding of how hallucinogens affect our brain, we will
broaden our understanding of our mind as well.
References:
Kalat, James W. (2004). Biological Psychology, 65-68.
California: Thompson/Wadsworth.
Nichols, David E. 2004. Hallucinogens. Pharmacology and
Therapeutics, 132-160.
Ion Channels Affected and Inhibitory and Excitatory Potential
Changes by LSD
Ricardo Agredano
Research with LSD has been very limited by two major factors:
lack of human subjects and laws against it as a controlled
substance. These deterrents have caused a big hole in what can
be discovered about this hallucinogen at the ion channels it
affects and in turn those effects on inhibitory and excitatory
potentials of the cell.
It was difficult to obtain clear explanations about exactly what
was going on at the neuron level. Later it was discovered that
most experiments were carried out on rodents. This may not sound
like it is such a bad thing because human subjects were not
being put in positions where their health could be affected by
the drug, but in fact there is a slight difference in rodent and
human brains. LSD affects a serotonergic receptor type 2A (5-
HT2A), which is different in rats to humans in its structure and
activity, and behavior "may not strictly parallel those in
humans" (Nichols, 2004). This could cause researches to get
different results in what they would see in experimental rats
and to what may actually be happening in humans.
Another deterrent that has somewhat slowed down the process of
understanding LSD at the neuron level is the law. LSD is
scheduled as a controlled substance; Schedule I, to be exact,
which means that it is illegal to posses, sell, or buy without a
DEA license. You can imagine what would happen if a researcher
was caught with a substantial amount of LSD, and possibly the
difficulty in obtaining a license that will allow someone to
posses a powerful illegal substance. These things are exactly
what will repel researchers from using such a substance.
The only almost certain aspect of LSD is that it has a similar
chemical composition as serotonin (5-HT) and will especially act
on 5-HT2 receptors. However, LSD is the only known hallucinogen
to bind to dopamine receptors. It will activate postsynaptic
dopamine receptors if the dose is high enough to do so. LSD also
binds to alpha-adrenergic and beta-adrenergic receptors that are
involved sympathetic nervous system control of smooth muscles.
It is also a competitive antagonist at histamine receptors and
will produce inhibitory messages. LSD also acts mysteriously on
the visual cortex. At low doses, LSD will stimulate the visual
cortex and higher doses will inhibit this area.
LSD research has flipped it from being an antagonist to an
agonist. Early research suggested that this hallucinogen was
blocking serotonin receptors, but later was said to also mimic
serotonin. Early research suggested that LSD inhibited serotonin
because when it was administered serotonergic cells did not
fire, especially in the raphe cell region. This would mean that
LSD was activating potassium channels to flood the cell and
prevent it from allowing postsynaptic firing potentials to
occur. Serotonin, by itself in the brain, acts on the cell the
same way by allowing potassium to flood in and inhibit firing.
But something else was going on and serotonin was found to be
both exciting and inhibiting actions on the serotonergic cells;
the same way LSD was later found to be doing.
A study done by Freedman (1961) found that LSD was raising
levels of serotonin in the brain after each systematic
administration (cited in Nichols, 2004). Rosecrans et al (1967)
also found that LSD was reducing "levels of the 5-HT metabolite
5-hydroxyindole acetic acid (5-HIAA)" which all suggested that
LSD was decreasing the turnover of serotonin in the brain (cited
in Nichols, 2004). This means that it may have only looked like
LSD was blocking 5-HT receptor sites, but it was not entirely
what was going on.
LSD has affinity directly to serotonin receptors the same way
serotonin would. An experiment looked at what LSD would do in
the absence of serotonin and found that LSD still caused a
release of serotonin from the cell. Even after serotonergic
cells where damaged, the postsynaptic cell would compensate this
serotonin loss by making more serotonin receptors which would
inevitably intensify LSD's effects when administered again
(Jacobs, 1987). This, again, suggested to researchers that LSD
was more of an agonist rather than an antagonist.
Researchers are trying to find exactly what hallucinogens like
LSD are doing to receptors to cause hallucinations. A big area
of importance has been the raphe cell. As mentioned above, this
area's firing was found to be suppressed by LSD. Sprouse &
Aghajanian (1987, 1988) found, however, that the receptor that
was causing raphe cell firing inhibition was actually from a
different serotonin receptor (5-HT1A) and "nonhallucinogenic 5-
HT1A agonists were identified that suppressed raphe firing but
which were not hallucinogenic" (cited in Nichols, 2004). LSD did
cause an inhibiting effect here, but it was not the right area
where researchers were hoping to find the occurrence of
hallucinations.
New research into this area has been finding that LSD is a
potent in vivo substance compared to other hallucinogenic
substances studied the same way. But what has become confusing
is that when LSD is tested for intrinsic activity, by using
chemical markers for receptor activity of PI hydrolysis (
phosphoinositide) at 5-HT2A, it only reported back 20-25% cell
activity compared to 100% caused by serotonin and near complete
agonist by those other hallucinogens. Even when a different
marker was put on arachidonic acid (AA) receptor activity, "LSD
is a weak agonist (ca. 50%) compared with behaviorally less
potent compounds" (Kurrasch-Orbaugh et al., 2003 as cited in
Nichols, 2004). At first it was thought that maybe it was
pharmacokinetic or metabolic factors, but there was no evidence
to support that this is what was happening.
The fact that LSD was not somehow being metabolized or leaving
the body means that it was doing something else. Researchers
decided that either LSD was activating "another receptor that is
synergistic with 5-HT2A receptor activation or the 5-HT2A receptor
may be coupled with another signaling pathway that has not yet
been identified" (Nichols, 2004). Nichols (2004) does hint
towards one path that has not been studied for any
hallucinogenic activation.
Phospholpase A2 (PLA2) is one pathway that was found to be
activated by activation of 5-HT2A receptors. Another
phospholipase is PLC (phospholipase C) that is also stimulated
by 5-HT2A receptors. The phospholipase D (PLD) is the one that
Nichols (2004) hinted about not yet being researched for effects
of hallucinogenic 5-HT2A receptors activity and could be another,
or even the missing, pathway to further understand LSD's and
other hallucinogens cause of hallucinations.
There are a couple of basics about the ion channels and
inhibitory or excitatory messages from LSD that are needed to
know. LSD mimics the effects of serotonin at the serotonin
receptor type 2A (5-HT2A). It will cause this receptor to be
stimulated and cause other pathways to activate that are not yet
understood. LSD also stimulates some dopamine receptors that
will excite and release dopamine, this is the only hallucinogen
known to do such a thing. And finally, more research is needed
to find out where and what exactly LSD is doing to neuron cells
to cause its well known hallucinatory effect.
References
Nichols, D.E. (2004). Hallucinogens. Pharmacology &
Therapeutics, 101, 131-181.
Jacobs, B.L. (1987). How hallucinogenic drugs work.
American Scientist, 75, 385-392.
George Adelman (Ed.). (1989). Encyclopedia of Neuroscience
Volume I & II. Birkhäuser: Boston.
Primary Behavior Changes and Side Effect Behavior Changes
in LSD Users
By Nicole Sesson
In 1938, Albert Hofmann created lysergic acid diethylamide (LSD-
25) at Sandoz pharmaceutical laboratories in Basel, Switzerland.
It was initially created to aid as a circulatory and respiratory
stimulant, and it was discovered to stimulate contraction of the
uterus. In 1943, it was unintentionally absorbed into Hofmann's
skin, and he discovered that it was an extremely potent
hallucinogen. Although a true hallucinogen is when a person sees
or hears something (without sensory cues) that does not exist,
and believes that the perceptions are real, LSD is considered a
hallucinogen which merely alters the perception of existing
sensory stimuli while most users are aware that their distorted
perception is caused by the drug, (Henderson, 37, 45). LSD
temporarily alters an individual's normal mode of perception,
reasoning, memory, thoughts, and feelings, while producing a
flood of intensified sensations. Colors, sounds, and visual
imagery become more intense, subjective time is altered, and
visual illusions including perceived movement of stationary
objects are experienced. "The primary emotional response may be
of euphoria and contentment, or less often a side effect of
confusion, fear, anxiety, and despair" may result, (Henderson,
2). "Hallucinogens have been used for centuries by various
people often in sacred rituals (Henderson, 37). LSD's most
profound psychic effect, the sense of contacting some profound
universal truth, cosmic consciousness, or transpersonal state,
often described as feeling that the mind is transcending the
boundaries of the individual self, with space, time, and
identity all disarranged, is often the motivation for LSD use,"
(Henderson, 43). This perception of transcending the boundaries
of the self are often interpreted as religious, mystical, or
metaphysical experiences," causing people to believe that they
have a lasting and profound knowledge of oneself (Henderson,
p.46).
"LSD was introduced into the United States in 1948 as a
psychiatric wonder drug . . . curing everything from
schizophrenia, criminal behavior, sexual perversions, and
alcoholism," (Henderson, p.3). Sandoz recommended that
psychiatrists take LSD in order to gain insight to the ideas and
sensations of their mental patients. LSD was expected to create
fundamental changes in attitude and personality, and shorten the
time consuming, expensive process of psychotherapy by enabling
patients to uncover unconscious material more quickly than
conventional methods, (Henderson, 47). It was reported that
"subjects would become less depressed, anxious, guilty, or
angry, and more self tolerant, religious, and sensually aware.
LSD therapy for the terminally ill was used to "help the patient
remain alert and aware while providing relief from pain and
discomfort. It was meant to lessen the sense of isolation, and
help the patient reach out to those close to him or her,"
(Henderson, 49). "In the early 1950's, the CIA became interested
in LSD as a potential 'truth drug' or mind control agent. In the
CIA's cold-war Operation MK-ULTRA, experiments were conducted
using numerous mind-altering drugs, and by the mid- 1960's,
about one thousand five hundred military personnel had received
LSD, (Henderson, 41). Although LSD was widely used among doctors
and the government, today it is illegal and current experimental
research no longer consists of human subjects, but instead uses
animal subjects or surveys of people who have taken the drug
outside of a clinical setting. Since the Controlled Substance
Act of 1970, LSD is considered a Schedule I drug meaning that it
is deemed to have no legitimate medical use in treatment,
(www.streetdrugs.org).
LSD affects the central nervous system at multiple sites. LSD's
molecular structure is similar to serotonin, causing it to act
as a serotonin antagonist and competitive inhibitor of serotonin
in the central nervous system, (Ungerleider, 31). Since LSD
stimulates serotonin receptors at inappropriate times or for
longer than usual durations, this interference of the normal
functioning of serotonin at serotonin receptors has a
significant role in altering sensory perception, and control of
mood, (Henderson, 42; Kalat, 458). LSD also affects the visual
processing in the retina, as well as interferes with the
electrical conduction of visual information to the brain, which
contributes to hallucinations. "LSD's effects are most
predominant in two brain regions. One is the cerebral cortex, an
area involved in mood, cognition, and perception; the other is
the locus ceruleus, which receives sensory signals from all
areas of the body and has been described as the brains 'novelty
detector' for important external stimuli," (NIDA research report
series online).
"LSD's effects begin to be noticeable thirty to sixty minutes
after ingestion, peak at two to five hours, and may continue for
eight to twelve hours, or more varying from person to person.
"There is usually a period of anywhere from one to three hours
after the drug begins to take effect where the user lies
perfectly still as though asleep. Following this period of time,
many users become more active and begin to walk and particularly
to seek outdoor surroundings, (Ungerleider, p.63). In terms of
varying responses between LSD users, research indicates that
people who have chronic tricyclic antidepressant administration
experience heightened LSD hallucinatory responses; while people
who chronically receive lithium, experience subjective decreases
in LSD effects, (Bonson, 229). Additionally, the duration and
intensity of the experience is highly dependent on the dose,
environmental factors, and tolerance level of the person,"
(Henderson, 44). An effective dose ranges from 20-100
micrograms, with larger doses lasting longer with more intense
perceptual distortions. "Tolerance, which develops quickly with
each successive LSD experience, is lost as quickly as it
develops (Henderson, 43; Ungerleider, p.26). "LSD users also
produce tolerance for other hallucinogenic drugs such as
psilocybin and mescaline, but not to drugs such as marijuana, or
amphetamines which do not act directly on the serotonin
receptors affected by LSD," (NIDA research report series
online). The physical effects appear first which include the
consistent neurological changes of dilated pupils (mydriasis),
and increased deep tendon reflexes (hyperreflexia), (Henderson,
44). Other effects may include elevated blood pressure,
increased heart rate (tachycardia), increased blood sugar, loss
of appetite, blurred vision, nausea, dry mouth, gooseflesh
(piloerection), weakness, tingling in the fingers and toes
(paresthesia), dizziness, sweating, tremors, and sometimes
drowsiness (Henderson, 44; www.usdoj.gov/dea). "All of these
physical effects except pupil dilation and other manifestations
of central sympathetic dominance usually subside by the time the
psychic symptoms appear," (Ungerleider, p.25). The psychic
effects are the primary reasons for LSD use.
LSD causes a "substance induced psychotic disorder,
characterized by hallucinations and delusions (positive symptoms
of schizophrenia)"; however, "someone who stops taking the drug
is likely to recover from these symptoms," (Kalat, p. 478, 485).
Euphoria is often the first reaction to LSD, however over the
course of the drugs effects, peoples moods can change rapidly
and abruptly. "This first psychological indication that LSD has
begun to act is a loosening of emotional inhibitions, which may
involve spontaneous laughter, smiling, or tears," (Ungerleider,
p. 33).Visual disturbances which are characteristic of LSD can
be experienced with eyes open or closed. Blind subjects who
could once see, and whose optic nerves retained some function,
could also perceive hallucinations. The most common images
involve geometric shapes and images perceived in patterns.
Flashes of color can occur and seem more intensified. Objects
may have halos or an after image. Stable objects may seem to
move especially if seen in the peripheral vision. "Pseudo
hallucinations, which are projections of a concept onto the
external world with retention of the knowledge that it is
unreal, are sometimes reported," (Ungerleider, p. 34). "Tactile
stimulations are also modified, and often described as more
sensitive or more meaningful," (Ungerleider, p.35).
Hallucinations of the other senses such as hearing, taste, and
smell, are rare; however, there is some synesthesia, cross
sensory perception in which sounds provoke perceptions of
colors, some hyperacusis, an increase in the perception of
sound, and music may take on an enhanced meaning and intensity,
(Henderson, p. 45; Ungerleider, 35).Other perceptual changes
include an overall heightened sense of beauty, love, and the
sacredness of the event, vulnerability to suggestion, and time
perceived to go slower, faster or in reverse creating a feeling
of timelessness, (Ungerleider, 39). Users often feel detachment
from their body similar to depersonalization but not to the
extreme of being delirious. This detachment can affect one's
physical coordination, (Henderson, p.46). Another common LSD
experience is the seemingly phasic waxing and waning in
intensity of mental alterations. For example, "the individual
may believe that he is 'back' only to find a few moments later
that he is 'way out," (Ungerleider, p. 27). In terms of common
thought patterns there may be a flight of ideas, or a sort of
primordial thinking/feeling/sensing state similar to the mental
activity of an infant, (Ungerleider, 36). At higher doses,
thinking may become fantasy laden, nonlogical, or dreamlike,
with thoughts perceived to have great power. For example, people
may believe that they are omnipotent, telepathic, grandiose, or
have narcissistic ideas of reference, (Ungerleider, 37). As ego
boundaries dissolve, differentiation of the self from the world
might be lost, and separation of external events from internal
memories may become difficult or impossible to distinguish,
(Ungerleider, 37). Under experimental conditions, the subject is
usually passive, saying little, and may stare at an object for
hours; however, activity can be stimulated by suggestion,
(Ungerleider, 38).
The side effects of LSD include "bad trips," flashbacks,
possible precipitation of an already existing psychosis, dangers
of time and space distortion when driving, "social
embarrassment" of mood swings, depression, "difficulties"
associated with impulsive behaviors, confusion, wandering, and
absentmindedness, (Henderson, 57). "After an LSD 'trip,' the
user may suffer acute anxiety or depression for a variable
period of time," (www.usdoj.gov/dea). The APA identifies organic
mental disorders that may result from hallucinogen use which
include "hallucinogen delusional disorder, hallucinogen mood
disorder, and post hallucinogen perception disorder, all of
which involve transient or long lasting effects during or
shortly after hallucinogen use, (Henderson, 56). ). "Also, LSD
users may develop long-lasting psychoses such as schizophrenia,"
(www.usdoj.gov/ndic). It is possible that LSD, a synthetic drug
derived from a natural hallucinogen in rye grass fungus, could
have been the cause of the unusual "mad" behavior of the Salem,
Massachusetts girls who were accused of witchcraft in 1692,
(www.apa.org). "A bad trip is an acute anxiety or panic reaction
following ingestion of LSD. As perceptions of stimuli, thoughts,
or time are distorted and/or amplified, some frightening
feelings when amplified may seem unbearable, and if the time
seems to be moving extremely slow, the person may feel that they
have lost control over the drug and that the 'trip' will never
end," (Henderson, p.58). "The perceptual distortions and changes
in ego integrity produce a feeling of loss of mastery which may
be perceived as frightening if the situation is chaotic or the
loss of control threatening," (Ungerleider, 33). "There is some
work to show that persons who place a premium on self-control,
planning, caution and impulse restriction and who sacrifice
spontaneity do particularly poorly on LSD," (Ungerleider, 64).
"The environmental and social setting of security or insecurity
will strongly influence the LSD state. Although bad trips are
one of the more common adverse reactions, many LSD users regard
bad trips as an opportunity for increased self-knowledge and as
just a part of the learning and growing process, (Henderson,
58). A "flashback is the transitory recurrence of perceptions
and emotions originally experienced while under the influence of
LSD," which occur without any additional drug use (Henderson, p.
60). "Many of the recurrences have to do with paranoid thoughts,
hallucinatory activity, feelings of unreality, and estrangement
that were experienced during the original LSD induced episode,"
(Ungerleider, 0.70). "Most flashbacks are episodes of visual
distortion that can last for a few seconds to several minutes,
or sometimes several hours," (Henderson, p. 60). While
flashbacks can occur spontaneously, specific situations, such as
emotional stress, fatigue, use of marijuana, or changing from a
light to dark environment, can trigger them (Henderson, 61).
"Flashbacks usually decrease in frequency and intensity with
time, and they seldom occur more than a few months after the
initial trip, but in some persons they have been reported as
much as two or three years later" (Henderson, p.60). In addition
to flashbacks, other potential chronic side effects of LSD
"include changes in personality, motivation, attitudes, and
values" (Ungerleider, 69). "There occurs on a chronic basis
among many users of LSD a subjective feeling of improvement but
an objective loss of functioning" (Ungerleider, p.72). For
example, people may believe that LSD use has caused them to have
omnipotent powers such as ESP (extrasensory perception), or the
heightened ability to perform a job; however, with objective
observation these people may have lost their job, or have ESP
powers no greater than that provided by chance (Ungerleider,
73). It is difficult to determine if the long term side effects
from LSD use are caused by the LSD or some other factor. Studies
conducted on people who have consumed LSD usually involve people
with a history of taking other drugs besides LSD, making it
difficult to determine which drug is responsible for behavioral
differences. Also, it is difficult to determine if the LSD user
would have exhibited unusual behavior regardless of the drug
side effects if, for example, the person has a history of mental
health issues before consuming the drug. Although it is possible
that the mental health issues of some LSD users are caused by
long term effects of LSD use, "at present, the literature
tentatively suggests that there are few if any, long-term
neuropsychological deficits attributable to hallucinogen use,"
(Halpern, 247).
References
Bonson, K.R., and Murphy, D.L. Alterations in responses to LSD
in humans associated with chronic administration of tricyclic
antidepressants, monoamine oxidase inhibitors or lithium.
Behavioral Brain Research, Vol. 73, Issues 1 and 2, p. 229-233,
(1995).
Daw, Jennifer. Why and how normal people go mad. American
Psychological Association, Vol. 33, No. 10 (November 2002).
Halpern, J.H., and Pope, H.G., Jr. Do hallucinogens cause
residual neuropsychological toxicity? Drug and Alcohol
Dependence, Vol. 53: p. 247-256, (1999).
Henderson, L.A. and Glass, W.J. LSD: Still With Us After All
These Years. New York: Lexington Books, 1994.
Kalat, J.W. Biological Psychology. Canada: Wadsworth a division
of Thomson Learning Inc., 2004.
Ungerleider, J.T., M.D. The Problems and Prospects of LSD.
Illinois: Charles C. Thomas Publisher, 1968.
www.drugabuse.com; NIDA Research Report Series: "Why do people
take hallucinogens?"
www.streetdrugs.org/lsd.htm
www.usdoj.gov/dea
www.usdoj.gov/ndic
Physiological Changes and Effects Reported by Users and/or
Survivors of LSD
By Kristen Kelley
Lysergic acid diethylamide is one of the most potent
hallucinogens on the drug circuit and had been in this top
position for many years. First discovered by Albert Hoffman when
it was absorbed through his fingers while he was conducting a
routine synthesis. Today LSD is a widely popular recreational
drug in which its users are looking for the non addictive
euphoria that comes with ingesting this substance. LSD is
derived from the fungus found on rye and is presented to users
in a variety of methods. Some of the most common ways LSD is
taken is by tablet, or in its liquid form laced into products
such as blotter paper, postage stamps and chewing gum. LSD is
commonly called "acid" by users and is an odorless, colorless
substance.
LSD has been in prevalent in society for decades and was
extremely popular in the 60's and 70's. Its popularity weekend
in the late 70's and throughout the 80's, but again is making a
comeback as one of the most abused drugs on the market today.
Users take LSD in varying doses the most common ranging from 20-
80 micrograms. According to the Drug Enforcement Administration
these levels are drastically reduced from the common doses of
the 60's and 70's. Common doses taken in that time were between
100 and 200 micrograms (National Institute on Drug Abuse, 2005).
Different doses account for the intensity of the experience was
has when taking LSD. All of the effects of LSD can be perceived
on a spectrum of intensity and prevalence. The contradiction to
this is if a user frequently uses this drug, they build up a
tolerance that can not be overturned just by taking LSD in
higher doses. Some minor effects may still occur but it will be
of little intensity and possibly of a shorter duration.
After one ingests LSD it is absorbed by their
gastrointestinal tract and is soon flowing in their blood stream
and in turn to the users brain. Onsets of the drug, when the
user will begin to notice effects, can ranger from thirty to
approximately ninety minutes. After the initial onset of the
drug, one may feel effects from it for twelve or more hours.
Unlike amphetamines which when using a urine test can be
detected for seventy two hours after use, LSD is usually
detected for only eight to ten hours after use (Mannaioni,
1984).
After the initial onset of LSD, the user can feel a
variety of effects both physically and sensationally based.
Common physical effects of LSD are an increased pulse, sweating,
dilated pupils and an increase of ones blood pressure. In less
common incidents the user may encounter nausea, loss of
appetite, sleepless ness and increased body temperature. As
noted by Dr. Paul Perry some severe physical side effects of LSD
can include things such as hypothermia, hyperglycemia, panic
reactions and piloerection (Paul Perry, Ph.D., BCPP, 1996).
In even more rare occurrences some extremely severe side
effects have presented themselves to users of LSD. In a
relatively small number of LSD users, instances of psychosis
have occurred. Again, we see a range of psychosis in length,
ranging from very brief to prolonged psychosis. There continues
to be a debate between researchers and medical professionals to
weather or not the use LSD possibly uncovers latent
schizophrenic tendencies or if it is a mere coincidence between
the drug and the development of the disease.
General mood changes are consistently noticed among both
users and observers of those taking the drug. Both groups have
reported visual and auditory hallucinations, a euphoria and
increase in laughter. Other effects can be severe and rapid mood
fluctuations, extreme feeling of emotion and distorted
perceptions of time and space. The loss of time and space
perception is demonstrated by the following comment from one
user "I was looking deeply in the picture until the objects in
the picture were beside me" (Blewett and Chwelos, 1959). A large
number of users have reported sensations that seem to "cross
over", in which they are able to hear colors and feeling sounds
(East Coast Drug Rehab, 2005). In some cases users can
experience an unpleasant experience, often called a "bad trip",
in which hallucinations are frightening and cause a lot of
anxiety and restlessness.
When a user experiences a "bad trip" there are extreme
feelings of depression and loss of ones self. These users can at
times be calmed by supportive friends and clam music. It is said
that one that encounters a negative experience has gone into the
"trip" with a previously nervous or negative attitude (East
Coast Drug Rehab, 2005). One can also feel completely out of
control and in some cases this has resulted in attempted or
successful suicide. In a study of 225 users, all of whom had
encountered adverse reactions to LSD, there were 19 attempted
suicides and 11 successful suicides (Smart and Bateman, 1967).
In this same series of cases, there were four attempted
homicides of which one was successful. Although these types of
occurrences are rare it demonstrates they varying degrees of
which LSD can effect one.
The stages one goes through during an LSD "trip" has been
described by many users and researchers alike. While there are
some variations, the basic stages are all the same. Strassman
attempts to define these stages by classifying them into grades
of the LSD reaction. His grades are based on reactions that
occur from common doses, grades one through three and reactions
that occur with higher doses, grade four. Strassman describes
grade one as being a time anxiety and nervousness without
hallucinations or distortions. Grade two is described as a
continuation of anxiety and nervousness but now with distortion
of what is being experienced by the user. Grade 3 is when true
hallucinations begin and the user is able to maintain insight,
this is also a time in which anxiety and nervousness still occur
but with less intensity. The final classification, grade four,
is when all of the above reactions are still occurring but
instead of insight of the drugs effects being maintained, they
are now lost (Strassman, 1984).
When reading reactions of users of LSD it is obvious that
there are multiple common themes among their experiences. The
first evidence of the similarities is the definition of the
grades of the reactions, and secondly we see very frequent
responses by users in terms of more abstract feelings. The later
is demonstrated by the following list compiled by D.B. Blewett
and N. Chwelos. These two professionals compiled the following
reactions of users based on different experiences with LSD. Some
of their examples were taken from other previously compiled
lists that were not cited in their work. The following is an
excerpt from that list. Many users feel a sense of being at one
with the universe. This feeling is apparent in the quote of one
responder who states "I had finally understood by experience.
The feeling of union with the cosmos." Another common theme
among users is the stated experience of being able to see
oneself objectively or a feeling that one has two identities.
"If we had the gift to see ourselves as others see us, well, I
did this morning. There seemed to be two of me and there seemed
to be a conflict between these two." The following respondent
felt a loss of perception in terms of their physical self. "I
had the feeling of leaving my body and drifting off into space.
I had no worldly connections and felt as if I was only a spirit"
(Blewett and Chwelos, 1959).
Sensory perception is a large part of the LSD experience
from preconceived ideas and sensations before the "trip", to the
loss and/ or increase in sensory abilities during the
experience, to the mildly frequent occurrence of flashbacks
after the experience. The occurrence of "flashbacks" is
increased when the past user is intoxicated by another drug such
as marijuana. A flashback can occur without warning and can make
the previous user feel as though they are again on the drug.
Flashbacks sometimes occur after a great deal of time has lapsed
since the last time the drug was taken. In some cases users
reported having flashbacks over a year after the last time they
had taken any amount of LSD (East Coast Drug Rehab, 2005).
In all age groups, overall LSD use is again on the rise,
the rate in which young adult use this drug has increased in
just one year. According to the National Institute on Drug Abuse
the annual use of LSD among 12th graders was at 2.2% and 1.6% for
10th graders (NIDA, 2004). This is contrasted with the statistics
from 2003 also published by the NIDA in which the annual rate
for 12th graders was 1.9%, and 1.3% for 10th graders. This number
is constantly rising, and although LSD is not an addictive drug,
it is one of the most abused drugs in our society today.
LSD can have a variety of effects on the person who ingests
this substance. Users of LSD can experience things ranging from
feelings of emptiness to euphoria and from visions of "breathing
walls" to people dying. LSD is an extremely potent drug that can
be easily abused by its recreational followers.
Reference:
Perry, P.(1996)
Clinical Psychopharmacology: LSD Psychosis
Mannaioni PF (1984). Clinical pharmacology of drug
dependence. Piccin Nova Libraria, S.P.A.
Smart FR, Bateman R (1967). Unfavorable reactions to LSD:
a review and analysis of the available case reports. Can Med
Assoc J 97:1214-1221.
Strassman RJ (1984). Adverse reactions to psychedelic
drugs. A review of the literature. J Nerv Ment Dis 172:577-94.
Chwelos, N., Blewett, D.B. Handbook for the Therapeutic Use of
Lysergic Acid Diethylamide,
25 Individual and group Procedures (1959)
National Institute on Drug Abuse: U.S. Department of Health
and Human Services (2005) www.drugabuse.gov
East Coast Drug Rehab (2005) www.eastcoastdrugrehab.com
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