PSYCHOTROPIC PLANTS AND PSYCHIATRY STUDY GUIDE

Theme - ANSWERSHallucinations and psychiatry lecture Can psychedelics have a role in psychiatry once again? BEN SESSA - ANSWERSPsychedelic or hallucinogenic drugs such as lysergic acid diethylamide (LSD), 3,4,5- trimethoxy-b-phenethylamine (mescaline), psilocybin, 3,4-methylenedioxymethamphetamine (MDMA), N,N-dimethyltryptamine (DMT) and their relations occur in abundance throughout the natural world, and have been used by humankind for thousands of years. In some cultures they are important tools for spiritual experiences, whereas in others they are labelled as dangerous drugs of misuse. What is less well known about these substances is the role they played in psychiatry for a brief historical interval. This article offers a short overview of this period and questions whether interest in these compounds might be emerging again.Initial work explored the possibility that psychedelics might be used as 'psychotomimetics', to mimic the mental states of patients with schizophrenia (Osmond, 1957), and many health professionals were encouraged to partake in self-discovery or shared psychedelic experiences with their patients. Other research looked into using psychedelic drugs as adjuncts to psychotherapy. The therapy took the form of two broad types: first, psycholytic ('mind loosening') psychotherapy involved taking low doses of LSD as part of ongoing psychoanalytical therapy. The drug had a loosening effect and facilitated the exploration of repressed materialThe second type, psychedelic ('mind manifesting') psychotherapy involved preparation sessions without LSD, then one single large-dose session that encouraged an intense reaction, followed by further non-drug sessions to explore the meaning of the material that emerged (Grinspoon & Bakalar, 1997). Charles S. Grob, M.D. 1998 - ANSWERSHallucinogens, throughout the breadth of time, have played a vital albeit hidden and mysterious role. They have often, in aboriginal and shamanic contexts, been at the absolute center of culture and world view (Dobkin de Rios, 1984). Opening up the doors to the spiritual planes, and accessing vital information imperative to tribal cohesion and survival, hallucinogenic plants became what some scholars have considered to be the bedrock of human civilization (Wasson, 1968; Wasson et al, 1978; Huxley, 1978). Within the context of shamanic society, these awe inspiring botanicals were utilized to facilitate healing, divine the future, protect the community from danger and enhance learning (e.g. teaching hunters the ways of animals) (Cordova-Rios, 1971).Hallucinogenic plants with magical as well as healing properties were essential elements of this indigenous pharmacopoeia. Members of the Solanaceae family with their alkaloids atropine and scopolamine, including a great number of species of the genus Datura, as well as mandrake, henbane, and belladonna, had wide application as agents of healing and transcendence (Harner, 1973). In taking action against the indigenous use of psychotropic plants, the Church sought to eliminate a perceived threat to its oligarchic powers and reassert its monopoly on legitimate access to the supernatural (O'Neil, 1987).As plant hallucinogens were attributed to have supernatural powers, they were quickly perceived by the European invaders as weapons of the Devil designed to prevent the triumph of Christianity over traditional Indian religion (Furst, 1976). An early Seventeenth Century Spanish observer of native customs, Hernando Ruiz de Alarcon, wrote of the idolatries he observed involving the consumption of the morning glory: "Olouihqui is a kind of seed-like lentils produced by a type of vine i The Psychotomimetic Model - ANSWERSPreoccupation with the hallucinogen induced psychotomimetic model continued through the 1950's. The psychotomimetic position was summarized by one its leading proponents, Harvard psychiatrist Max Rinkel: "The psychotic phenomena produced were predominantly schizophrenia-like symptoms, manifested in disturbances of thought and speech, changes in affect and mood, changes in perception, production of hallucinations and delusions, depersonalizations and changes in behavior. Rorschach tests and concrete abstract thinking tests showed responses quite similar to those obtained with schizophrenics" (Rinkel and Denber, 1958)., it became increasingly apparent, however, that although an impressive array of psychiatric researchers and theoreticians had elucidated and elaborated upon the startling degree of resemblance between schizophrenia and the hallucinogenic experience, a growing consensus was emerging that the dissimilarities between the two states essentially obviated the value of the chemical psychosis model (Grinspoon and Bakalar, 1979). Speaking at the First International Congress of Neuropsychopharmacology in 1959, the legendary Manfred Bleuler enunciated the central argument in opposition to the psychotomimetic model. He stated that it was the gradual and inexorable progression of a symptom complex that included disturbed thought processes, depersonalization and auditory hallucinations, evolving into a generalized functional incapacitation that was characteristic of schizophrenia. He concluded with the demonstrative declaration that although the psychotomimetic drugs may have strengthened our conceptual understanding of organic psychoses, they have "contributed nothing to the understanding of the pathogenesis of schizophrenia" (Bleuler, 1959). The Psycholytic Treatment Model - ANSWERSIn subjects given a relatively low dose of LSD, there appeared to occur a release of repressed psychic material, particularly in anxiety states and obsessional neuroses. By allowing this otherwise repressed and threatening material to flow effortlessly into consciousness, investigators surmised that low dose LSD treatment could facilitate the psychotherapy process (Stoll, 1947). Application of the low dose model in Europe as well as the United States ascertained that psycholytic treatment had particular value with patients with rigid defense mechanisms and excessively strict superego structures. By facilitating ego regressionuncovering early childhood memories, and inducing an affective release, psychiatrists claimed to have achieved a breakthrough in reducing the duration and improving the outcome of psychotherapeutic treatment (Chandler and Hartmann, 1960).Problems arose with the psycholytic paradigm, however, as critics noted that the content of regressed material released from the unconscious was extremely sensitive to the psychiatrist's own analytic orientation, in most cases Freudian or Jungian. Questions arose over whether the phenomena observed in the psychotherapeutic sessions, including the often positive treatment outcome, were not simply attributable to the presence of heightened powers of suggestibility. Moreover, with psycholytic treatments, care had to be taken to utilize sufficiently low dosages of the hallucinogen that the patient's ego would not be overwhelmed to the point where verbal analysis would be inhibited. When in the course of psycholytic psychotherapy higher dosages were utilized, the resultant experience could no longer be contained within the intended theoretical framework, thus necessitating delineation of an entirely new paradigm.In response to escalating fears that hallucinogens had bec Franz X. Vollenweider and Michael Kometer 2010 - ANSWERSHowever, research into psychedelics did not begin until the 1950s after the breakthrough discovery of the classical hallucinogen lysergic acid diethylamide (LSD) by Albert Hofmann2 (timeline). The classical hallucinogens include indoleamines, such as psilocybin and LSD, and phenethylamines, such as mescaline and 2,5-dimethoxy-4-iodo-amphetamine (DOI). Research into psychedelics was advanced in the mid 1960s by the finding that dissociative anaesthetics such as ketamine and phencyclidine (PCP) also produce psychedelic-like effects3 (BOX 1). Given their overlapping psychological effects, both classes of drugs are included here as psychedelics.Depending on the individual taking the drug, their expectations, the setting in which the drug is taken and the drug dose, psychedelics produce a wide range of experiential states, from feelings of boundlessness, unity and bliss on the one hand, to the anxietyinducing experiences of loss of ego-control and panic on the other hand4-7. Researchers from different theoretical disciplines and experimental perspectives have emphasized different experiential states. One emphasis has been placed on the LSD-induced perceptual distortions — including illusions and hallucinations, thought disorder and experiences of split ego7,8This perspective has prompted the use of psychedelics as research tools for unravelling the neuronal basis of psychotic disorders, such as schizophrenia spectrum disorder. The most recent work has provided compelling evidence that classical hallucinogens primarily act as agonists of serotonin (5-hydroxytryptamine) 2A (5-HT2A) receptors12 and mimic mainly the socalled positive symptoms (hallucinations and thought disorder) of schizophrenia10Emphasis has also been placed on the early observation that LSD can enhance self-awareness and facilitate the recollection of, and r Several preclinical studies in the 1990s revealed an important role for the NMDA glutamate receptor in the mechanism of action of antidepressants - ANSWERSThese findings consequently gave rise to the hypothesis that the NMDA-antagonist ketamine might have potential as an antidepressant24. This hypothesis was validated in an initial double-blind placebo-controlled clinical study in seven medication-free patients with major depression. Specifically, a significant reduction in depression scores on the Hamilton depression rating scale (HDRS) was observed 3 hours after a single infusion of ketamine (0.5 mg per kg), and this effect was sustained for at least 72 hours25. Several studies have since replicated this rapid antidepressant effect of ketamine using larger sample sizes and treatment- resistant patients with depression26-30. Given that 71% of the patients met response criteria (defined as a 50% reduction in HDRS scores from baseline) within 24 hours26, this rapid effect has a high therapeutic value. In particular, patients with depression who are suicidal might benefit from such a rapid and marked effect as their acute mortality risk is not considerably diminished with conventional antidepressants owing to their longdelay in onset of action (usually 2-3 weeks). Indeed, suicidal ideations were reduced 24 hours after a single ketamine infusion28. However, despite these impressive and rapid effects, all but 2 of the patients relapsed within 2 weeks after a single dose of ketamine26. Previous relapse prevention strategies, such as the administration of either five additional ketamine infusions29 or riluzole (Rilutek; Sanofi-aventis) on a daily basis30, yielded success only in some patients andother strategies should be tested in further studies. Moreover, the use of biomarkers that are rooted in psychopathology, neuropsychology and/or genetics might help to predict whether ketamine therapy will be appropriate for a given patient with depression31. In line with this idea, de recent study by Moreno and colleagues37 evaluated case reports and findings from studies performed in the 1960s that indicated that psilocybin and LSD are effective in the treatment of OCD22,38 - ANSWERSThey subsequently carried out a study showing that psilocybin given on four different occasions at escalating doses (ranging from sub-hallucinogenic to hallucinogenic doses) markedly decreased OCD symptoms (by 23-100%) on the Yale-brown obsessive compulsive scale in patients with OCD who were previously treatment resistant37. The reduction in symptoms occurred rapidly, at about 2 h after the peak psychedelic effects, and endured up to the 24-h post-treatment rating37. This symptom relief was not related to the dose of the psych edelic drug or to the intensity of the psychedelic experience, and extended beyond the observed acute psychological effect of 4-6 h, raising intriguing questions regarding the mechanisms that underlie this protracted effect37. Further research on how this initial relief of symptoms in response to psilocybin — and the subsequent return of symptoms — is linked to functional changes in the brain could contribute not only to a mechanistic explanation of the potentially beneficial effects of psychedelics but also to the development of novel treatments for OCD. Encouraged by early findings (BOX 2), several clinical centres have begun to investigate the potential beneficial effects of psilocybin (ClinicalT: NCT, NCT and NCT) and LSD (ClinicalT: NCT) in the treatment of anxiety and depression in patients with terminal cancer, using state of the art, double-blind, placebo-controlled designs. - ANSWERSOne of these studies has recently been completed and revealed that moderate doses of psilocybin improved mood and reduced anxiety and that this relief variably lasted between 2 weeks and 6 months in patients with advanced cancer (C.S. Grob, personal communication). Finally, another recent study reported that psilocybin and LSD aborted attacks, terminated the cluster period or extended the remission period in people suffering from cluster headaches41. Taken together, these findings support early observations in the 1960s that classical hallucinogens have antinociceptive potential and may not only reduce symptoms but also induce long-lasting adaptive processes. The classical hallucinogens are comprised of three main chemical classes: - ANSWERSthe plant-derived tryptamines (for example, psilocybin) and phenethylamines (for example, mescaline), and the semisynthetic ergolines (for example, LSD)48. Although all classical hallucinogens display high affinity for 5-HT2 receptors, they also interact to some degree with 5-HT1, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 receptors12. In contrast to the tryptamines, the ergolines also show high intrinsic activity at dopamine D2 receptors and at α-adrenergic receptors49. Converging evidence from pharmacological50, electrophysiological51,52 and behavioural studies in animals53,54 suggests that classical hallucinogens produce their effects in animals and possibly in humans primarily through agonistic actions at cortical 5-HT2A receptors (FiG. 1aImportantly, administration of the 5-HT2A receptor antagonist ketanserin abolishes virtually all of the psilocybin-induced subjective effects in humans56. Recent studies have demonstrated that hallucinogenic and non-hallucinogenic 5-HT2A agonists differentially regulate intracellular signalling pathways in cortical pyramidal neurons and that this results in a differential expression of downstream signalling proteins, such as early growth response protein 1 (EGR1), EGR2 and β-arrestin 255,57. This suggests that further elucidation of hallucinogen-specific signalling pathways may aid the development of functionally selective ligands with specific therapeutic properties — for example, ligands that have antidepressant effects but no hallucinogenic effects.However, more recent studies suggest that stimulation of postsynaptic 5-HT2A receptors55,58,59 on a subpopulation of pyramidal cells in the deep layers of the PFC59 leads to an increase in glutamatergic recurrent network activity59,62. The increase in glutamatergic synaptic activity can be abolished not only by specific 5-HT2A antagonists but als Activation of 5-HT2A and 5-HT1A receptors in the medial PFC (mPFC) also has downstream effects on serotonergic and dopaminergic activity through descending projections to the dorsal raphe and the ventral tegmental area (VTA). - ANSWERSFor example, activation of 5-HT2A receptors in the mPFC increases the firing rate of 5-HT neurons in the dorsal raphe and of dopamine neurons in the VTA, resulting in an increased release of 5-HT in the mPFC58,66 and of dopamine in mesocortical areas67 in animals. In a study in humans, the hallucinogenic 5-HT2A agonist psilocybin increased striatal dopamine concentrations, and this increase correlated with euphoria and depersonalization phenomena68. blocking dopamine D2 receptors by haloperidol, however, reduced these effects by only about 30%. This suggests that the dopaminergic system contributes only moderately to the broad spectrum of psilocybin-induced psychological alterations56.Interestingly, 5-HT2A receptor activation not only seems to underlie the preponderance of the acute psychedelic effects of hallucinogens but may also lead to neuroplastic adaptations in an extended prefrontal-limbic network. For example, in rats a single dose of the hallucinogen DOI transiently increased the dendritic spine size in cortical neurons69 and repeated doses of LSD downregulated cortical 5-HT2A but not 5-HT1A receptors; effects that were the most pronounced in the frontomedial cortex and ACC70,71 Finally, with regard to the finding that LSD reduces anxiety and pain in cancer patients20, - ANSWERSprefrontal 5-HT2A density correlated with responses to tonic pain but not with responses to short phasic pain stimuli. This suggests a role of the 5-HT2A receptors in the cognitive evaluation of pain experiences86 and points to additional therapeutic potential for hallucinogens in individuals with chronic pain.According to current models of emotion regulation the PFC, including the ACC, exerts 'cognitive', top-down control over emotion and stress responses through its connections to the amygdala and dorsal raphe47,85. Reduced prefrontal glutamate levels that are associated with attenuated PFC activationin response to emotional stimuli34,112,113 have been reported in patients with depression. Further, depressed individuals46 and subjects with high trait anxiety114 show reduced PFC activity when executive control is engaged, and might suffer from decreased topdown inhibition of amygdala activity115,116. Conversely, chronic treatment with selective serotonin reuptake inhibitors (SSRIs) increases the functional connectivity between the amygdala and the PFC117, and attenuates the amygdala response to the presentation of images showing sad faces in patients with depression118,119. This suggests that the normalization of this dysregulated network might be important in the recovery from depression46 Given that both psilocybin and ketamine increase extracellular glutamate levels in the prefrontal-limbic circuitry in rats and that the antidepressant effects of both drugs outlast their acute psychotropic effects in depressed patients, - ANSWERSwe propose that a normalization of this network through a glutamate-dependent neuroplastic adaptation is the common therapeutic mechanism of these drugs. Specifically, we posit that psychedelics enhance neuroplasticity by increasing AMPA-type glutamate receptor trafficking and by raising the level of brainderived neurotropic factor (bDNF). Deficits in these neuroplastic mechanisms have been implicated in the pathophysiology of depression34,120. Normalization of these neuroplastic deficits might contribute not only to the relatively sustained antidepressant effects of ketamine121,122 but also to those of psilocybin. In addition, to optimize the clinical benefits of psychedelics and to reduce their unwanted side effects, a deeper understanding of various factors is necessary. - ANSWERSThese include structure-activity relationships, dose- response relationships and the influence of psychotherapeutic approaches on the effects of psychedelics. In this context, it is interesting to note that there was no indication of prolonged psychosis, persisting perception disorder or subsequent drug abuse after psilocybin126 or ketamine127 administration in a large sample of psychotherapeutically wellprepared healthy subjects in a supportive research setting. Similar observations were reported in small samples of patients with depression29 and OCD37. Nonetheless, it is often claimed that the dissociative effects of, for example, ketamine may limit clinical use, despite its reported efficacy24,94 Psychotropics - ANSWERSPsychotropics are an essential part of modern psychiatry. They help manage and treat a variety of mental disorders, including depression, schizophrenia and anxiety disorders. The wave of pharmaceutical drugs originally developed in the 1950s led to a variety of antidepressants, antipsychotics and many other types of drugs that altered neurotransmitters etc. These drugs are quite different to psychotropics originally used in psychiatric research, and have longer lasting, if less potent effects than hallucinogens associated with Psychiatry In the mid 19th century research began in earnest on the effect of certain plants on the human body, which helped indentify many different psychedelic compounds, including lophophorine, Pellotine, Anhalonidine, and Mescaline In 1959, St John's Wort, also known as Hypericum perforatum, a fairly common plant, began to be studied for it's ability to combat bacteria. It was eventually found to be a treatment for bacteria, and a study in 2005 found it to be significantly more effective than Prozac (Fava et al.) This is just one example of plants being used to aid the psychiatric process, and is by no means the most famous one. LSD and psychiatry - ANSWERSAfter LSD was originally marketed to psychiatrists in 1947, it was used to create what is known as the Psychotomimetic model as an aid in understanding psychotic symptoms in patients. It did this by using LSD and other psychotropics to induce schizophrenic like symptoms in subjects so that they could be observed, and changes in behaviour could be documented. Psycholytic treatment - ANSWERSThis research eventually led to what is known as psycholytic treatment, in which subjects were given small doses of LSD to help patients release repressed emotions and obsession neuroses. This was thought to aid the psychoanalytic process Neurotic patients, patients suffering from anxiety, depression, OCD, or various psychosomatic disorders were given LSD in slowly increasing doses while being subjected to Freudian style analysis. It was thought that using LSD would loosen the mind's natural defenses, allowing the patient to become aware of their unconscious thought patterns, and could start to therefore resolve problematic thought patterns. (Passie 1997;Grof 1980) This eventually led Grof (1985) to conclude that if used long enough, LSD in treatment could allow patients to experience highly traumatic birth and pre-birth memories. These were called the perinatal matrices. This idea has since been thoroughly debunked by researchers, as evidence suggests that infants lack the mental capacity to retain memories. However, it is important to note that this is still a method promoted in the media sometimes. Psychiatrist Humphrey Osmond worked with Abram Hoffer on treating alcoholism with LSD. Unlike psycholytic treatment, this psychedelic treatment relied on a small number of very high doses to simulate the experience of a life-changing realisation. They hoped that the unconscious mind would be manifested in hallucinatory images, which could leas to deep insight and therefore lifestyle transformation (Passie, 1997) Interestingly, a second wave of psychedelic therapy occurred in Southern California, where Sidney Cohen and Oscar Janiger provided similar experiences to clients in Hollywood (Novak, 1997). This eventually brought psychedelic treatment much notoriety in the mainstream media LSD illegalised...What next? - ANSWERSIn 1966 LSD became illegal in the USA and in the UK, and research dried up over the next few years. It was not allowed to continue until 1991. In the same time period Psilocybin was another drug used to treat anxiety and other conditions There were far fewer negative effects than LSD Phenethylamines - ANSWERSThe next major step in psychotropic assisted therapy was the discovery of phenethylamines by chemist Alexander Shulgin, such as MDA, MDMA and 2-CB. The key difference is that these drugs, when used, gave patients an expansion of awareness that was mainly emotional, with few perceptual changes. (Shulgin & Shulgin 1991) MDMA, or Ecstasy, was the most successful of these drugs when used with psychotherapy, helping patients build an open relationship with psychiatrists, and helping to repair disabling trauma. (Eisner, 1989) JOHN H. HALPERN Research 1996 - ANSWERSAbuzzahab and Anderson's 1971 review of 31 investigations from 1953 to 1969 on the effects of LSD on 1, I05 alcoholics (variably defined, with a mean length of alcoholism of 19.4 years) did reach some interesting conclusions.There are five studies noted in which a single LSD dose (mean 342 pg) was given to alcoholics and control groups (Jensen, 1962; Jensen et al., 1963; Johnson, 1969; Ludwig et al., 1969; Smart et al., 1966). Combined improvement in alcoholics is reported as 75% versus 43.7% of controls on a mean follow-up of about 10 months. As for the three studies in which multiple doses of LSD were given (MacLean et d., 1967; Osmond et al., 1967; Van Dusen et al., 1967) improvement was 57.5% for patients and 70.5% for controls after a mean follow-up of 20 months. The mean dose, unfortunately, could not be determined because MacLean et al. (1967) did not report the maximum total dose. Still it should be noted that the average follow-up in these three studies is twice as long as in the former five single-dose studies mentioned Such a contention supports the hypothesis that lysergamide (ex. LSD), indolealkylamine (ex. DMT, ibogaine, psilocybin), and/or phenethylamine (ex. mescaline, MDMA) hallucinogens offer anti-addictive properties that last an undetermined but finite average length of time. - ANSWERSSmart, Storm, Baker, and Solursh (1967), also admit that there has been "little consideration of the role of multiple doses of LSD in the treatment of alcoholism. . . . It is possible that a long series of administrations would have provoked more change." One of the better designed studies (Hollister, Shelton, and Krieger, 1969) had subjects (N = 72) randomly assigned to two groups in which one was given a single dose of 600 pg of LSD and the other 60 mg of dextroamphetamine. - ANSWERSNo psychotherapy was provided to either group, and LSD or amphetamine was administered double-blind. Both groups were independently rated for level of alcoholism on two and six month follow-up. At two months the investigators report a statistically significant (p < 0.01) improvement with the LSD treated group over the amphetamine group when comparing scores on a "Drinking Behavior Scale." This scale, formulated by the authors, is intended to be "based on the three general areas of drinking habits, social behavior, and occupational adjustment." At six months the two groups showed no difference. It is quite possible, then, that this hallucinogen had up to a two-month anti-addictive property with these alcoholics. If true, this would also explain why the single-dose LSD experiment of Smart, Storm, Baker, and Solursh (1 967) found no improvement in alcohol consumption in their well-designed, double-blind, placebo and drug controlled experiment (N = 30): follow-up of all subjects occurred at six and 18 months HALLUCINOGEN ADMINISTRATION IN THE TREATMENT OF OPIATE DEPENDENCE - ANSWERSSavage and McCabe ( 1973) did, however, track 74 narcotic addicts for one year with daily urine monitoring for continued abstinence. Subjects randomly assigned to the study group stayed for six weeks in a half-way house and were given several weeks of preparatory psychotherapy prior to being given a single moderate to high dose of LSD (200 to 500 pg). Controls were placed in an outpatient clinic program with weekly group psychotherapy. Other than the initial period of residential treatment culminating in LSD administration, study subjects and controls were treated identically. Their results after one year: 25% of the study group remained abstinent from opiates as opposed to only 5% of the control group (p < 0.05). The authors cautiously note that LSD was only one component of the six week initial therapy and as such "one is not able to say that it was the drug factors alone which accounted for the therapeutic yield." Indeed, the residential treatment given to the study group may have skewed these results. Still, it would appear that LSD had a distinct effect on outcome. They encouraged further research with hallucinogens in the treatment of narcotic addicts, but by 1973, when their study was published, human research with these controversial substances had essentially come to an end in America One hallucinogen that has lately been touted as an anti-craving agent for various chemical addictions is ibogaine ("Endabuse") (Lotsof, 1985; Lotsof, 1986; Lotsof, 1989; Lotsof, 199 1 ). - ANSWERSExtracted from the West African shrub Tabernanthe iboga, this indolealkylamine's effect is reported to last 24 to 38 hours (Sheppard, 1994). Contrastingly, Lotsof claims a duration of only 10-15 hours at 20mgkg of body weight (1995). Anecdotal reports describe a lasting benefit of weeks to months in many human subjects given ibogaine. Although without controls, Sheppard (1994) reports that out of seven daily heroin users (mean length of addiction 7.4 years), two remained drug free for "a number of weeks" and three remained drug free for 14 weeks or more; this, after being given one dose of ibogaine (700-1 800 mg).Most of the research into ibogaine have been pre-clinical. A significant decrease in cocaine self administration by Wistar rats was found after receiving ibogaine (40 mgkg IV) (Cappendijk and Dzoljic, 1993). This effect lasted for more than 48 hours, and the researchers found that a longer positive response would occur after three daily doses were given. Moreover, cocaine self-administration diminished in a consistent trend in those rats infused with one 40 mg/kg dose each week for three weeks. In another study (Sershen, Hashim, and Lajtha ( I 993), cocaine intake diminished 38% for five days (p c 0.05) after C57BU6By mice were given two 40 mgkg doses IV. This strain had been chosen for its noted susceptibility to cocaine dependence.Animal studies with ibogaine have also shown a decrease in some physical withdrawal signs from morphine (Dzoljic, Kaplan, and Dzoljic, 1988; Aceto et al., 1989; Click et al., 1991; Click et al., 1992; Maisonneuve et al., 1992; Sershen et al., 1992), cocaine (Cappendijk and Dzoljic 1993), and amphetamines (Maisonneuve, Keller, and Glick, 1992). There might, however, be a cause for some concern about ibogaine in a way that has not been demonstrated for the other hallucinogens. O'Heam Modern psychotropics in psychology - ANSWERSPsychedelic research takes place, albeit in a far more limited capacity than the 60s. The Multidisciplinary Association for Psychedelic Studies (MAPS) is one of the major bodies dedicated to helping researchers find funding and carry out research on psychedelics. However, despite the reduced use of hallucinogens in both research and treatment, psychotropics have become an essential part of treating psychological conditions in the modern age. Drugs are often the first line of treatment for severe mental illness, despite their often severe side effects. Serotonergic psychedelics - ANSWERSHallucinogens such as mescaline, psilocybin and LSD induce profound effects on cognition, emotion and sensory processing - similar to symptoms of psychosis = fear of long-term harm ? Flashbacks and Hallucinogen persisting perception disorder (HPPD) DSM: re-experiencing of perceptual symptoms: geometric hallucinations false perceptions of movement flashes of colour Research is sparse and incoherent, but suggest flashbacks hay have a range of triggers, including: Entering dark room Anxiety Use of or withdrawal from other substance including cannabis, alcohol and even SSRIs Cannabis and psychosis - ANSWERSAround 1 in 10 cannabis users have unpleasant experiences, including confusion, hallucinations, anxiety and paranoia Anxiety reactions and panic attacks are the symptoms most frequently associated with use (Royal College of Psychiatrists, 2012; Crippa et al., 2009) These transient schizophrenia-like symptoms especially likely in those prone to psychoticism (D'Souza et al., 2009); however this relationship is bidirectional Griffith-Lendering et al.,(2013): large scale (N=2120) longitudinal study finding : Adolescent cannabis use predictive of psychosis vulnerability Psychosis vulnerability at 13, 16yo predictive of cannabis use at 16, 19yo Total elimination of use may reduce schizophrenia rates by up to 8% Serotonergic psychedelics - ANSWERSSeveral studies indicate even amongst those that do report flashbacks, they are generally occur rarely and non-disruptive (van Amsterdam et al., 2011; Studerus et al.,2011; Baggott et al., 2011) Jan van Amsterdama, Corresponding author contact information, E-mail the corresponding author, Antoon Opperhuizena, Wim van den Brinkb 2011 - ANSWERSpresent paper is a revised version of the technical report used in the assessment of magic mushrooms by the CAM (Coordination point Assessment and Monitoring new drugs). The CAM, an advisory board of experts that provides science-based advises about recreational drugs, was asked by the Dutch Minister of Health to assess the overall risk of psilocine and psilocybine containing mushrooms, i.e. magic mushrooms. The reason to request the assessment was the fatal accident of a French girl who allegedly had consumed magic mushrooms before the accident occurred (cf. case 8 in Section 6.5). Moreover, some other magic mushroom related incidents preceded this fatal accident, and in the same period a report from the Municipal Health Service about magic mushroom related incidents appeared. The expert panel of the CAM, consisting of toxicologists, pharmacists, pharmacologists, policy officers, clinicians, police men, and social scientist/anthropologist, assessed the acute and chronic toxicity, public health, prevalence of use, availability and public order aspects of magic mushrooms. Details on the procedure have been described recently (van Amsterdam et al., 2010). The first author of this review is the secretary of the CAM. 2. Methods The thematic report of the European Monitoring Center for Drugs and Drug Addiction (EMCDDA), Hallucinogenic mushrooms: an emerging trend case study (EMCDDA, 2010), was taken as a basis for this report. In addition, two literature reviews in Dutch (Bosch et al., 1997 and CAM, 2000) were available. This current report was updated with the literature retrieved using searches in the Medline database . Search terms were: 'magic mushrooms', 'hallucinogenic mushrooms', 'LSD', 'psilocybin', 'psilocin', 'suicide', and 'alcohol'. The present review refers to mushrooms that contain psilocybin and/or conclusion - ANSWERSIt is concluded, that the use of magic mushrooms rarely (if ever) leads to physical or psychological dependence, that acute and chronic adverse effects are relatively infrequent and generally mild, that public health and public order effects are very limited and that criminality related to the use, production and trafficking of magic mushrooms is almost non-existent. However, attention should be paid to the infrequent occurrence of flashbacks and accidents. More specifically, in the absence of proper surveillance of the user the panic attacks evoked by magic mushroom use may lead to severe and sometimes fatal accidents. The list mentioned in Section 6.5 is partly based on newspaper articles and will probably not be complete. On the other hand, fatal accidents were sometimes (e.g. case 8-11) attributed to the use of magic mushrooms although the evidence was not available (no autopsy or blood test report). Furthermore, the reported fatal accidents and suicides will not always appear as mushroom related deaths in the official statistics. Still, the infrequent but severe adverse effects are often associated with overdosing and the combined use with other drugs, including alcohol. When using magic mushrooms, many, if not all, accidents can be prevented by a supporting setting, such as surveillance by a 'sober' person. An attractive option is to make psilocybin available for use only on premises, e.g. in specially designed environments for this purpose. The results of this review have been used in a recent study to rank the relative harm of magic mushrooms compared to a selection of 19 illicit drugs, including heroin, cocaine, ecstasy and cannabis. Based on the rating of 19 experts for 19 recreational drugs for dependence potential, acute and chronic adverse health effects, prevalence, social harm and criminality, magic mu PSYCHOTROPIC PLANTS AND ANTI-PSYCHOTICS - ANSWERSRationale l-Stepholidine, a dopamine D2 antagonist with D1 agonist activity, should in theory control psychosis and treat cognitive symptoms by enhancing cortical dopamine transmission. Though several articles describe its impact on the dopamine system, it has not been systematically evaluated and compared to available antipsychotics. D2 receptor antagonist/D1 agonist and 5-HT1A receptor agonistic dual properties Reduction in positive and negative symptoms of schizophrenia Main side effects - Prolactin elevation and catalepsy MING GAO,1 HONG-YUAN CHU,1 GUO-ZHANG JIN,1 ZHANG-JIN ZHANG,2 JIE WU,3 AND XUE-CHU ZHEN1* 2011 - ANSWERSRecent work has highlighted the role of serotonin (5-HT) receptors in antipsychotic practice (Meltzer, 1999). Indeed, the serotonin system not only plays an important role in many brain functions such as emotion and cognition (Cools et al., 2008), but also contributes to dopaminergic transmission (Diaz-Mataix et al., 2005; Ichikawa et al., 2001). Consistently altered serotoninergic function is believed to be involved in negative symptom and cognitive defects in schizophrenia (Silver et al., 2009). As a result, modulation of 5-HT1A receptor has been a key point in current antipsychotic drugs development (Millan, 2000). Some atypical antischizophrenia drugs increase DA release in prefrontal cortex (PFC) via the 5-HT1A receptor- mediated excitation of VTA DA neurons (Diaz- Mataix et al., 2005; Ichikawa et al., 2001; Kuroki et al., 1999; Rollema et al., 1997), which is believed to associate with the improvement of those drugs on negative symptoms and cognitive dysfunctions in schizophrenia (Millan, 2000).l-Stepholidine (l-SPD), isolated from the Chinese herb Stephania, is a tetrahydroprotoberberine alkaloid. We have demonstrated that l-SPD not only acts as a D1-like receptor agonist (Dong et al., 1997a; Jin et al., 2002; Xu et al., 1989; Zou et al., 1997), but also acts as a D2-like receptor antagonist (Dong et al., 1997b; Jin et al., 2002; Zou et al., 1997). Very recently, we further demonstrated that l-SPD functions as a 5- HT1A receptor partial agonist. Moreover, the latter is found to be critical for the l-SPD-attenuated l-DOPAinduced dyskinesia in Parkinson's diseases (Mo et al., 2008). Therefore, the unique pharmacological profile makes l-SPD a promising antipsychotic candidate. As evidenced, several clinical and experimental studies have demonstrated that l-SPD not only improves positive and negative symptoms of sch Methods - ANSWERSMale SD rats, weighing between 270 and 300 g, were anesthetized with chloral hydrate (400 mg kg21, i.p., with supplemental doses administered via a lateral tail vein) and mounted in a stereotaxic instrument. Body temperature was maintained at 378C with a heating pad throughout the experiment. VTA DA neurons were identified and recorded extracellularly using techniques similar to those previously described (Gao et al., 2007): biphasic (positive-negative) or triphasic (positive-negative-positive) spike waveform with a duration of greater than 3.0 ms, a broad initial positive phase (>1 ms, measured from the start of action potential to the negative trough), an initial segment- somatodendritic break in the initial positive phase, and a slow firing rate (<10 spikes s21). In addition, DA neurons can also be distinguished from non- DA neurons by the characteristic low-pitched sound that produced on an audio monitor. Interspike intervals (ISI) were collected on-line through an acquisition system developed by Fudan University and our lab (Shanghai, China) and stored in a computer for off-line analysis (Zhang et al., 2008a,b). After recording, the rats were killed and their brains were dissected for histological exam to confirm the recording site. Discussion - ANSWERSThe present study reported that l-SPD not only increases VTA DA neuron firing rate, but also alters the firing pattern as evidenced by the changes in SO. We further demonstrated that 5-HT1A agonistic activity of l-SPD is critical for the drug-mediated activation of VTA DA neuron since 5-HT1A selective antagonist completely abolished l-SPD-induced stimulation of DA neuronal activity.Clinical studies found that coadministration of l-SPD with a typical antipsychotic drug significantly enhanced therapeutic effects and remarkably reduced the tardive dyskinesia induced by typical antipsychotic drugs in schizophrenic patients (Cai, 1988). l-SPD alone was shown to improve both positive and negative symptoms without inducing significant extrapyramidal side effects both in animal models of schizophrenia and in clinical trials (Ellenbroek et al., 2006; Wang et al., 2000; Xing et al., 2002). l-SPD and its derivatives have merged as a promising candidate for schizophrenia drug therapy (Guo et al., 2009; Mo et al., 2007Since the hypodopaminergic activity in PFC is believed to contribute to the disturbance in working memory and negative symptom in schizophrenia, l-SPD may increase DA release in cortical area by exciting VTA DA neurons via 5-HT1A receptor and enhance the excitatory inputs. Whereas activation of D1 receptor in PFC via D1-agonistic activity of l-SPD could further facilitate this effect (Goldman-Rakic and Selemon, 1997; Jin et al., 2002; Mo et al., 2005).Thus we propose that the increase in firing rate of VTA DA neurons induced by l-SPD maybe, to a larger extent, due to the blockade of D2- like receptors while the changes in firing pattern aremainly attributed to the activation of 5-HT1A receptors. This hypothesis is partially consistent with the fact that the blockade of D2-like receptors by its specific antagonist only R. Andrew Sewell, MD; John H. Halpern, MD; and Harrison G. Pope, Jr., MD 2011 - ANSWERSCluster headache, often considered the most painful of all types of headache,1 affects predominantly men (0.4% vs 0.08% of women) and typically begins after age 20 years. The disorder is categorized as either episodic, occurring for 1-week to 1-year periods, interspersed with pain-free remission periods, or chronic, in which the headaches occur constantly for more than a year with no remission longer than 1 month.2 Ten percent of episodic cluster headaches ultimately evolve into the chronic form, and these are termed secondary chronic. In standard descriptions of cluster headache, an attack refers to the actual paroxysm of pain, a cluster period refers to a period of time when attacks occur regularly, and a remission period refers to a prolonged attack-free interval. 3Second, unlike other ergot-based medications, which must be taken daily, a single dose of LSD was described as sufficient to induce remission of a clus-ter period, and psilocybin rarely required more than three doses. Third, given the apparent efficacy of subhallucinogenic doses, these drugs might benefit cluster headache by a mechanism unrelated to their psychoactive effects. Limitations - ANSWERSSeveral limitations of this study should be considered. First, it is subject to recall bias, because it relies primarily on participants' retrospective reports. However, 6 participants (11%) provided detailed headache diaries that corroborated their recall. In addition, 3 (6%) of the 53 participants tried psilocybin for the first time subsequent to consenting to participate in the study but before being questioned; 2 reported complete efficacy and 1 reported partial efficacy—a prospective response rate consistent with our retrospective findings. A second consideration is the possibility of selection bias, in that individuals with a good outcome may have been more likely to participate. Recruitment over the Internet also selects for younger, more educated, and more motivated subjects,4 likely leading to increased reported efficacy. Third, participants were not blind to their treatment, raising the possibility of a placebo response. However, cluster headache is known to respond poorly to placebo; controlled trials have shown a placebo response of 0% to prophylactic medications such as verapamil, 5 capsaicin,6 and melatonin,7 and less than 20% to abortive medications such as sumatriptan.8 Therefore, it seems unlikely that we would have found more than 50 cases of apparent response to psilocybin or LSD through placebo effects alone. Our observations must be regarded as preliminary, in that they are unblinded, uncontrolled, and subject to additional limitations as described above St John's Wort - ANSWERSDerived from the plant hypericum perforatum Has been used as medicine as far back as Ancient Greece for many illnesses including depression (Linde, Ramirez, Mulrow, Pauls, Weidenhammer & Melchart, 1996) Has a long history as a treatment for depression and has been argued to be one of the best treatments for minor to moderate depression (Pakseresht, Bousyani, Azemi, Nilsaz, Bebapour & Haghdust, 2012) Unclear exactly how St John's wort actually works - it is thought to inhibit serotonin and decrease serotonin receptor density whilst stimulating GABA receptors (Pakseresht et al , 2012) Linde, Berner & Kinston, (2008) They Found: Hypericum is better than placebo in those patients suffering major depression Hypericum is similarly effective as standard antidepressants and has less side effects. Kasper, Caraci, Forti, Drago & Aguglia, (2010) They found: Extracts of hypericum were significantly more effective than placebo At least as effective as synthetic antidepressent drugs Hypericum was better tolerated than standard synthetic drugs. How does it compare to synthetic antidepressants - ANSWERSPakseresht et al (2012) Found that a combination of tricyclic antidepressants and St John's Wort was more effective than using tricyclic antidepressants alone for major depression. Dhingra & Parle (2012) Found no significant conclusions and insufficient evidence for major depression. However did find that hypericum was more effective than placebo and as effective as standard antidepressants for minor to moderate depression Sun sensitivity Allergic reactions Light headedness Dry mouth Gastrointestinal discomfort Constipation Interference with other drugs including SSRI's and oral contraceptives Connor, Kathryn M.a; Payne, Victoriab; Davidson, Jonathan R.T.a 2006 - ANSWERSThe study sample comprised data from three controlled trials of kava in GAD. The first trial (Connor and Davidson, 2002) was a 4-week evaluation of kava vs placebo in patients who fulfilled DSM-IV criteria for GAD, using a modified duration requirement of 1 month, and with a minimum baseline HAM-A Scale (Hamilton, 1959) score of 16. A second trial was conducted using similar entry criteria, including patients with milder anxiety symptoms (baseline HAM-A score of 12-20). The third study was a randomized trial of patients meeting DSM-IV criteria for GAD (including minimum symptom duration of 6 months) of moderate severity (minimum baseline HAM-A score of 18) who were randomized to 8 weeks of treatment with kava, venlafaxine-XR, or placebo. In each study, double-blind treatment was preceded by a 1-week, single-blind placebo run-in period. Patients who failed to meet the entry criteria following the run-in period were excluded from the study. Key exclusion criteria included the following: history within the previous 6 months of major depression, panic disorder, obsessive-compulsive disorder, or posttraumatic stress disorder; history within previous 12 months of a substance use disorder (6 months for study 3); a lifetime history of bipolar disorder, psychotic disorder, organic brain syndrome, or mental retardation; clinically significant abnormalities on screening laboratory tests or electrocardiograms; an unstable medical condition; prescription medications or medicinal herbs with psychotropic effects; or pregnancy or lactation. Use of kava in these study populations failed to confirm any beneficial effect in GAD. While this botanical treatment was well tolerated (Connor et al., 2001) and appeared safe in this limited sample with respect to liver function, its therapeutic benefit was not readily apparent. While the t Discussion - ANSWERSWe acknowledge several limitations in this study that should be considered in interpreting the report's findings. Firstly, it is important to consider the limitations inherent in using and interpreting findings from analyses of pooled data. Secondly, the samples from which the data were drawn were relatively small, particularly the venlafaxine-XR sample. Thirdly, while the study designs of the studies included in this report were very similar, there were several differences, most notably in the duration of GAD at study entry (1 month for studies 1 and 2 vs 6 months for study 3) and in the duration of study treatment (4 weeks for studies 1 and 2 vs 8 weeks for study 3). Lastly, the average age of patients (50 years) is considerably higher than the average age of participants in controlled treatment trials of GAD, here subjects tend to be in the mid to late 30s, and this difference could influence the generalizability of the study results. Safety and Ethics - ANSWERSIn recent years we have seen the number of new psychiatric drugs being introduced fall and its been discussed that this may be due to the fact that it is difficult to manufacture effective drugs to target psychiatric illnesses when often they are multi-factorial in nature and due to a single cause. This is where phototherapy offers new opportunities by introducing a range of plant constituents to treat illness, or be used as complementary medicines alongside traditional forms of psychiatry. Wernicke, Turner & Priebe - evidence base for use of psychotropic treatments is very limited. Best evidence for use of st. Johns wort. May lead to higher adherence than with conventional drugs alone "Systematic clinical trials are needed to test promising substances. " The main criticism of the use of psychotropic plants in psychiatry is the limited amount of research. Whilst there has been a lot of research into some psychotropic plants such as st. johns wort, passion flower and valerian, the evidence base is still very limited, and there is a lot we don't know about how the various plant constituents effect people on an individual basis and how they affect the body as a whole. So we clearly need a lot more research before we could argue the safety of psychotropic plants in psychiatry Issues arise regarding safety and efficacy of psychotropic plants, as well as other psychiatric treatments. Cases reported of patients suffering due to the use of psychotropic plants. - ANSWERS. This is the case with the use of psychotropic plants as well other treatments, sometimes they may not be as safe or effective as we would like to believe. There have been reported cases of patients treatments being interrupted by the use of psychotropic plants and complimentary medicines. There was a girl being treated for depression and she suffered a series of relapses, and researchers believed it was due to a herb-drug interactionSarris, Hong and Schweitzer discuss how research into genetics can be applied to the use of psychotropic drugs The goal is to analyse genetic variations in individuals to predict their response to medications "The possibilities of side effects or insufficient response to the herb can also be assessed" All psychotropic drugs come with side effects! - ANSWERSPhysical side effects from medication may include, but are not limited to, dizziness, drowsiness, changes in appetite, sleep disturbance, and/or weight gain. Side effects can also be emotional/psychological in presentation, including mood swings, loss of interest, or emotional numbness (not being able to laugh or cry) Use of certain psychotropic medication(s) can also cause permanent damage, such as tardive dyskinesia or Parkinsonism, and may even result in death. A consequence of taking too much medication and becoming numb to feelings is the increased likelihood that a person won't become conscious of the underlying emotional or somatic burdens which often fuel symptoms. Before a patient is offered a psychotropic medication, a thorough diagnostic evaluation and careful review of the patient's history (including past symptoms and response to treatment) are essential. Learning what the patient's hopes, greatest concerns, and motivations are is essential to developing an appropriate therapeutic strategy that may include the use of psychopharmacological agents to address specific target symptoms. The goal is to prescribe psychotropic medications only when they are clearly indicated and when there is a strong evidence base. In many circumstances, combined biological and psychosocial interventions may offer the greatest therapeutic benefit. This approach is in keeping with that of Ghaemi and Goodwin,9 who have emphasized that clinical innovation in psychiatry should not be discouraged but, rather, should occur under ethical conditions. Clinical innovation should be based on a scientific hypothesis. In addition, clinicians should report their observations, such as unexpected psychotropic effects, so that they can be evaluated by the scientific community. Throughout treatment, a high standard of informed consent—along with Robin L. Carhart-Harrisa,b, David Erritzoea,c, Tim Williamsb, James M. Stonea, Laurence J. Reeda, Alessandro Colasantia, Robin J. Tyackea, Robert Leechd, Andrea L. Maliziab, Kevin Murphye, Peter Hobdene, John Evanse, Amanda Feildingf, Richard G. Wisee, and David J. Nutta - ANSWERSPsilocybin has been used for centuries in healing ceremonies (1) and more recently in psychotherapy (2); it is capable of stimulating profound existential experiences (3), which can leave a lasting psychological impression (4). However, despite a wealth of literature on its phenomenology, we currently know very little about how its effects are produced in the brain. The present study sought to address this question using complementary functional MRI (fMRI) techniques and a protocol designed to image the transition from normal waking consciousness to the psychedelic state. Two groups of healthy subjects were scanned using arterial spin labeling (ASL) perfusion and blood-oxygen level-dependent (BOLD) fMRI during intravenous infusion of psilocybin. Infused over 60 s (2 mg in 10-mL saline), psilocybin's subjective effects begin within seconds (5), allowing the capture of the corresponding change in brain state. Discussion - ANSWERSPsilocybin significantly decreased brain blood flow and venous oxygenation in a manner that correlated with its subjective effects, and significantly decreased the positive coupling of two key structural hubs (the mPFC and the PCC). Our use of fMRI to measure resting-state brain activity after a psychedelic is unique, and because the results are unexpected, they require some explanation. The effect of psilocybin on resting-state brain activity has been measured before with PET and glucose metabolism (8). This study found a global increase in glucose metabolismafter oral psilocybin, which is inconsistent with our fMRI results. One possible explanation for this discrepancy relates to the fact that the radiotracer used to measure glucose metabolism (18F-fluorodeoxyglucose) has a long half-life (110 min). Thus, the effects of psilocybin, as measured by PET, are over much greater timescales than indexed by our fMRI measures It has been commonly assumed that psychedelics work by increasing neural activity; however, our results put this into question. Psilocin is a mixed serotonin receptor agonist, but there is a general consensus that the characteristic subjective and behavioral ef