---------- Biological Basis of Behavior ------ ----
---------- SPRING, 2005 ----------

                            
                            
                       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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