Matteo Favero e Edoardo Musso
INTRODUCTION
LSD was synthesized for the first time in 1938 in Sandoz Laboratories in Basel by Albert Hofmann (1906-2008). Hofmann was doing research on the alkaloids present in squill and ergot in an attempt to obtain substances used as drugs. Its psychedelic properties were not recognized, however, until 1943, when Hofmann fell one drop of the substance on his hand that, once transpired, it caused the dizziness and hallucinations. This experience led him to personally test the psychoactive effects of LSD (which he called LSD-25 because it came from the sample number 25). As noted in the book My Problem Child (published in 1979) written by Hofmann himself: "In the final step of synthesis, during purification and crystallization of lysergic acid diethylamide in the form of a tartrate (tartaric acid salt), I was forced to interrupt my work because of strange sensations. The following description of this incident is from the report that I sent to Professor Stoll:
Last Friday, April 16,1943. I have been forced to interrupt my work in the laboratory right in the middle of the afternoon and proceed home, being affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a hallucinogenic-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly loud), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. About two hours later this condition faded away"
The LSD is considered one of the most used hallucinogens.
My Problem Child - Albert Hofmann
HALLUCINOGENS ASSUMPTION
In 2010, there were 1.2 million persons aged 12 or older who had used hallucinogens for the first time within the past 12 months. This estimate was not significantly different from the estimate in 2009 (1.3 million), but was higher than the estimates from 2003 to 2005 (ranging from 886,000 to 953,000).
The number of past year initiates of LSD aged 12 or older was 377,000 in 2010, which was similar to the number in 2009 (337,000), but higher than the estimates from 2003 to 2007 (ranging from 200,000 to 270,000).In 2011 the estimated number of initiates was 270,000.
For what concerns other hallucinogens Ecstasy is the most popular one, with 1.1 million of initiates in 2009 and 2010, far more than in the previous years when the number of new doped was 642,000 in 2003 and 615,000 in 2005
Less used is PCP, whose initiates are constantly decreasing. From 123,000 in 2002 to 45,000 in 2010 and 2011.
National Survey on Drug Use and Health
BIOCHEMICAL ACTION
LSD mimics the effect of serotonin and produces its effects with an hallucinogenic action caused by a serotonin agonist. Due to an interference on the receptors that control the ion permeability, serotonin LSD suppresses almost entirely (in a dose-dependent way) the flow of Ca++ ions and interferes with the conductance of K+ ions. The inhibition of the release of 5-HT, resulting from activation of 5-HT1A receptors, plays a fundamental role in the LSD hallucinogenic action, through a reduction of the competition among 5-HT and LSD, exerted by 5-HT postsynaptic receptors. On one hand LSD binding 5HT pre-synaptic receptors inhibits the release of serotonin; on the other, due to this reduction in intra-synaptic serotonin, reduces the competition on the post synaptic receptors, reserving all the space of binding receptors per itself.
Alterations in the gene expression induced by LSD may interfere with the receptors controlling ion channels: the glutamate signal might be modulated by LSD causing neuroplasticity conditions. The action of the serotonergic agonist LSD takes place in a totally changed neuroendocrine scene. LSD alterates neurotransmitters and hormones.
The hallucinogenic effects of LSD were mainly attributed to the interaction with the serotonergic system but nowadays it seems more conceivable that it is the result of a complex interaction of the drug with both the serotonergic system an the dopamine. In particular it has been seen that the LSD acts as a partial agonist on the D2 dopamine receptors. Hallucinogens such as LSD exert their effects on sensory, perceptual, cognitive and affective processing, through interaction with the 5HT-2 receptors and a modulation of NMDA receptors. The results of a study carried out by Krebs and Geyer in 1994, called Cross-tolerance studies of serotonin receptors involved in behavioral effects of LSD in rats supports the hypothesis that the final effects of LSD may be a combination of several effects on 5HT1 and 5HT2, confirming the existence of an interaction between 5HT1 and 5HT2 serotonin receptors.
However, the mechanism by which these substance causes an unusual behavior remains unclear despite a great amount of studies on the subject.
The study Lysergic acid diethylamide: evidence for stimulation of pituitary dopamine receptors, 1977 by Meltzer&Co. showed that the LSD has a powerful effect as a dopamine agonist in some brain regions (hypothalamus and pituitary) and a subsequent inhibitory action on the secretion of prolactin in plasma.
Effects of LSD on Ca++ currents in central 5-HT-containing neurons, 1994
EFFECTS
LSD (as well as other hallucinogens) temporarily changes the ordinary state of consciousness with more or less intense variations of the sensory perceptions. Auditory, visual and tactile perceptions mingle and take special tones and frequencies. Time flow is strangely altered, just like oneself perception, the conception of the surrounding world and the faculty of judgment. From thirty minutes to an hour after the assumption, the colors start to appear sharper, moving objects leave a trail behind them, you can have visions with your eyes closed and you may see ambiguous forms in darkness or see vibrating objects. Two hours later the effects become more intense, the visions can be seen with eyes open, fantastic immages appear from nowhere, time appears to slow until it almost stops and feeling like you are in a different world. For some people this may have a deeper and mystical meaning, yet may instill a sense of fear in others.
LSD stimulates centers in the sympathetic nervous system causing mydriasis (dilated pupils), increased body temperature and increased level of blood sugar.
There is little knowledge of the biochemical mechanisms that cause the LSD psychic effects. The main danger of LSD lies not in its toxicity, but on its unpredictable psycho-physical effects. Since the first intake, on subjects with prior psychiatric troubles or psychologically weak, the LDS can bring out psychosis and other serious mental disorders as dissociative states, paranoia, panic, anxiety and mood-alterations.
Even in healthy subjects the abuse of this drug can, for various reasons (eg: personal condition, inadequate environment, excessive frequency of intake ...) lead to a severe mental confusion, like impaired perception and judgment, that may drive to accidents and dangerous actions, or death of the subjects themselves or others (people assume they can fly, they are launched into space, etc..).
Dizziness and nausea are possible. It is often found fake LSD containing the wrong amounts of acid. An overdose of these substances can cause bad trips, with strong agitation, anxiety, paranoia, panic disorder with psychological consequences that can be severe and affect the psychological balance of the person permanently.
Insomnia may occur for 1 or 2 days. The usual methods (relaxation, chamomile) can give a substantial help.
LSD does not induce physical dependence, but it has proved the onset of tolerance (and you'll need increasing doses to feel the same effects) and a risk of psychological dependence.
Permanent brain damage hasn't been scientifically linked to the abuse of LSD, but often arise, especially in those subjects who have not completed their psychological development. These damages may impair the mental balance, triggering depression, insomnia, psychosis and paranoid disorders.
Tiredness and irritability appear when the effect fades away. The ideal would be to take a day off. In difficult conditions, if the context or the environment are not reassuring, there is the risk of developing a depressive tendency.
A couple of days after the assumption you may experience flashbacks. They can be completely random or due to a stimulus associated to the memories of the LSD intake and its effects may reappear and for brief moments you can relive the sensations caused by this substance. This can be dangerous if you are driving a vehicle or if you are undertaking any activity that requires attention. It is still not clear what causes these flashbacks but it is known that situations of physical and psychological stress can increase the likelihood of the event.
Timing of the effects: the minimum dose able to produce a hallucinogenic effect in humans is estimated to be about 20μg. 150-400μg can cause powerful and heavy effects, while over 400μg the situation could become very dangerous.
LSD is, in terms of weight, one of the most powerful drugs known. The doses are then measured in micrograms (millionths of a gram). Most of the other drugs are normally measured in milligrams.
The rise time of the acid effects varies from 30 to 60 minutes. However, important phenomena rarely begin within a couple of hours, reaching their maximun after 3-4 hours. In 6 hours from the intake of LSD the sensations begin to fade. After approximately 8 hours the trip usually ends, although some residual effects may remain. With high doses the time duration can be increased and the effects can last even 12 hours.
BRAIN REWARDING AND DRUGS PATHWAYS
How does experimental use of substances of abuse lead to drug addiction in some individuals? How do these drugs cause intoxication? Part of the answer lies in a common reinforcement pathway in the human brain which drugs of abuse stimulate, potentially leading to addiction. This reinforcement pathway, which is composed of both central nervous system structures and endogenous neurotransmitters communicating between these structures, has been termed the “reward pathway”. The reward pathway evolved to promote activities that are essential to the survival of the human race as well as other mammals.
One may compare the mechanism of drugs of abuse with that of viruses. Viruses and drugs of abuse are both foreign to humans. Viruses enter an animal’s cells and use the pre-existing cell “machinery” to synthesize more viruses, thus promoting their own survival. As the viruses infect more and more cells, the organism may become ill. Illicit drugs can take advantage of an organism in a similar fashion. Just as viruses take over cell function throughout the body, drugs of abuse modify cell function in these important brain structures leading to modifications in behavior. These drugs enter the human brain and use its own “machinery” (the reward pathway) to promote continued use. Just as the cell’s survival is dependent on its “machinery” so is the survival of the organism dependent on an intact brain reward pathway. Drugs of abuse, although harmful to the organism, are able to capture this “machinery “ in some individuals driving further drug use.
Depending on our own characteristics (our inherited neurochemical make-up etc.) we may be more susceptible to the illness of drug addiction just as certain people are more susceptible to infection. Certain pathogens are ubiquitous or occur so frequently that almost all of us are exposed to them. Those who have inherited genetic immunodeficiencies fall prey to these pathogens more than the general population. Similarly, individuals who have a genetic predisposition, may be more vulnerable to addiction after exposure to the drug.
As noted earlier, substances of abuse affect the brain reward pathway, which is made of neurons that release chemicals when they are stimulated. This release leads to subjective feelings of well being. This brain reward system evolved to subserve activities essential to species survival, such as sexual activity and feeding behaviors. Activities that activate this pathway become associated with ‘feeling good’. For example, sexual intercourse causes release of chemicals activating this pathway, and the result is a feeling of well being. Thus, the reward pathway serves to promote survival of the species by rewarding behaviors necessary for continued survival (seeking food, reproduction, shelter, drink, etc). Drugs of abuse stimulate this “brain reward” pathway in a similar fashion, and this is why substance users experience feelings of pleasure or “high” when they use them. When drugs of abuse are repeatedly used, they may “commandeer” the brain reward system, driving compulsory drug use to the exclusion of other adaptive activities. Thus, “addiction” can be partially explained by the action of drugs of abuse on this common reward pathway, in which drug use stimulates further use and drug seeking behavior.
As already mentioned previously, LSD acts as an agonist of serotonin, the molecule responsible for different pathways in the brain.Serotonin is an neurotransmitter that is affected by many of the drugs of abuse, including cocaine, amphetamines, LSD, and alcohol. Serotonin is produced by neurons in the Raphe nuclei. Raphe nuclei neurons extend processes to and dump serotonin onto almost the entire brain, as well as the spinal cord. Serotonin plays a role in many brain processes, including regulation of body temperature, sleep, mood, appetite and pain. Problems with the serotonin pathway can cause obsessive-compulsive disorder, anxiety disorders, and depression. Most of the drugs used to treat depression today work by increasing serotonin levels in the brain.
Neuroanatomy and Physiology of the “Brain Reward System”
Beyond the Reward Pathway,Study by University of Utah
PARANOID DELUSION
To be paranoid is to have great fear or anxiety about something. Having delusions means believing something that is not true and is possibly far-fetched. Taken together, paranoid delusions create fearfulness or anxiety, amplified by feeling or believing things that are false. It’s often thought paranoid delusions are only present in illnesses like schizophrenia, but other illnesses may feature them. The most common illnesses associated with paranoid delusions are schizophrenia, paranoid personality disorder, delusional disorder and bipolar I, which may show such symptoms during mood swings.
Some examples of paranoia may include people believing they are privately or publically someone of extreme importance (fact or fiction); that others, including those otherworldly are attempting to harm them, that they have a special relationship with someone, particularly someone famous, or that they believe a specific person is hurting them with behaviours such as infidelity. These delusional stances stand quite opposed to repeated demonstration of evidence to the contrary.
Paranoid delusions can lead people to act in a number of self-damaging ways. A belief of being able to fly could lead a person to attempt to do so; paranoid jealousy could destroy a relationship. Other characteristics may be present with delusions, making life much more difficult. Depending on other conditions present, a person might hear voices, hallucinate, have additional phobias, or be quite unable to function at most times. Though often mocked because beliefs can seem so outlandish, paranoia is truly no joke, and can destroy the chance for living normally while it exists.
How paranoid delusions get treated may depend on the underlying condition. In many instances, medicines called anti-psychotics are used to help tame this symptom and other symptoms like hallucinations, which may or may not be present. Mood stabilizers are used in the treatment of bipolar disorder to prevent cycling moods that might produce paranoid states.
Additional support is necessary for people through counseling. Though a biological component may exist for paranoid delusions, they may also spring from traumatic experiences, that when processed, help to produce more normalized thinking. No single treatment or single medicine is appropriate for all cases and significant work in therapy requires the cooperation of the person suffering from these delusions to address stabilization.
People suffering from what they believe to be paranoid delusions may want to begin by speaking to a psychiatrist, who may help with medication and can provide initial or ongoing therapy. Should a delusion be so severe that it suggests a person must die or commit self-harm, they should immediately contact emergency services or emergency psychiatric services in their community to get the help they need. Of course, the nature of these delusions is that people greatly believe in them, and they may be unwilling to take this step. When danger is suspected, friends or family are advised to try to help by getting in touch with professionals for advice.
ADDICTION AND TOLLERANCE
There isn't a real addiction to LSD, or at least not from the chemico-physical point of view. However a dependence can exist in a psychological form. Moreover, LSD tolerance grows very quickly and you must increase the dose to take after the first experiences. If the employment continues, it will take up to 10-20 times the normal dose to achieve the original effects.
LSD tolerance is directly proportional to the age of the subject, so adults have lower risk of depending on the drug. The problem is that in recent years the use of that substance has been gradually increasing among adolescents.
National Survey on Drug Use and Health
LSD EFFECTS ON ATTENTION AND ITS DEFICIT
A recent study has investigated the relationship between ADHD, attention deficit hyperactivity disorder, symptoms and cigarette smoking, alcohol use and illicit drug use, mainly hallucinogens. The participants were 10,987 students from 14 to 16 years old in the final three years of their compulsory education in Iceland. The participants completed questionnaires in class relating to anxiety, depression and antiestablishment attitudes, ADHD symptoms, smoking, alcohol consumption and illicit drug use. The results was that of the total sample, 5.4% met screening criteria for ADHD. Smoking, alcohol and illicit drug use were significantly related to ADHD symptoms. In addition, the number of different illicit drugs consumed was significantly higher among the ADHD symptomatic than the nonsymptomatic participants, including the illicit use of sedatives. The main distinguishing illicit drug substances were lysergic acid diethylamide (odds ratio or OR = 8.0), cocaine (OR = 7.5), mushrooms (OR = 7.1) and amphetamines (OR = 6.5). Logistic multiple regressions showed that after controlling for gender and school grade, ADHD symptoms predicted smoking, alcohol use and illicit drug use independent of anxiety, depression and antiestablishment attitudes. The findings underscore the vulnerability of young persons with ADHD symptoms to smoking, alcohol and illicit drug use, possibly as a means of self-medication, and emphasize a need for early identification and treatment to reduce the risk of escalation.
Journal of Child Psychology and Psychiatry
Link between substance use and ADHD
