Hallucinogens are drugs which cause an altered state of consciousness that is characterized by distortions of perception, hallucinations or visions, ecstasy, dissolution of self boundaries and the experience of union with the world. Depending on the set (the individual taking the drug), the setting (the place where the drug is taken) and the drug dose, the effects could be very different.
Psychedelics usually derive from vegetables and for this reason they were widely used by indigenous cultures in medical and religious practices; they are still employed in some parts of South America, such as Mexico or Peru. (The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 2010 )
HISTORY.
After the breakthrough discovery of lysergic acid diethylamide (LSD) by Albert Hoffman in 1938, a lot of studies were carried out to prove the therapeutic potential of psychedelics. In the 1950s, the psycholytic and the psychedelic therapy models used hallucinogen-assisted treatment to enhance the standard psychotherapeutic process. While the psycholytic method used low to moderate doses and frequent sessions, the psychedelic method used higher doses in fewer sessions to induce a mystical experience, which often led to changes in emotional response and behavior by enabling participants to work through and integrate difficult feelings and situations. (Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012 )
Unfortunately, their abuse for recreational purposes during the 1960s and the 1970s led to the halt of research in that field (as a matter of fact, hallucinogens were depicted as highly dangerous and placed in schedule in many countries). Despite that, a renewed interest in research with psychedelics has increased since the 1990s. (The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 2010 )
TWO CLASSES OF HALLUCINOGENS.
We can divide hallucinogens into two classes: the classical hallucinogens and the dissociative anaesthetics. The first ones comprise LSD, an ergotamine derived, psilocybin, contained in the so called “magic mushrooms”, dimethyltryptamine, consumed by indigenous Amazonian Amerindian cultures through the consumption of ayahuasca (a beverage created from a mixture of the vine “Banisteriopsis caapi” and the bush “Psychotria viridis”), and mescaline, contained in the peyote cactus. The second ones consist of ketamine and phencyclidine (PCP). (Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012 )
PHARMACOKYNETICS.
Psychedelics behave as serotonin 5HT-2A receptors agonists (principally), as antagonists of NMDA receptors, as kappa opioid receptor agonists and as muscarinic acetylcholine receptor antagonists.
The hallucinogenic activity of classical psychedelics is mediated by their action on 5HT-2A serotonin receptors, which lead to neuroplastic adaptation. Actually, they not only bind to this subtype of serotonin receptors, but their action on other subtypes is much lower. Stimulation of 5HT-2A receptors causes activation of pyramidal cells in cerebral cortex.
Classical hallucinogens may have secondary effects on the glutamatergic system: psilocybin, LSD and mescaline increase extracellular glutamate levels in the prefrontal cortex through stimulation of serotonin 5HT-2A receptors located on glutamatergic pyramidal cells in deep cortical layers projecting to layer V pyramidal neurons. This glutamate release leads to the activation on AMPA and NMDA receptors on cortical pyramidal neurons. By means of this two pathways, the expression of the brain-derived neurotrophic factor (BDNF, a protein that encourage the growth and differentiation of new neurons and synapses; Brain-derived neutrophic factor) increases. (The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 2010 )
According to the “agonist trafficking of receptor signaling theory” of Moreno et al., the activation of the 5TH-2A/mglu2 heterocomplex by hallucinogens is necessary for their pharmacological and behavioral effects. (Psilocybin--summary of knowledge and new perspectives. 2013)
Dimethyltryptamine has been shown to bind sigma-1 receptors, which are chaperone proteins at the Endoplasmic reticulum. (When the Endogenous Hallucinogenic Trace Amine N,N-Dimethyltryptamine Meets the Sigma-1 Receptor. 2009)
This receptors are implicated in lots of mechanisms, including schizofrenia, depression, the effects of cocaine abuse and cancer. (Sigma-1 receptor.)
Psilocybin also indirectly increases, via 5HT-2A receptors, striatal dopamine concentration, by acting on D2, D3 and D4. However, dopamine is not the primary mediator of hallucinogenic effects, because haloperidol (an antagonist of D2, D3 and D4 receptors) decreases the effects of psilocybin by only 30%. The effects on the ventral striatum are correlated with symptoms of depersonalization and euphoria. (Psilocybin--summary of knowledge and new perspectives. 2013)
The result of all these mechanisms is an increase in prefrontal network activity.
As regards dissociative anaesthetics (ketamine and phencyclidine), they primarily block inhibitory GABA-ergic interneurons in cortical and subcortical brain areas, leading to enhanced firing of glutamatergic projection neurons and increased extracellular glutamate levels in the prefrontal cortex. Ketamine also blocks NMDA receptors on cortical pyramidal neurons, so the increased glutamate release in the cortex is thought to stimulate cortical AMPA more than NMDA receptors. (The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 2010 )
Also in this case there is an increased expression of BDNF and an increase in prefrontal network activity, as well as in its interaction with subcortical stations.
THE IMPORTANCE OF SET, SETTING AND SUBSTANCE.
The effects caused by hallucinogens depend on three factors:
1. The substance: the dose, the frequency of administration and the quality of assimilation of the hallucinogen;
2. The set: it consists of the expectation of the participants, their psychiatric and physical conditions, their psychological readiness for undergoing non-ordinary states of consciousness and the preparation for the experience;
3. The setting: the nature of the environment in which the treatment takes place, but also the quality of containment and guidance of the experience and the appropriateness of the broader therapeutic framework.
(Therapeutic effects of ritual ayahuasca use in the treatment of substance dependence--qualitative results. 2014)
The complications that can occur during psychedelics experiences can be significantly reduced by controlling these three factors. As a matter of fact, although these substances are not addictives and do not cause known physical side effects, psychological side effects (anxiety, paranoid experiences, derealization, depersonalization, long lasting unpleasant experiences, psychotic reactions and hallucinogen persisting perception disorders) can occur.
HALLUCINOGENS USE IN THE TREATMENT OF DEPRESSION AND ANXIETY DISORDERS.
5HT-2A serotonin receptors were found to be increased in the prefrontal cortex in post-mortem and in vivo patients with major depression. Therefore, the employment of repeated doses of LSD, that down regulate the expression of 5HT2A receptors, could be seen as a treatment for depression, anxiety and chronic pain. (The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 2010 )
Furthermore, reduced prefrontal glutamate levels (associated with attenuated prefrontal cortex activation in response to emotional stimuli) were found in patients with depression, suggesting a deficit in neuroplastic mechanisms controlling the expression of glutamate receptors. These individuals may suffer from decrease top-down inhibition of amygdale (a nucleus involved in emotional reactions) activity, leading to an exaggerated reaction to the presentation of images showing sad faces. Psychedelics lead to an increased expression of AMPA glutamate receptor trafficking and to a rise in the level of the brain derived neurotropic factor (BNDF), which could fill the deficit affecting the patients affected by depression. (The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 2010 )
These adaptations may explain some of the antidepressant effects observed in clinical studies with ketamine and psilocybin. In several studies ketamine has proved to be useful to improve symptoms of depression in patients with treatment-resistant major depression and bipolar depression. The effects of ketamine, lasting a week or more, seem to be related to the increased activity of AMPA receptors relative to NMDA receptors. In particular, stronger antidepressant effects are found in patients with family history of alcohol dependence. (Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012 ) In particular, ketamine administration was found to be helpful for suicide victims because, in contrast with conventional antidepressants (acting in 2-3 weeks), it acts in 24 hours. However, more studies should be carried out on the potential of ketamine in the treatment of suicide victims, because of contrasting results. (The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 2010 ) Whereas, after the administration of psilocybin, the patients reported significantly increased current personal well-being or life satisfaction, as well as positive attitudes about one’s life and oneself. The positive mood changes following the psilocybin session showed a dose-related pattern. (Psilocybin--summary of knowledge and new perspectives. 2013 ; Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012)
Due to their potential effects against depression and anxiety, hallucinogens were proposed as an adjunct to psychotherapy in patients with life-threatening illness. Clinical trials with LSD (Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. 2014), ketamine and psilocybin were carried out, especially on end-stage cancer patients. In 2011, Grob led a pilot study in which he administered psilocybin to terminally ill cancer patients. The positive results of the treatment were not demonstrated, although the low dose of hallucinogen may have limited the efficacy of the process. (Psilocybin--summary of knowledge and new perspectives. 2013)
These studies suggest the potential of these three hallucinogens in reducing anxiety and depression in patients with life-threatening diseases. Despite that, more trials should be carried out.
HALLUCINOGENS USE IN THE TREATMENT OF SUBSTANCE DEPENDENCE.
Most of the experiments during the 1950s and the 1960s where led to evaluate the potential of psychedelics in the treatment of addiction, especially in the treatment of alcoholism. Indeed, their association with traditional psychotherapeutic methods seems to accelerate this process.
In a 2012 clinical trial performed on a group of alcoholics, a single dose of LSD, unlike what happened in control cases, had a significant beneficial on alcohol misuse in the short-term (3 months after treatment) and in the medium-term (6 months after treatment), as well as a beneficial effect of LSD on abstinence was seen at short- and at medium-term follow-up. Moreover, the maintained abstinence from alcohol in this individual, after LSD, was higher compared to control treatments.(Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012 ; Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. 2012)
The effects of LSD are similar to those of mescaline (contained in peyote and other psychedelic cactus), psilocybin (magic mushrooms) and dimethyltryptamine (ayahuasca). Regular consumption of peyote and ayahuasca has been claimed by indigenous groups to be helpful in maintaining sobriety from alcohol and other addictive drugs. Several studies have shown decreased rates of alcohol dependence among members of religions that use classical hallucinogens as a regular part of their practice, including the Native American Church, which uses the peyote as a sacrament, and both Brazilian and US sects using ayahuasca. (Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012 )
Ayahuasca-assisted treatment for substance dependence is currently offered in several countries of the American continent, including Peru, Brazil, Ecuador, Colombia, Argentina, Chile and Mexico. According to the experience of some therapists ayahuasca can catalyze therapeutic processes, making them shorter and more effective. (Therapeutic effects of ritual ayahuasca use in the treatment of substance dependence--qualitative results. 2014)
Ketamine has been investigated in Russia as a potential treatment for both alcohol and heroin dependence. Alcoholics who volunteered to receive ketamine-assisted psychotherapy showed significant higher rates of abstinence at one year; in the same way, a decrease in anxiety and depression was found in heroin addicts for at least six months, while a higher dose of ketamine induced a greater and more enduring reduction in craving. (Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012 )
The reason of the success of hallucinogens towards addiction is due to their effects on patients’ psyche. These acute psychological effects have the potential to contribute to lasting changes in the individual, including changes in addictive behavior. By the means of mystical experiences inflicted by hallucinogens, patients seem to be able not only to understand the futility of the use of substances in solving their problems, but also to bring to mind, take note and finally overcome the mechanisms and the events that led to the onset of addiction. The positive change in mood achieved by these experiences results in lower use of various substances. In fact, depression and anxiety are often related to substance abuse, although this has not been fully tested. In addition, these experiences can cause a larger opening and a decrease in neuroticism, two other factors related to substance abuse. All this results in an increase in self-efficacy, that is to say the patient has more confidence in himself, especially with regard to the possibility of interrupting the dependence, and with an increase in the motivation to stop. (Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012 ;"Therapeutic effects of ritual ayahuasca use in the treatment of substance dependence--qualitative results. 2014":http://www.ncbi.nlm.nih.gov/pubmed/24830187)
Furthermore, serotonergic neurotransmission is involved in the modulation of craving. Therefore, medications increasing central serotonergic activity, such as hallucinogens, could theoretically reduce craving and relapse. As a matter of fact, in the animal models ethanol consumption decreased as serotonergic activity increased, and consumption increased with reductions in serotonergic activation. Indeed, SSRI antidepressants (selective serotonin reuptake inhibitors) seem to reduce craving for alcohol under some circumstances. (Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012 )
Moreover, classical hallucinogens, through their action on 5HT-2A receptors, increase the levels of brain-derived neurotrophic factor (BNDF) and glial cell line-derived factor (GDNF). This effect leads to the stabilization of some synapsis in affected regions. This could be significant in treating alcoholism, because GDNF and BNDF levels have been found to be inversely related to alcohol consumption in animal models. (Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. 2012 )
HALLUCINOGENS AND OBSESSIVE-COMPULSIVE DISORDERS (OCD).
Obsessive-compulsive disorder is a chronic condition characterized by disturbing, intrusive thoughts and compulsive rituals. Serotonin plays a role in OCD (obsessive compulsive disorder) symptom reduction. (Psilocybin and Obsessive Compulsive Disorder. 2014 )
Case reports and clinical trials have reported improvement of obsessive-compulsive disorder symptoms after psilocybin administration. A study by Moreno and collagues demonstrated that the use of psilocybin on patients affected by OCD, and previously treatment resistant, leads to a reduction of symptoms of OCD only two hours after the peak of psychedelic effects. However, no real test of efficacy has been demonstrated. (The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. 2010 )
Here is an experience of a 38 year-old male affected by an obsessive-compulsive disorder, who, after years of inconclusive therapies, suggested by a friend, began to consume some “magic mushrooms” labeled as “psilocybin cubensis” trying to calm down the symptoms of his disease, which prevented him from living a peaceful life. The subject found the immediate experience to be unpleasant and anxiety-provoking; however, the next day, his intrusive thoughts were significantly reduced. The patient reported relief from anxiety and rituals as well. This individual reported that each time that he ingested approximately two grams of psilocybin mushrooms, he experienced about three weeks of relief and denied side-effects or emotional distress from the use of psilocybin. Despite this encouraging report, we can not know if these mushrooms were actually of the psilocybin type and the fact that this individual had no medical or scientific supervision during his self-experimentation does not guarantee the veracity of this testimony. Therefore, more scientific research should be performed to prove the potential use of psilocybin in the treatment of OCD. (Psilocybin and Obsessive Compulsive Disorder. 2014 )
HALLUCINOGENS AND HEADACHES.
Mushrooms containing psilocybin seem to improve individual attacks and stop the cycle of cluster headaches attacks. A possible explanation of this effect is the reduction in blood flow to the hypothalamus induced by the psilocybin or the activity of psilocybin at 5HT1B/D receptors. However, further research will be necessary to clarify this prospective. (Psilocybin--summary of knowledge and new perspectives. 2013)
Moreover, various researches, carried out by the fisician Torsten Passie, suggest that LSD, as well as psilocybin, may prevent cluster headaches. In addition, Passie promoted the development of the Bromo-LSD (a derivative of lysergic acid invented by Albert Hofmann) as a medicine for painful and debilitant headaches. (From Hofmann to the Haight Ashbury, and into the future: the past and potential of lysergic acid diethlyamide. 2014)
CONCLUSION.
The results of several studies and clinic trials suggested a potential use of hallucinogens in the treatment of dependences, depression, anxiety, obsessive-compulsive disorders and headaches. Obviously, psychedelics should not be understood as primary psychological interventions, but they should be considered as catalysts with a therapeutic value, when the set and the setting are properly managed.
