Some modulators have also been shown to lack the desensitizing effect that some agonists have.  Nicotinic acetylcholine receptors , for example, quickly desensitize in the presence of agonist drugs, but maintain normal function in the presence of PAMs. [ 13 ]


Allosteric modulation has demonstrated as beneficial to many conditions that have been previously difficult to control with other pharmaceuticals. These include:


L -α-Glycerophosphorylcholine  ( alpha-GPC ,  choline alfoscerate ,  sn -glycero-3-phosphocholine ) is a natural  choline  compound found in the brain. It is also a  parasympathomimetic   acetylcholine  precursor [ 1 ]  which has been investigated for its potential for the treatment of  Alzheimer's disease [ 2 ]  and other  dementias . [ 3 ]


Alpha-GPC rapidly delivers  choline  to the brain across the  blood–brain barrier  and is a biosynthetic precursor of  acetylcholine . [ 2 ]  It is a non-prescription drug in most countries. The  FDA  determined that intake of no more than 196.2 mg/person/day is considered  generally recognized as safe  (GRAS). [ 4 ]


Industrially, alpha-GPC is produced by the chemical or enzymatic deacylation of  phosphatidylcholine  enriched soya  phospholipids  followed by  chromatographic purification . Alpha-GPC may also be derived in small amounts from highly purified soy  lecithin  as well as from purified sunflower lecithin. [ 5 ] [ 6 ]


Alpha-GPC metabolizes to  trimethylamine n-oxide  in the gastrointestinal tract, which has implications for cardiovascular health. In one study, risk of stroke over a ten-year period was increased by about 40% in users of alpha-GPC. [ 7 ]


Founded in 1961, the  American College of Neuropsychopharmacology (ACNP)  is a professional organization of leading  brain  and  behavior  scientists. [ 1 ]  The principal functions of the College are research and education. Their goals in research are to offer investigators an opportunity for cross-disciplinary communication and to promote the application of various scientific disciplines to the study of the brain's effect on behavior, with a focus on  mental illness  of all forms.  Their educational goals are to encourage young scientists to enter research careers in  neuropsychopharmacology  and to develop and provide accurate information about  behavioral disorders  and their pharmacological treatment.


The College is an  honorific  society.  Members are selected primarily on the basis of their original research contributions to the broad field of  neuroscience . [ 2 ]   The membership of the College is drawn from scientists in multiple fields including behavioral  pharmacology ,  neuroimaging ,  chronobiology , clinical  psychopharmacology ,  epidemiology ,  genetics ,  molecular biology ,  neurochemistry ,  neuroendocrinology ,  neuroimmunology ,  neurology ,  neurophysiology ,  psychiatry , and  psychology . [ 3 ]


The annual meeting of the College is a closed meeting; only the ACNP members and their invited guests may attend. [ 4 ]  Because of the College's intense concern with, and involvement in, the education and training of tomorrow's brain scientists, the College selects a number of young scientists to be invited to the annual meeting through a competitive process open to all early career researchers. This meeting, a mix of foremost brain and behavior research world-wide, is designed to encourage dialogue, discussion, and synergy by those attending.


The ACNP offers the following awards. [ 5 ]


The Springer-Nature Publishing Group journals  Neuropsychopharmacology  and  NPP-Digital Psychiatry and Neuroscience  are their official publications.  Neuropsychopharmacology   [ 6 ]  was first published in 1987 and  NPP-Digital Psychiatry and Neuroscience  is an Open Access journal that started in 2023.


Anabaseine  (3,4,5,6-tetrahydro-2,3′-bipyridine) is an  alkaloid   toxin  produced by  Nemertines  worms and  Aphaenogaster  ants. [ 1 ]  It is structurally similar to  nicotine  and  anabasine . [ 2 ]  Similarly, it has been shown to act as an  agonist  on most  nicotinic acetylcholine receptors  in the  central nervous system  and  peripheral nervous system . [ 2 ]


The  iminium  form of anabaseine binds to most  nicotinic acetylcholine receptors  in both the  peripheral nervous system  and  central nervous system . But, there is a higher binding affinity for receptors in the brain with a α7 subunit, as well as skeletal muscle receptors. [ 3 ]  Binding causes the  depolarization  of neurons, and induces the release of both  dopamine  and  norepinephrine . [ 2 ]


Anabaseine causes paralysis in  crustaceans  and  insects , but not in  vertebrates , presumably by acting as an agonist on peripheral neuromuscular nicotinic acetylcholine receptors. [ 2 ]


The anabaseine molecule consists of a non- aromatic  tetrahydropyridine ring connected to the 3rd carbon of a 3- pyridyl  ring. It can exist in three forms at physiological pH:  a  ketone ,  imine , or  iminium  structure. [ 2 ]  Due to conjugation between the imine and 3-pyridyl ring, anabaseine exists as a nearly coplanar molecule.


Spath and Mamoli first synthesized anabaseine in 1936. [ 4 ]  The researchers reacted  benzoic anhydride  with δ- valerolactam  to yield  N -benzoylpiperidone. Then,  N -benzoylpiperidone is reacted with nicotinic acid ethyl ester to produce α-nicotinoyl- N -benzoyl-2-piperidone. This product then is  decarboxylated , undergoes a  ring closure , and  amide hydrolysis  to form anabaseine.


Additional synthetic strategies have since been developed by Bloom, [ 5 ]  Zoltewicz, [ 6 ]  Smith, [ 7 ]  and Villemin. [ 8 ]


Due to anabaseine’s fairly non-specific binding to nicotinic acetylcholine receptors, the molecule was largely discarded as a useful tool in research or medicine. However, anabaseine derivatives have been identified with a more selective α7 binding profile. One such derivative ( GTS-21 , 3-(2,4-dimethoxybenzylidene)-anabaseine) has been studied as a drug candidate for cognitive and memory deficits, particularly associated with  schizophrenia ; it has been studied in  phase II clinical trials  without progression to phase III. [ 9 ]  Moreover, the modification of the anabaseine pyridine nucleus led to the obtainment of new derivatives endowed with binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype. [ 10 ]


Chemical


Neurological


Biohappiness , or  bio-happiness , is the elevation of well-being in humans and other animals through biological methods, including  germline engineering  through screening embryos with genes associated with a high level of happiness, or the use of drugs intended to raise baseline levels of happiness. The object is to facilitate the achievement of a state of "better than well". [ 1 ]


Proponents of biohappiness include the  transhumanist  philosopher  David Pearce , whose goal is to  end the suffering  of all  sentient  beings [ 2 ]  and the Canadian ethicist  Mark Alan Walker . Walker coined the term "bio-happiness" to describe the idea of directly manipulating the biological roots of happiness in order to increase it. [ 3 ]  He sought to defend it on the grounds that happiness ought to be of interest to a wide range of moral theorists; and that  hyperthymia , a state of high baseline happiness, is associated with better outcomes in health and human achievement. [ 4 ] [ 5 ]


A significant danger of bio happiness is the ethical problems of altering the natural human emotional state through technological methods. Molding organic brain chemistry or genetic structures to achieve happiness would raise concerns about the authenticity of the human body/experience. [ 3 ] [ 6 ]  It is argued that tampering with the state of the human mind and creating an eternal happiness would disrupt the natural range of emotions that a human will experience. Sadness, grief and anger are all crucial for emotional growth, empathy and understanding. Additionally, the long term effects of bio happiness are not yet understood, meaning later down the line, issues could arise. Loss of individuality, emotional depth and the risk of being dependent on an external source for happiness are all concerns regarding this. [ 3 ]


A  counterirritant  is a substance which creates irritation or mild inflammation in one location with the goal of lessening discomfort and/or inflammation in another location. [ 1 ]  This strategy falls into the more general category of  counterstimulation .


Topical counter-irritants are non-analgesic, non-anesthetic substances or treatments used to treat pain.  Capsaicin ,  menthol  (mint oil),  methyl salicylate , and  camphor  are examples of counterirritants. Heat and cold therapy and massage relieve pain by counterstimulation. [ citation needed ]


The US  Food and Drug Administration  defines a counterirritant as "An externally applied substance that causes irritation or mild inflammation of the skin for the purpose of relieving pain in muscles, joints and viscera distal to the site of application. They differ from the  anesthetics ,  analgesics , and  antipruritic  agents, however, in that the pain relief they produce results from stimulation—rather than depression—of the cutaneous sensory receptors and occurs in structures of the body other than the skin areas to which they are applied as for example, in joints, muscles,  tendons  and certain viscera. The use of these products dates from antiquity." [ 2 ]


This  dermatologic   drug  article is a  stub . You can help Wikipedia by  expanding it .


A  ganglionic blocker  (or  ganglioplegic ) is a type of medication that inhibits transmission between  preganglionic  and  postganglionic  neurons in the  autonomic nervous system , often by acting as a  nicotinic receptor antagonist . [ 1 ]  Nicotinic acetylcholine receptors are found on skeletal muscle, but also within the route of transmission for the parasympathetic and sympathetic nervous system (which together comprise the autonomic nervous system). More specifically, nicotinic receptors are found within the ganglia of the autonomic nervous system, allowing outgoing signals to be transmitted from the presynaptic to the postsynaptic cells. Thus, for example, blocking nicotinic acetylcholine receptors blocks both sympathetic (excitatory) and parasympathetic (calming) stimulation of the heart. The nicotinic antagonist hexamethonium, for example, does this by blocking the transmission of outgoing signals across the autonomic ganglia at the postsynaptic nicotinic acetylcholine receptor.


Because ganglionic blockers block both the  parasympathetic nervous system  and  sympathetic nervous system , the effect of these drugs depends upon the dominant tone in the organ system. [ 2 ]


The opposite of a ganglionic blocker is referred to as a  ganglionic stimulant . Some substances can exhibit both stimulating and blocking effects on autonomic ganglia, depending on dosage and/or duration of action. An example for such a "dual" action is nicotine, which does this via depolarization block (see classification below).


The first ganglion-blocker to be used clinically was  tetraethylammonium , although it was soon superseded by better drugs. [ 3 ]


Nicotinic receptor antagonists:


Nicotinic receptor agonists (acting through  depolarization block ):


Blocking ACh release in autonomic ganglia (although these have many other actions elsewhere):


Ganglionic blockers are used less frequently now than they were in the past, because  antihypertensives  with fewer side effects are now available.  Hexamethonium  has been described as the "first effective antihypertensive drug". [ 4 ]  However, they are still used in some emergency situations, such as  aortic dissection  or  autonomic dysreflexia .


The  effects of long-term benzodiazepine use  include  drug dependence  as well as the possibility of adverse effects on cognitive function, physical health, and mental health. [ 1 ]  Long-term use is sometimes described as use not shorter than three months. [ 2 ]  Benzodiazepines are generally effective when used therapeutically in the short term, [ 3 ]  but even then the risk of dependency can be significantly high. There are significant physical, mental and social risks associated with the long-term use of  benzodiazepines . [ 3 ]  Although anxiety can temporarily increase as a withdrawal symptom, there is evidence that a reduction or  withdrawal from benzodiazepines  can lead to a reduction of anxiety symptoms in the long run. [ 4 ] [ 5 ]  Due to these increasing physical and mental symptoms from long-term use of benzodiazepines, slow withdrawal is recommended for long-term users. [ 6 ] [ 7 ] [ 8 ] [ 9 ]  Not everyone, however, experiences problems with long-term use. [ 10 ]


Some of the symptoms that could possibly occur as a result of a withdrawal from benzodiazepines after long-term use include emotional clouding, [ 1 ]  flu-like symptoms, [ 5 ]   suicide , [ 11 ]   nausea ,  headaches ,  dizziness ,  irritability ,  lethargy , sleep problems,  memory impairment , personality changes,  aggression ,  depression , social deterioration as well as employment difficulties, while others never have any side effects from long-term benzodiazepine use. Abruptly or rapidly stopping benzodiazepines can be dangerous; when withdrawing, a gradual reduction in dosage is recommended, under professional supervision. [ 7 ] [ 12 ] [ 9 ]


While benzodiazepines are highly effective in the short term, adverse effects associated with long-term use, including impaired cognitive abilities, memory problems, mood swings, and overdoses when combined with other drugs, may make the risk-benefit ratio unfavourable. In addition, benzodiazepines have reinforcing properties in some individuals and thus are considered to be addictive drugs, especially in individuals that have a "drug-seeking" behavior; further, a  physical dependence  can develop after a few weeks or months of use. [ 13 ]  Many of these adverse effects associated with long-term use of benzodiazepines begin to show improvements three to six months after withdrawal. [ 14 ] [ 15 ]


Other concerns about the effects associated with long-term benzodiazepine use, in some, include dose escalation,  benzodiazepine use disorder ,  tolerance  and  benzodiazepine dependence  and benzodiazepine withdrawal problems. Both physiological tolerance and dependence can be associated with worsening the adverse effects associated with benzodiazepines. Increased risk of death has been associated with long-term use of benzodiazepines in several studies; however, other studies have not found increased  mortality . Due to conflicting findings in studies regarding benzodiazepines and increased risks of death including from cancer, further research in long-term use of benzodiazepines and mortality risk has been recommended; most of the available research has been conducted in prescribed users, even less is known about illicit misusers. [ 16 ] [ 17 ]  The long-term use of benzodiazepines is controversial and has generated significant debate within the medical profession. Views on the nature and severity of problems with long-term use of benzodiazepines differ from expert to expert and even from country to country; some experts even question whether there is any problem with the long-term use of benzodiazepines. [ 18 ]


Effects of long-term benzodiazepine use may include  disinhibition , impaired concentration and memory,  depression , [ 19 ] [ 20 ]  as well as  sexual dysfunction . [ 6 ] [ 21 ]  The long-term effects of benzodiazepines may differ from the adverse effects seen after acute administration of benzodiazepines. [ 22 ]  An analysis of cancer patients found that those who took  tranquillisers  or  sleeping tablets  had a substantially poorer quality of life on all measurements conducted, as well as a worse clinical picture of symptomatology. Worsening of symptoms such as  fatigue ,  insomnia ,  pain ,  dyspnea  and  constipation  was found when compared against those who did not take tranquillisers or sleeping tablets. [ 23 ]  Most individuals who successfully discontinue  hypnotic  therapy after a gradual taper and do not take benzodiazepines for 6 months have less severe sleep and anxiety problems, are less distressed and have a general feeling of improved health at 6-month follow-up. [ 15 ]  The use of benzodiazepines for the treatment of anxiety has been found to lead to a significant increase in healthcare costs due to accidents and other adverse effects associated with the long-term use of benzodiazepines. [ 24 ]


Long-term benzodiazepine use can lead to a generalised impairment of  cognition , including sustained attention, verbal learning and  memory  and  psychomotor ,  visuo-motor  and  visuo-conceptual  abilities. [ 25 ] [ 26 ]  Transient changes in the brain have been found using  neuroimaging  studies, but no brain abnormalities have been found in patients treated long term with benzodiazepines. [ 27 ]  When benzodiazepine users cease long-term benzodiazepine therapy, their cognitive function improves in the first six months, although deficits may be permanent or take longer than six months to return to baseline. [ 28 ]  In the elderly, long-term benzodiazepine therapy is a risk factor for amplifying cognitive decline, [ 29 ]  although gradual  withdrawal  is associated with improved cognitive status. [ 30 ]  A study of  alprazolam  found that 8 weeks administration of alprazolam resulted in deficits that were detectable after several weeks but not after 3.5 years. [ 31 ]


Sleep can be adversely affected by benzodiazepine dependence. Possible adverse effects on sleep include induction or worsening of sleep disordered breathing. Like  alcohol ,  benzodiazepines  are commonly used to treat insomnia in the short term (both prescribed and self-medicated), but worsen sleep in the long term. Although benzodiazepines can put people to sleep, while asleep, the drugs disrupt sleep architecture, decreasing sleep time, delayed and decreased REM sleep, increased alpha and beta activity, decreased  K complexes  and delta activity, and decreased deep  slow-wave sleep  (i.e., NREM stages 3 and 4, the most restorative part of sleep for both energy and mood). [ 32 ] [ 33 ] [ 34 ]


The long-term use of benzodiazepines may have a similar effect on the brain as  alcohol , and is also implicated in  depression ,  anxiety , post-traumatic stress disorder (PTSD), mania, psychosis,  sleep disorders , sexual dysfunction, delirium, and neurocognitive disorders. [ 35 ] [ 36 ]  However a 2016 study found no association between long-term usage and dementia. [ 37 ]  As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of  serotonin  and  norepinephrine , are believed to be responsible for their effects on mood and anxiety. [ 38 ] [ 39 ] [ 40 ] [ 41 ] [ 42 ] [ 43 ]  Additionally, benzodiazepines can indirectly cause or worsen other psychiatric symptoms (e.g., mood, anxiety, psychosis, irritability) by worsening sleep (i.e., benzodiazepine-induced sleep disorder). These effects are  paradoxical  to the use of benzodiazepines, both clinically and  non-medically , in management of mental health conditions. [ 44 ] [ 45 ]


Long-term benzodiazepine use may lead to the creation or exacerbation of physical and mental health conditions, which improve after six or more months of abstinence. After a period of about 3 to 6 months of abstinence after completion of a gradual-reduction regimen, marked improvements in mental and physical wellbeing become apparent. For example, one study of hypnotic users gradually withdrawn from their hypnotic medication reported after six months of abstinence that they had less severe sleep and anxiety problems, were less distressed, and had a general feeling of improved health. Those who remained on  hypnotic  medication had no improvements in their insomnia, anxiety, or general health ratings. [ 15 ]  A study found that individuals having withdrawn from benzodiazepines showed a marked reduction in use of medical and mental health services. [ 46 ] [ non-primary source needed ]


Approximately half of patients attending mental health services for conditions including  anxiety disorders  such as  panic disorder  or  social phobia  may be the result of alcohol or benzodiazepine dependence. [ 47 ]  Sometimes anxiety disorders precede  alcohol  or benzodiazepine dependence but the alcohol or  benzodiazepine dependence  often acts to keep the anxiety disorders going and often progressively makes them worse. [ 47 ] [ non-primary source needed ]  Many people who are addicted to alcohol or prescribed benzodiazepines decide to quit when it is explained to them they have a choice between ongoing ill mental health or quitting and recovering from their symptoms. It was noted that because every individual has an individual sensitivity level to alcohol or sedative hypnotic drugs, what one person can tolerate without ill health will cause another to develop very ill health, and that even moderate drinking in sensitive individuals can cause rebound anxiety syndromes and sleep disorders. A person who experiences the toxic effects of alcohol or benzodiazepines will not benefit from other therapies or medications as they do not address the root cause of the symptoms. [ 47 ]  Recovery from benzodiazepine dependence tends to take a lot longer than recovery from alcohol, [ 47 ] [ 48 ]  but people can regain their previous good health. [ 47 ] [ medical citation needed ]  A review of the literature regarding benzodiazepine  hypnotic  drugs concluded that these drugs cause an unjustifiable risk to the individual and to public health. The risks include  dependence , accidents and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep. [ 49 ]


Daily users of benzodiazepines are also at a higher risk of experiencing  psychotic  symptomatology such as  delusions  and  hallucinations . [ 50 ]  A study found that of 42 patients treated with alprazolam, up to a third of long-term users of the benzodiazepine drug alprazolam ( Xanax ) develop  depression . [ 40 ]  Studies have shown that long-term use of benzodiazepines and the benzodiazepine receptor agonist  nonbenzodiazepine   Z drugs  are associated with causing depression as well as a markedly raised suicide risk and an overall increased  mortality  risk. [ 41 ] [ 51 ]


A study of 50 patients who attended a benzodiazepine withdrawal clinic found that, after several years of chronic benzodiazepine use, a large portion of patients developed health problems including  agoraphobia ,  irritable bowel syndrome ,  paraesthesiae , increasing anxiety, and  panic attacks , which were not preexisting. The mental health and physical health symptoms induced by long-term benzodiazepine use gradually improved significantly over a period of a year following completion of a slow withdrawal. Three of the 50 patients had wrongly been given a preliminary diagnosis of  multiple sclerosis  when the symptoms were actually due to chronic benzodiazepine use. Ten of the patients had taken  drug overdoses  whilst on benzodiazepines, despite the fact that only two of the patients had any prior history of depressive symptomatology. After withdrawal, no patients took any further overdoses after one year post-withdrawal. The cause of the deteriorating mental and physical health in a significant proportion of patients was hypothesised to be caused by increasing tolerance where withdrawal-type symptoms emerged, despite the administration of stable prescribed doses. [ 52 ]  Another theory is that chronic benzodiazepine use causes subtle increasing toxicity, which in turn leads to increasing psychopathology in long-term users of benzodiazepines. [ 53 ]


Long-term use of benzodiazepines can induce  perceptual  disturbances and  depersonalization  in some people, even in those taking a stable daily dosage, and it can also become a  protracted withdrawal  feature of the  benzodiazepine withdrawal syndrome . [ 54 ]


In addition, chronic use of benzodiazepines is a risk factor for  blepharospasm . [ 55 ]  Drug-induced symptoms that resemble withdrawal-like effects can occur on a set dosage as a result of prolonged use, also documented with  barbiturate -like substances, as well as alcohol and  benzodiazepines . This demonstrates that the effects from chronic use of benzodiazepine drugs are not unique but occur with other GABAergic  sedative  hypnotic drugs, i.e., alcohol and barbiturates. [ 56 ]


Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department. [ 57 ]   Diazepam  and  clonazepam  have been found to have long-lasting, but not permanent, immunotoxic effects in fetuses of rats. However, single very high doses of diazepam have been found to cause lifelong immunosuppression in neonatal rats. No studies have been done to assess the immunotoxic effects of diazepam in humans; however, high prescribed doses of diazepam, in humans, have been found to be a major risk of pneumonia, based on a study of people with tetanus. It has been proposed that diazepam may cause long-lasting changes to the GABA A  receptors with resultant long-lasting disturbances to behaviour,  endocrine  function and immune function. [ 58 ]


Use of prescribed benzodiazepines is associated with an increased rate of suicide or attempted  suicide . The prosuicidal effects of benzodiazepines are suspected to be due to a psychiatric disturbance caused by side effects or withdrawal symptoms. [ 11 ]  Because benzodiazepines in general may be associated with increased suicide risk, care should be taken when prescribing, especially to at-risk patients. [ 59 ] [ 60 ]  Depressed adolescents who were taking benzodiazepines were found to have a greatly increased risk of  self-harm  or  suicide , although the sample size was small. The effects of benzodiazepines in individuals under the age of 18 requires further research. Additional caution is required in using benzodiazepines in depressed adolescents. [ 61 ]   Benzodiazepine dependence  often results in an increasingly deteriorating clinical picture, which includes social deterioration leading to comorbid  alcohol use disorder  and  substance use disorder .  Benzodiazepine misuse  or misuse of other  CNS depressants  increases the risk of suicide in drug misusers. [ 62 ] [ 63 ]  Benzodiazepine has several risks based on its biochemical function and symptoms associated with this medication like exacerbation of sleep apnea, sedation, suppression of self-care functions, amnesia and disinhibition are suggested as a possible explanation to the increase in mortality. Studies also demonstrate that an increased mortality associated with benzodiazepine use has been clearly documented among 'drug misusers'. [ 17 ]


There has been some controversy around the possible link between benzodiazepine use and development of cancer; early cohort studies in the 1980s suggested a possible link, but follow-up case-control studies have found no link between benzodiazepines and cancer. In the second U.S. national cancer study in 1982, the  American Cancer Society  conducted a survey of over 1.1 million participants. A markedly increased risk of cancer was found in users of sleeping pills, mainly benzodiazepines. [ 64 ]  Fifteen  epidemiologic  studies have suggested that  benzodiazepine  or  nonbenzodiazepine   hypnotic  drug use is associated with increased  mortality , mainly due to increased  cancer  death. The cancers included cancer of the  brain ,  lung ,  bowel ,  breast , and  bladder , and other  neoplasms . It has been hypothesised [ by whom? ]  that benzodiazepines depress immune function and increase viral infections and could be the cause or trigger of the increased rate of cancer. While initially  U.S. Food and Drug Administration  reviewers expressed concerns about approving the  nonbenzodiazepine   Z drugs  due to concerns of cancer, ultimately they changed their minds and approved the drugs. [ 65 ]  A 2017 meta-analysis of multiple observational studies found that benzodiazepine use is associated with increased cancer risk. [ 66 ]


In a study in 1980 in a group of 55 consecutively admitted patients having engaged in non-medical use of exclusively sedatives or hypnotics, neuropsychological performance was significantly lower and signs of intellectual impairment significantly more often diagnosed than in a matched control group taken from the general population. These results suggested a relationship between non-medical use of sedatives or hypnotics and cerebral disorder. [ 67 ]


A publication asked in 1981 if  lorazepam  is more toxic than  diazepam . [ 68 ]


In a study in 1984, 20 patients having taken long-term benzodiazepines were submitted to brain CT scan examinations. Some scans appeared abnormal. The mean  ventricular-brain ratio  measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics. There was no significant relationship between CT scan appearances and the duration of benzodiazepine therapy. The clinical significance of the findings was unclear. [ 69 ]


In 1986, it was presumed that permanent brain damage may result from chronic use of benzodiazepines similar to  alcohol-related brain damage . [ 70 ]


In 1987, 17 inpatient people who used high doses of benzodiazepines non-medically have anecdotally shown enlarged  cerebrospinal fluid  spaces with associated  cerebral atrophy .
Cerebral atrophy reportedly appeared to be dose dependent with low-dose users having less atrophy than higher-dose users. [ 71 ]


However, a CT study in 1987 found no evidence of cerebral atrophy in prescribed benzodiazepine users. [ 72 ]


In 1989, in a 4- to 6-year follow-up study of 30 inpatient people who used benzodiazepines non-medically,  Neuropsychological  function was found to be permanently affected in some people with long-term high dose non-medical use of benzodiazepines.  Brain damage  similar to  alcoholic  brain damage was observed. The  CT scan  abnormalities showed dilatation of the  ventricular system . However, unlike people who consume excessive alcohol, people who use sedative hypnotic agents non-medically showed no evidence of widened  cortical   sulci . The study concluded that, when  cerebral  disorder is diagnosed in people who use high doses of sedative hypnotic benzodiazepines, it is often permanent. [ 73 ]


A CT study in 1993 investigated brain damage in benzodiazepine users and found no overall differences to a healthy control group. [ 74 ]


A study in 2000 found that long-term benzodiazepine therapy does not result in brain abnormalities. [ 75 ]


Withdrawal from high-dose use of  nitrazepam  anecdotally was alleged in 2001 to have caused severe  shock  of the whole brain with diffuse slow activity on  EEG  in one patient after 25 years of use. After withdrawal, abnormalities in hypofrontal brain wave patterns persisted beyond the withdrawal syndrome, which suggested to the authors that organic brain damage occurred from chronic high-dose use of nitrazepam. [ 76 ]


Professor Heather Ashton , a leading expert on benzodiazepines from  Newcastle University  Institute of Neuroscience, has stated that there is no structural damage from benzodiazepines, and advocates for further research into long-lasting or possibly permanent symptoms of long-term use of benzodiazepines as of 1996. [ 77 ]  She has stated that she believes that the most likely explanation for lasting symptoms is persisting but slowly resolving functional changes at the  GABA A   benzodiazepine receptor  level. Newer and more detailed brain scanning technologies such as PET scans and MRI scans had as of 2002 to her knowledge never been used to investigate the question of whether benzodiazepines cause functional or structural brain damage. [ 78 ]


A 2018 review of the research found a likely causative role between the use of benzodiazepines and an increased risk of dementia, [ 79 ]  but the exact nature of the relationship is still a matter of debate. [ 80 ]


Benzodiazepines, when introduced in 1961, were widely believed to be safe drugs but as the decades went by increased awareness of  adverse effects  connected to their long-term use became known. Recommendations for more restrictive medical guidelines followed. [ 81 ] [ 82 ]  Concerns regarding the long-term effects of benzodiazepines have been raised since 1980. [ 83 ]  These concerns are still not fully answered. A review in 2006 of the literature on use of benzodiazepine and nonbenzodiazepine hypnotics concluded that more research is needed to evaluate the long-term effects of hypnotic drugs. [ 84 ]  The majority of the problems of benzodiazepines are related to their long-term use rather than their short-term use. [ 85 ]  There is growing evidence of the harm of long-term use of benzodiazepines, especially at higher doses. In 2007, the  Department of Health  recommended that individuals on long-term benzodiazepines be monitored at least every 3 months and also recommended against long-term substitution therapy in benzodiazepine drug misusers due to a lack of  evidence base  for effectiveness and due to the risks of long-term use. [ 86 ]  The long-term effects of benzodiazepines are very similar to the  long-term effects of alcohol consumption  (apart from organ toxicity) and other sedative-hypnotics. Withdrawal effects and dependence are not identical. Dependence can be managed, with a medical professional of course, but withdrawal can be fatal. Physical dependence and withdrawal are very much related but not the same thing. A report in 1987 by the Royal College of Psychiatrists in Great Britain reported that any benefits of long-term use of benzodiazepines are likely to be far outweighed by the risks of long-term use. [ 87 ]  Despite this benzodiazepines are still widely prescribed. The  socioeconomic  costs of the continued widespread prescribing of benzodiazepines is high. [ 88 ]


In 1980, the  Medical Research Council (United Kingdom)  recommended that research be conducted into the effects of long-term use of benzodiazepines [ 89 ]  A 2009  British Government   parliamentary inquiry  recommended that research into the long-term effects of benzodiazepines must be carried out. [ 90 ]  The view of the Department of Health is that they have made every effort to make doctors aware of the problems associated with the long-term use of benzodiazepines, [ 91 ]  as well as the dangers of benzodiazepine drug addiction. [ 92 ]


In 1980, the  Medicines and Healthcare products Regulatory Agency 's  Committee on the Safety of Medicines  issued guidance restricting the use of benzodiazepines to short-term use and updated and strengthened these warnings in 1988. When asked by  Phil Woolas  in 1999 whether the Department of Health had any plans to conduct research into the long-term effects of benzodiazepines, the Department replied, saying they have no plans to do so, as benzodiazepines are already restricted to short-term use and monitored by regulatory bodies. [ 93 ]  In a  House of Commons  debate, Phil Woolas claimed that there had been a cover-up of problems associated with benzodiazepines because they are of too large of a scale for governments, regulatory bodies, and the pharmaceutical industry to deal with.  John Hutton  stated in response that the Department of Health took the problems of benzodiazepines extremely seriously and was not sweeping the issue under the carpet. [ 94 ]  In 2010, the All-Party Parliamentary Group on Involuntary Tranquilliser Addiction filed a complaint with the  Equality and Human Rights Commission  under the  Disability Discrimination Act 1995  against the Department of Health and the  Department for Work and Pensions  alleging discrimination against people with a benzodiazepine prescription drug dependence as a result of denial of specialised treatment services, exclusion from medical treatment, non-recognition of the protracted  benzodiazepine withdrawal syndrome , as well as denial of rehabilitation and back-to-work schemes. Additionally the APPGITA complaint alleged that there is a "virtual prohibition" on the collection of statistical information on benzodiazepines across government departments, whereas with other controlled drugs there are enormous volumes of statistical data. The complaint alleged that the discrimination is deliberate, large scale and that government departments are aware of what they are doing. [ 95 ]


The  Medical Research Council (UK)  held a closed meeting among top UK medical doctors and representatives from the pharmaceutical industry between 30 October 1980 and 3 April 1981. The meeting was classified under the  Public Records Act 1958  until 2014 but became available in 2005 as a result of the  Freedom of Information Act . The meeting was called due to concerns that 10–100,000 people could be dependent; meeting chairman Professor Malcolm Lader later revised this estimate to include approximately half a million members of the British public suspected of being dependent on therapeutic dose levels of benzodiazepines, with about half of those on long-term benzodiazepines. It was reported that benzodiazepines may be the third- or fourth-largest drug problem in the UK (the largest being alcohol and tobacco). The chairman of the meeting followed up after the meeting with additional information, which was forwarded to the Medical Research Council neuroscience board, raising concerns regarding tests that showed definite cortical atrophy in 2 of 14 individuals tested and borderline abnormality in five others. He felt that, due to the methodology used in assessing the scans, the abnormalities were likely an underestimate, and more refined techniques would be more accurate. Also discussed were findings that tolerance to benzodiazepines can be demonstrated by injecting diazepam into long-term users; in normal subjects, increases in  growth hormone  occurs, whereas in benzodiazepine-tolerant individuals this effect is blunted. Also raised were findings in animal studies that showed the development of tolerance in the form of a 15 percent reduction in binding capacity of benzodiazepines after seven days administration of high doses of the partial agonist benzodiazepine drug  flurazepam  and a 50 percent reduction in binding capacity after 30 days of a low dose of diazepam. The chairman was concerned that papers soon to be published would "stir the whole matter up" and wanted to be able to say that the Medical Research Council "had matters under consideration if questions were asked in parliament". The chairman felt that it "was very important, politically that the MRC should be 'one step ahead'" and recommended epidemiological studies be funded and carried out by Roche Pharmaceuticals and MRC sponsored research conducted into the biochemical effects of long-term use of benzodiazepines. The meeting aimed to identify issues that were likely to arise, alert the Department of Health to the scale of the problem and identify the pharmacology and nature of benzodiazepine dependence and the volume of benzodiazepines being prescribed. The  World Health Organization  was also interested in the problem and it was felt the meeting would demonstrate to the WHO that the MRC was taking the issue seriously. Among the psychological effects of long-term use of benzodiazepines discussed was a reduced ability to cope with stress. The chairman stated that the "withdrawal symptoms from valium were much worse than many other drugs including, e.g., heroin". It was stated that the likelihood of withdrawing from benzodiazepines was "reduced enormously" if benzodiazepines were prescribed for longer than four months. It was concluded that benzodiazepines are often prescribed inappropriately, for a wide range of conditions and situations. Dr Mason ( DHSS ) and Dr Moir ( SHHD ) felt that, due to the large numbers of people using benzodiazepines for long periods of time, it was important to determine the effectiveness and toxicity of benzodiazepines before deciding what regulatory action to take. [ 89 ]


Controversy resulted in 2010 when the previously secret files came to light over the fact that the Medical Research Council was warned that benzodiazepines prescribed to millions of patients appeared to cause  cerebral atrophy  similar to hazardous alcohol use in some patients and failed to carry out larger and more rigorous studies.  The Independent on Sunday  reported allegations that "scores" of the 1.5 million members of the UK public who use benzodiazepines long-term have symptoms that are consistent with brain damage. It has been described as a "huge scandal" by  Jim Dobbin , and legal experts and MPs have predicted a class action lawsuit. A solicitor said she was aware of the past failed litigation against the drug companies and the relevance the documents had to that court case and said it was strange that the documents were kept 'hidden' by the MRC. [ 96 ]


Professor Lader, who chaired the MRC meeting, declined to speculate as to why the MRC declined to support his request to set up a unit to further research benzodiazepines and why they did not set up a special safety committee to look into these concerns. Professor Lader stated that he regrets not being more proactive on pursuing the issue, stating that he did not want to be labeled as the guy who pushed only issues with benzos. Professor Ashton also submitted proposals for grant-funded research using MRI, EEG, and cognitive testing in a randomized controlled trial to assess whether benzodiazepines cause permanent damage to the brain, but similarly to Professor Lader was turned down by the MRC. [ 96 ]


The MRC spokesperson said they accept the conclusions of Professor Lader's research and said that they fund only research that meets required quality standards of scientific research, and stated that they were and continue to remain receptive to applications for research in this area. No explanation was reported for why the documents were sealed by the Public Records Act. [ 96 ]


Jim Dobbin , who chaired the All-Party Parliamentary Group for Involuntary Tranquilliser Addiction, stated that:


Many victims have lasting physical, cognitive and psychological problems even after they have withdrawn. We are seeking legal advice because we believe these documents are the bombshell they have been waiting for. The MRC must justify why there was no proper follow-up to Professor Lader's research, no safety committee, no study, nothing to further explore the results. We are talking about a huge scandal here. [ 96 ]


The legal director of  Action Against Medical Accidents  said urgent research must be carried out and said that, if the results of larger studies confirm Professor Lader's research, the government and MRC could be faced with one of the biggest group actions for damages the courts have ever seen, given the large number of people potentially affected. People who report enduring symptoms post-withdrawal such as neurological pain, headaches, cognitive impairment, and memory loss have been left in the dark as to whether these symptoms are drug-induced damage or not due to the MRC's inaction, it was reported. Professor Lader reported that the results of his research did not surprise his research group given that it was already known that alcohol could cause permanent brain changes. [ 96 ]


Benzodiazepines spurred the largest-ever  class-action lawsuit  against  drug manufacturers  in the United Kingdom, in the 1980s and early 1990s, involving 14,000 patients and 1,800  law firms  that alleged the manufacturers knew of the potential for dependence but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of  dependence  and  withdrawal . This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines. [ 97 ]  The court case against the drug manufacturers never reached a verdict;  legal aid  had been withdrawn, leading to the collapse of the trial, and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in  British law , making class-action lawsuits more difficult. [ 98 ]


Benzodiazepines have been found to cause teratogenic malformations. [ 99 ]  The literature concerning the safety of benzodiazepines in pregnancy is unclear and controversial. Initial concerns regarding benzodiazepines in pregnancy began with alarming findings in animals but these do not necessarily cross over to humans. Conflicting findings have been found in babies exposed to benzodiazepines. [ 100 ]  A recent analysis of the Swedish Medical Birth Register found an association with preterm births, low birth weight and a moderate increased risk for congenital malformations. An increase in pylorostenosis or  alimentary tract   atresia  was seen. An increase in orofacial clefts was not demonstrated, however, and it was concluded that benzodiazepines are not major teratogens. [ 101 ]


Neurodevelopmental disorders  and clinical symptoms are commonly found in babies exposed to benzodiazepines  in utero . Benzodiazepine-exposed babies have a  low birth weight  but catch up to normal babies at an early age, but smaller head circumferences found in exposed infants persists. Other adverse effects of benzodiazepines taken during pregnancy are deviating  neurodevelopmental  and clinical symptoms including  craniofacial  anomalies, delayed development of pincer grasp, deviations in  muscle tone  and pattern of movements. Motor impairments in the babies are impeded for up to 1 year after birth. Gross  motor development  impairments take 18 months to return to normal but fine motor function impairments persist. [ 102 ]  In addition to the smaller head circumference found in benzodiazepine-exposed babies  mental retardation , functional deficits, long-lasting behavioural anomalies, and  lower intelligence  occurs. [ 103 ] [ 104 ]


Benzodiazepines, like many other sedative hypnotic drugs, cause  apoptotic   neuronal  cell death. However, benzodiazepines do not cause as severe  apoptosis  to the developing brain as alcohol does. [ 105 ] [ 106 ] [ 107 ]  The  prenatal  toxicity of benzodiazepines is most likely due to their effects on  neurotransmitter systems ,  cell membranes  and  protein synthesis . [ 104 ]  This, however, is complicated in that  neuropsychological  or  neuropsychiatric  effects of benzodiazepines, if they occur, may not become apparent until later  childhood  or even  adolescence . [ 108 ]  A review of the literature found data on long-term follow-up regarding neurobehavioural outcomes is very limited. [ 109 ]  However, a study was conducted that followed up 550 benzodiazepine-exposed children, which found that, overall, most children developed normally. There was a smaller subset of benzodiazepine-exposed children who were slower to develop, but by four years of age most of this subgroup of children had normalised. There was a small number of benzodiazepine-exposed children who had continuing developmental abnormalities at 4-year follow-up, but it was not possible to conclude whether these deficits were the result of benzodiazepines or whether social and environmental factors explained the continuing deficits. [ 110 ]


Concerns regarding whether benzodiazepines during pregnancy cause major malformations, in particular cleft palate, have been hotly debated in the literature. A  meta analysis  of the data from  cohort studies  found no link but  meta analysis  of  case–control studies  did find a significant increase in major malformations. (However, the cohort studies were homogenous and the case–control studies were heterogeneous, thus reducing the strength of the case–control results). There have also been several reports that suggest that benzodiazepines have the potential to cause a syndrome similar to  fetal alcohol syndrome , but this has been disputed by a number of studies. As a result of conflicting findings, use of benzodiazepines during pregnancy is controversial. The best available evidence suggests that benzodiazepines are not a major cause of  birth defects , i.e. major malformations or  cleft lip  or  cleft palate . [ 111 ]


Significant toxicity from benzodiazepines can occur in the elderly as a result of long-term use. [ 112 ]   Benzodiazepines , along with  antihypertensives  and drugs affecting the cholinergic system, are the most common cause of drug-induced  dementia  affecting over 10 percent of patients attending memory clinics. [ 113 ] [ 114 ]  Long-term use of benzodiazepines in the elderly can lead to a pharmacological syndrome with symptoms including  drowsiness ,  ataxia , fatigue,  confusion ,  weakness ,  dizziness ,  vertigo ,  syncope , reversible  dementia ,  depression , impairment of intellect,  psychomotor  and  sexual dysfunction ,  agitation ,  auditory  and  visual hallucinations ,  paranoid ideation ,  panic ,  delirium ,  depersonalization ,  sleepwalking ,  aggressivity ,  orthostatic hypotension  and  insomnia . Depletion of certain neurotransmitters and  cortisol  levels and alterations in immune function and biological markers can also occur. [ 115 ]  Elderly individuals who have been long-term users of benzodiazepines have been found to have a higher incidence of post-operative confusion. [ 116 ]  Benzodiazepines have been associated with increased body sway in the elderly, which can potentially lead to fatal accidents including falls. Discontinuation of benzodiazepines leads to improvement in the balance of the body and also leads to improvements in cognitive functions in the elderly benzodiazepine  hypnotic  users without worsening of insomnia. [ 117 ]


A review of the evidence has found that whilst long-term use of benzodiazepines impairs memory, its association with causing dementia is not clear and requires further research. [ 118 ]  A more recent study found that benzodiazepines are associated with an increased risk of dementia and it is recommended that benzodiazepines be avoided in the elderly. [ 119 ]  A later study, however, found no increase in dementia associated with long-term usage of benzodiazepine. [ 37 ]


María Teresa Miras Portugal  (19 February 1948 – 27 May 2021) [ 1 ]  was a Spanish  scientist , pharmacist, biochemist, molecular biologist and  Emeritus   professor  at the  Complutense University of Madrid . She was a member of the Spanish " Real Academia Nacional de Farmacia " and served as President of this Institution from 2007 to 2013, becoming the first woman to be elected for this position in a Spanish " Real Academia ". [ 2 ] [ 3 ]  She was Honorary President. [ 4 ]


She was also a member of several scientific institutions such as the Spanish Biophysical Society, the Spanish Society of Biochemistry and Molecular Biology, the Spanish Society of Neuroscience, the  European Society for Neurochemistry , the  International Society for Neurochemistry , the Advisory Board of Chromaffin Cells, the Purinergic Club, the editorial board of the  Journal of Neurochemistry , the  IUPHAR  sub-committee for the nomenclature of  P2Y nucleotide receptors  and the Scientific Panel of the  NATO . [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]


María Teresa Miras Portugal was born in 1948 in  O Carballiño  ( Orense ), where she completed her primary and secondary studies. She started her university studies in Pharmacy in the  University of Santiago de Compostela  and continued them at the  Complutense University of Madrid . Her marks at the  Licenciate  university degree led her to get a Special Mention at National Level. [ 10 ]  She completed a PhD in Sciences at the  University of Strasbourg  and Pharmacy at the Complutense University of Madrid. [ 11 ]  She later became a professor of Biochemistry and Molecular Biology at the  University of Oviedo , the  University of Murcia  and the Complutense University of Madrid. [ 12 ]


In her more than 40 years engaged in research, she focused in the study of nucleotide receptors and their impact on neurodegenerative diseases [ 13 ] [ 14 ]  and published more than 350 research articles in specialized journals, [ 2 ]  combining this research with teaching and institutional work. In 2012, she was appointed president of the Committee of Experts for the study of the need for reforms in the Spanish university system. [ 4 ]


In 2005 she received the Alberto Sols Medal to Research in Biochemistry, [ 4 ]  in 2008 the María Josefa Wonenburger Planells Prize by the Xunta de Galicia, [ 15 ]  in 2011 the Community of Madrid honoured her with the Miguel Catalán Research Award for her entire professional career [ 13 ]  and in 2016 in Galicia received the Castelao Medal. [ 16 ]


She was given  honorary doctorates  from the  University of Murcia  and the  King Juan Carlos University  and was an honorific member of the Academia Nacional de Farmacia y Bioquímica de Argentina, Académie Nationale de Pharmacie de France, Académie Européenne des Sciences des Arts et des Lettres and the  European Academy  (physiology and medicine). [ 2 ]


Neuropharmacology  is a  peer-reviewed   scientific journal  in the field of  neuroscience . It was established in 1962 as the  International Journal of Neuropharmacology  and obtained its current name in 1970.


This article about a  neuroscience   journal  is a  stub . You can help Wikipedia by  expanding it .


Neuropsychopharmacology , an interdisciplinary science related to  psychopharmacology  (study of effects of drugs on the mind) and fundamental  neuroscience , is the study of the neural mechanisms that drugs act upon to influence behavior. It entails research of mechanisms of  neuropathology ,  pharmacodynamics (drug action) ,  psychiatric illness , and states of  consciousness . These studies are instigated at the detailed level involving  neurotransmission / receptor  activity,  bio-chemical  processes, and  neural  circuitry. Neuropsychopharmacology supersedes psychopharmacology in the areas of "how" and "why", and additionally addresses other issues of brain function. Accordingly, the clinical aspect of the field includes  psychiatric  (psychoactive) as well as  neurologic  (non-psychoactive) pharmacology-based treatments. Developments in neuropsychopharmacology may directly impact the studies of  anxiety disorders ,  affective disorders ,  psychotic disorders ,  degenerative disorders ,  eating behavior , and  sleep behavior .


Drugs such as  opium ,  alcohol , and certain plants have been used for millennia by humans to ease suffering or change awareness, but until the modern scientific era knowledge of how the substances actually  worked  was quite limited, most pharmacological knowledge being more a series of observation than a coherent model. The first half of the 20th century saw  psychology  and  psychiatry  as largely  phenomenological , in that behaviors or themes which were observed in patients could often be correlated to a limited variety of factors such as childhood experience, inherited tendencies, or injury to specific brain areas. Models of mental function and dysfunction were based on such observations. Indeed, the  behavioral  branch of psychology dispensed altogether with what actually happened inside the brain, regarding most mental dysfunction as what could be dubbed as "software" errors. In the same era, the nervous system was progressively being studied at the microscopic and chemical level, but there was virtually no mutual benefit with clinical fields—until several developments after  World War II  began to bring them together. Neuropsychopharmacology may be regarded to have begun in the earlier 1950s with the discovery of drugs such as  MAO inhibitors ,  tricyclic antidepressants ,  thorazine  and  lithium  which showed some clinical specificity for mental illnesses such as depression and schizophrenia. [ 1 ]  Until that time, treatments that actually targeted these complex illnesses were practically non-existent. The prominent methods which  could  directly affect brain circuitry and neurotransmitter levels were the  prefrontal lobotomy , and  electroconvulsive therapy , the latter of which was conducted without muscle relaxants and both of which often caused the patient great physical and psychological injury.


The field now known as neuropsychopharmacology has resulted from the growth and extension of many previously isolated fields which have met at the core of psychiatric medicine, and engages a broad range of professionals from psychiatrists to researchers in genetics and chemistry. The use of the term has gained popularity since 1990 with the founding of several journals and institutions such as the  Hungarian College of Neuropsychopharmacology . [1]  This rapidly maturing field shows some degree of flux, as research hypotheses are often restructured based on new information.


An implicit premise in neuropsychopharmacology with regard to the psychological aspects is that all states of  mind , including both normal and drug-induced altered states, and diseases involving mental or  cognitive   dysfunction , have a  neurochemical  basis at the fundamental level, and certain circuit pathways in the  central nervous system  at a higher level. (See also:  Neuron doctrine ) Thus the understanding of nerve cells or  neurons  in the brain is central to understanding the mind. It is reasoned that the mechanisms involved can be elucidated through modern  clinical  and research methods such as  genetic manipulation  in animal subjects, imaging techniques such as  functional magnetic resonance imaging  ( fMRI ), and  in vitro  studies using selective binding agents on live tissue cultures. These allow neural activity to be monitored and measured in response to a variety of test conditions. Other important observational tools include  radiological imaging [2]  such as  positron emission tomography  ( PET ) and  single-photon emission computed tomography  ( SPECT ). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10 −10  M such as found with extrastriatal D 1  receptor for dopamine.


One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of  neuropathological  conditions and  psychiatric disorders . More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop  drugs  which act on very specific receptors within a neurotransmitter system. These "hyperselective-action" drugs would allow the direct targeting of specific sites of relevant neural activity, thereby maximizing the  efficacy  (or technically the  potency ) of the drug within the clinical target and minimizing  adverse effects . However, there are some cases when some degree of pharmacological promiscuity is tolerable and even desirable, producing more desirable results than a more selective agent would. An example of this is  Vortioxetine , a drug which is not particularly selective as a serotonin reuptake inhibitor, having a significant degree of serotonin modulatory activity, but which has demonstrated reduced discontinuation symptoms (and reduced likelihood of  relapse ) and greatly reduced incidence of  sexual dysfunction , without loss in antidepressant efficacy.


The groundwork is currently being paved for the next generation of  pharmacological  treatments, which will improve quality of life with increasing efficiency. For example, contrary to previous thought, it is now known that the adult brain does to some extent grow new  neurons —the study of which, in addition to  neurotrophic factors , may hold hope for neurodegenerative diseases like  Alzheimer's ,  Parkinson's ,  ALS , and types of  chorea . All of the  proteins  involved in neurotransmission are a small fraction of the more than 100,000 proteins in the brain. Thus there are many proteins which are not even in the direct path of  signal transduction , any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week. [3]


So far as we know, everything we perceive, feel, think, know, and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the  action potential  may affect the firing of as many as a thousand other neurons in a process called  neurotransmission . In this way signals are generated and carried through networks of neurons, the bulk electrical effect of which can be measured directly on the scalp by an  EEG  device.


By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained. [4]  These features are:


The more recent advances involve understanding at the  organic  molecular level; biochemical action of the  endogenous   ligands ,  enzymes ,  receptor proteins , etc. The critical changes affecting cell firing occur when the signalling neurotransmitters from one neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter systems and receptors are well known, and research continues toward the identification and characterization of a large number of very specific subtypes of receptors. For the six more important neurotransmitters  Glu ,  GABA ,  Ach ,  NE ,  DA , and  5HT  (listed at  neurotransmitter ) there are at least 29 major subtypes of receptor. Further "sub-subtypes" exist together with variants, totalling in the hundreds for just these 6 transmitters.  - (see  serotonin receptor  for example.)  It is often found that receptor subtypes have differentiated function, which in principle opens up the possibility of refined intentional control over brain function.


It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the transmembrane  ion channels  which control the membrane currents via the  ions   K + ,  Na + , and  Ca ++ , and of lesser importance  Mg ++  and  Cl − . The concentration differences between the inside and outside of the cell determine the membrane voltage.


Precisely how these currents are controlled has become much clearer with the advances in receptor structure and  G-protein coupled  processes. Many receptors are found to be pentameric clusters of five transmembrane proteins (not necessarily the same) or  receptor subunits , each a chain of many amino acids. Transmitters typically bind at the junction between two of these proteins, on the parts that protrude from the cell membrane. If the receptor is of the  ionotropic  type, a central pore or channel in the middle of the proteins will be mechanically moved to allow certain ions to flow through, thus altering the ion concentration difference. If the receptor is of the  metabotropic  type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties.


The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying  gene transcription . The  synthesis  of cellular proteins from nuclear  DNA  has the same fundamental machinery [5]  for all cells; the exploration of which now has a firm basis thanks to the  Human Genome Project  which has enumerated the entire human DNA sequence, although many of the estimated 35,000 genes remain to be identified. The complete neurotransmission process extends to the genetic level.  Gene expression  determines protein structures through type II  RNA polymerase . So enzymes which synthesize or breakdown neurotransmitters, receptors, and ion channels are each made from  mRNA  via the DNA transcription of their respective gene or genes. But neurotransmission, in addition to controlling ion channels either directly or otherwise through  metabotropic  processes, also actually modulates gene expression. This is most prominently achieved through modification of the  transcription initiation process  by a variety of transcription factors produced from receptor activity.


Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of  gene knockout . Living specimens can be created using  homolog recombination  in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense.


The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. " dirty drug ") and safe to consume. The 2005  Physicians' Desk Reference  lists twice the number of  prescription drugs  as the 1990 version. [6]  Many people by now are familiar with " selective serotonin reuptake inhibitors ", or SSRIs which exemplify modern  pharmaceuticals . These SSRI  antidepressant  drugs, such as Paxil and Prozac, selectively and therefore primarily inhibit the transport of serotonin which prolongs the activity in the synapse. There are numerous categories of selective drugs, and transport blockage is only one mode of action. The  FDA  has approved drugs which selectively act on each of the major neurotransmitters such as  NE  reuptake inhibitor antidepressants,  DA  blocker  anti-psychotics , and  GABA   agonist   tranquilizers  ( benzodiazepines ).


New endogenous chemicals are continually identified. Specific receptors have been found for the drugs  THC  (cannabis) and  GHB , [7]  with endogenous transmitters anandamide and GHB.  Another recent major discovery occurred in 1999 when  orexin , or hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors the condition of  narcolepsy . Orexin agonism may explain the antinarcoleptic action of the drug  modafinil  which was already being used only a year prior.


The next step, which major  pharmaceutical companies  are currently working hard to develop, are receptor subtype-specific drugs and other specific agents. An example is the push for better anti-anxiety agents ( anxiolytics ) based on GABA A (α2) agonists,  CRF 1  antagonists, and 5HT 2c  antagonists. [8]  Another is the proposal of new routes of exploration for antipsychotics such as  glycine reuptake inhibitors . [9]  Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide  anatomical  specificity. By altering receptor function in one part of the brain, abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D 2  altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of  dyskinesias  by their action on motor cortex.


Modern studies are revealing details of mechanisms of damage to the nervous system such as  apoptosis  (programmed cell death) and  free-radical  disruption.  Phencyclidine  has been found to cause cell death in striatopallidal cells and abnormal  vacuolization  in  hippocampal  and other neurons. The  hallucinogen persisting perception disorder  (HPPD), also known as  post-psychedelic perception disorder , has been observed in patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can decrease some effects of LSD intoxication). The damage may be the result of an  excitotoxic  response of 5HT 2   interneurons . [Note: the vast majority of LSD users do not experience HPPD. Its manifestation may be equally dependent on individual brain chemistry as on the drug use itself.] As for  MDMA , aside from persistent losses of 5HT and  SERT , long-lasting reduction of serotonergic  axons  and terminals is found from short-term use, and regrowth may be of compromised function.


Many functions of the brain are somewhat localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioral, and genetic correlates of receptor action, completing the knowledge of neural signalling  (see also:  Human Cognome Project ) . The signal paths of neurons are hyperorganized beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may be seen in the following abstracts.


Almost all drugs with a known potential for abuse have been found to modulate activity (directly or indirectly) in the mesolimbic dopamine system, which includes and connects the ventral tegmental area in the midbrain to the hippocampus, medial prefrontal cortex, and amygdala in the forebrain; as well as the nucleus accumbens in the ventral striatum of the basal ganglia. [ 2 ]  In particular, the nucleus accumbens (NAc) plays an important role in integrating experiential memory from the hippocampus, emotion from the amygdala, and contextual information from the PFC to help associate particular stimuli or behaviors with feelings of pleasure and reward; continuous activation of this reward indicator system by an addictive drug can also cause previously neutral stimuli to be encoded as cues that the brain is about to receive a reward. This happens via the selective release of dopamine, a neurotransmitter responsible for feelings of euphoria and pleasure. The use of dopaminergic drugs alters the amount of dopamine released throughout the mesolimbic system, and regular or excessive use of the drug can result in a long-term downregulation of dopamine signaling, [ 3 ]  even after an individual stops ingesting the drug. This can lead the individual to engage in mild to extreme drug-seeking behaviors as the brain begins to regularly expect the increased presence of dopamine and the accompanying feelings of euphoria, but how problematic this is depends highly on the drug and the situation.


Significant progress has been made on central mechanisms of certain  hallucinogenic drugs . It is at this point known with relative certainty that the primary shared effects of a broad pharmacological group of hallucinogens, sometimes called the "classical psychedelics", can be attributed largely to agonism of serotonin receptors. The 5HT 2A  receptor, which seems to be the most critical receptor for psychedelic activity, and the 5HT 2C  receptor, which is a significant target of most psychedelics but which has no clear role in hallucinogenesis, are involved by releasing  glutamate  in the  frontal cortex , while simultaneously in the  locus coeruleus  sensory information is promoted and spontaneous activity decreases. 5HT 2A  activity has a net pro-dopaminergic effect, whereas 5HT 2C  receptor agonism has an inhibitory effect on dopaminergic activity, particularly in the prefrontal cortex. One hypothesis suggests that in the frontal cortex, 5HT 2A  promotes late asynchronous  excitatory postsynaptic potentials , a process antagonized by serotonin itself through 5HT 1  receptors, which may explain why SSRIs and other serotonin-affecting drugs do not normally cause a patient to hallucinate. However, the fact that many classical psychedelics do in fact have significant affinity for 5HT 1  receptors throws this claim into question. The head twitch response, a test used for assessing classical psychedelic activity in rodents, is produced by serotonin itself only in the presence of beta-Arrestins, but is triggered by classical psychedelics independent of beta-Arrestin recruitment. [ 4 ]  This may better explain the difference between the pharmacology of serotonergic neurotransmission (even if promoted by drugs such as SSRIs) and that of classical psychedelics. Newer findings, however, indicate that binding to the 5HT 2A - mGlu2   heterodimer  is also necessary for classical psychedelic activity. [ 5 ] [ 6 ] [ 7 ]  This, too, may be relevant to the pharmacological differences between the two. While early in the history of psychedelic drug research it was assumed that these hallucinations were comparable to those produced by psychosis and thus that classical psychedelics could serve as a model of psychosis, it is important to note that modern neuropsychopharmacological knowledge of psychosis has progressed significantly since then, and we now know that psychosis shows little similarity to the effects of classical psychedelics in mechanism, reported experience or most other respects aside from the surface similarity of "hallucination"..


Circadian rhythm , or sleep/wake cycling, is centered in the  suprachiasmatic nucleus  (SCN) within the hypothalamus, and is marked by  melatonin  levels 2000–4,000% higher during sleep than in the day. A circuit is known to start with  melanopsin  cells in the eye which stimulate the SCN through glutamate neurons of the  hypothalamic tract . GABAergic neurons from the SCN inhibit the  paraventricular nucleus , which signals the  superior cervical ganglion  (SCG) through  sympathetic  fibers. The output of the SCG, stimulates NE receptors ( β ) in the  pineal gland  which produces N-acetyltransferase, causing production of melatonin from serotonin. Inhibitory melatonin receptors in the SCN then provide a positive feedback  pathway . Therefore, light  inhibits  the production of melatonin which " entrains " the 24-hour cycle of SCN activity. [10] [11]  The SCN also receives signals from other parts of the brain, and its (approximately) 24-hour cycle does not only depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle  in vitro  for many days. Additionally, (not shown in diagram), the  basal nucleus  provides GABA-ergic inhibitory input to the  pre-optic anterior hypothalamus  (PAH). When  adenosine  builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity.  Caffeine  is known to block adenosine receptors, thereby inhibiting sleep among other things.


Research in the field of neuropsychopharmacology encompasses a wide range of objectives. These might include the study of a new chemical compound for potentially beneficial cognitive or behavioral effects, or the study of an old chemical compound in order to better understand its mechanism of action at the cell and neural circuit levels. For example, the addictive stimulant drug cocaine has long been known to act upon the reward system in the brain, increasing dopamine and norepinephrine levels and inducing euphoria for a short time. More recently published studies however have gone deeper than the circuit level and found that a particular G-protein coupled receptor complex called A2AR-D2R-Sigma1R is formed in the NAc following cocaine usage; this complex reduces D2R signaling in the mesolimbic pathway and may be a contributing factor to cocaine addiction. [ 8 ]  Other cutting-edge studies have focused on genetics to identify specific biomarkers that may predict an individual's specific reactions or degree of response to a drug or their tendency to develop addictions in the future. [ 9 ]  These findings are important because they provide detailed insight into the neural circuitry involved in drug use and help refine old as well as develop new treatment methods for disorders or addictions. Different treatment-related studies are investigating the potential role of peptide nucleic acids in treating Parkinson's disease and schizophrenia [ 10 ]  while still others are attempting to establish previously unknown neural correlates underlying certain phenomena. [ 11 ]


Research in neuropsychopharmacology comes from a wide range of activities in neuroscience and clinical research. This has motivated organizations such as the  American College of Neuropsychopharmacology  (ACNP) , the  European College of Neuropsychopharmacology  (ECNP) , and the  Collegium Internationale Neuro-psychopharmacologicum  (CINP)  to be established as a measure of focus.
The  ECNP  publishes  European Neuropsychopharmacology , and as part of the  Reed Elsevier Group , the ACNP publishes the journal  Neuropsychopharmacology , and the CINP publishes the journal  International Journal of Neuropsychopharmacology [ permanent dead link  ]  with  Cambridge University Press .
In 2002, a recent comprehensive collected work of the ACNP, "Neuropsychopharmacology: The Fifth Generation of Progress" was compiled. It is one measure of the state of knowledge in 2002, and might be said to represent a landmark in the century-long goal to establish the basic neurobiological principles which govern the actions of the brain.


Many other journals exist which contain relevant information such as  Neuroscience .
Some of them are listed at  Brown University Library .


Neurotrophin mimetics  are small molecules or peptide like molecules that can modulate the action of the neurotrophin receptor.
One of the main causes of  neurodegeneration  involves changes in the expression of  neurotrophins  (NTs) and/or their receptors ( TrkA ,  TrkB ,  TrkC  and  p75NTR ). Indeed, these imbalances or changes in their activity, lead to neuronal damage resulting in neurological and neurodegenerative conditions. The therapeutic properties of neurotrophins attracted the focus of many researchers during the years, but the poor  pharmacokinetic  properties, such as reduced  bioavailability  and low metabolic stability, the  hyperalgesia , the inability to penetrate the  blood–brain barrier  and the short  half-lives  render the large neurotrophin proteins not suitable to be implemented as drugs. [ 1 ]


For this reason, several efforts have been made to develop neurotrophin mimetics (small molecules and  peptidomimetics ) that can modulate the action of the neurotrophin receptors ( Trks  and p75NTR) and possess drug-like pharmacokinetic and  pharmacodynamic  profiles. Specifically, these mimetics can be classified as TrkA and TrkB receptor agonists and p75NTR modulators/antagonists. [ 2 ]


Among the TrkA agonists, the small molecule gambogic amide exerts a potent neurotrophic activity decreasing  apoptosis  in primary  hippocampal  neurons. [ 3 ]  The non-peptidic TrkA agonist MT2 protects neurons from  Aβ amyloid -mediated death in  NGF -deficient neurons [ 4 ]  and talaumidin and its derivatives show  neuroprotective  effects, promoting  neurite outgrowth  in  PC12 cells . [ 5 ]  Furthermore, the  peptidomimetic   cerebrolysin  is known for its  protective  role in  Alzheimer's disease  (AD). [ 6 ]  It was shown to improve the activities of daily living and the psychiatric symptoms in patients with mild to severe form of AD, after intravenous administration in a  double-blind trial . [ 7 ]  In addition, the cyclic peptide  tavilermide  (MIM-D3), acting as a partial  TrkA  receptor agonist, showed a relevant improvement of  cognitive capacities  of treated aged rats, leading to a selective survival of the  cholinergic neurons . [ 8 ]


A  phase 3 clinical trial  of 5% and 1% tavilermide ophthalmic solutions for the treatment of dry eye was completed in 2020 (NCT03925727), with positive results concerning safety and efficacy. Recent studies demonstrated the neurotrophic activity of  carvacrol  by inducing neurite outgrowth and  phosphorylation  of TrkA in cells deprived of NGF. [ 9 ]  The same research group investigated the neurotrophic effect of the well-known antibiotic  doxycycline  and they found that it prevents amyloid toxicity in a  Drosophila  model of AD both  in vitro  and  in vivo  and induces neuritogenesis by activation of TrkA. [ 10 ]


Additionally, some novel  DHEA  derivatives were shown to be TrkA agonists. In particular, the C17-spiroepoxy derivative,  BNN-27 , [ 11 ]  induces phosphorylation of TrkA in neuronal and  glial cells  in culture and it exerts  antiapoptotic  effect without inducing  hyperalgesia . [ 12 ]  Moreover, it improved memorizing abilities in rats after i.p. administration [ 13 ]  and restored the  myelin  loss in cuprizone-induced  demyelination   in vivo . [ 14 ]  Moreover, the C17-spirocyclopryl DHEA derivatives, ENT-A010 and ENT-A013, were shown to be potent TrkA agonists. [ 15 ] [ 16 ]  In particular, ENT-A010 acts as dual TrkA and TrkB agonist while, ENT-A013 acts as a selective TrkA agonist. Both induce phosphorylation of TrkA and its  downstream signaling pathways , and promote  cell survival  of PC12 cells from serum deprivation. In addition, they exhibit potent neuroprotective effects in  dorsal root ganglia  and anti-amyloid activity in hippocampal neurons. [ 15 ] [ 16 ]


TrkB agonists have received extensive interest from the scientific community resulting in the synthesis and biological evaluation of a large number of mimetics.  Deoxygedunin , with a selective TrkB activity, is able to promote  axon regeneration  in topical treatments. [ 17 ]  Furthermore, it shows efficacy in two  Parkinson's disease  (PD) animal models, leading to the protection of  locomotor function  and the reduction of  neuronal death  in  dopaminergic neurons . [ 18 ]  A number of studies corroborated that the  flavonoid  7,8-Dihydroxyflavone (7,8-DHF) shows neuroprotection in PD and  Huntington's disease  (HD) models [ 19 ] [ 20 ]  together with  antioxidant activity [ 21 ]  and enhancement of motor neuronal survival, motor function and spine density in  amyotrophic lateral sclerosis  (ALS) model. [ 22 ]  The benzothiazole  riluzole  exerts neuroprotective effects by increasing  BDNF  and  GDNF  levels with improvement of motor neuron survival. It has been approved for the treatment of ALS and delays the onset of  ventilator-dependence  or  tracheostomy  in some people and may increase survival by two to three months. [ 23 ]  Furthermore, several combinations of riluzole with other drugs are in clinical trials (NCT02588677, NCT03127267).


Brimonidine  exerts neuroprotective effects in  retinal ganglion cells  (RGCs) through up-regulation of the expression of BDNF in these cells. [ 24 ]  It is used in the treatment of  glaucoma  as eye drops to reduce  intraocular pressure  (IOP) under the brand name Lumify®. Different drugs, used against PD also behave as neurotrophin mimetics such as  rotigotine ,  selegiline ,  rasagiline ,  memantine  and  levodopa  interacting with TrkB and increasing BDNF expression. [ 25 ]  Furthermore, of particular note, the groups of F. Longo and S. Massa discovered small molecule neurotrophic mimetics exhibiting  specificity  for TrkB at  nanomolar concentrations . [ 26 ]  In particular,  LM22A-4 , prevents neuronal death in  in vitro  models of AD, HD and PD. [ 27 ]


Among the peptidomimetic TrkB agonists, the dimeric dipeptide GSB-106 showed neurotrophic and neuroprotective effects by specific activation of TrkB and its  signaling pathways . [ 28 ] [ 29 ]  Furthermore, the tricyclic dimeric peptide TDP6 acts as a TrkB agonist mimicking BDNF and induces  autophosphorylation  of TrkB in primary  oligodendrocyte  cultures, leading to oligodendrocyte myelination. [ 30 ]  Regarding DHEA derivatives, the C17-spiroepoxy analogue,  BNN-20 , binds with high affinity to TrkB, showing antiapoptotic activity  in vitro . Its neuroprotective activity was analyzed in the  Weaver mouse  genetic model of PD in which long term administration of BNN-20 protects the dopaminergic neurons by mimicking BDNF and induces antiapoptotic, antioxidant and anti-inflammatory effects. [ 11 ] [ 31 ]


In this class it is worthwhile to highlight the small non-peptide molecules LM22A-24 and  LM11A-31  developed by Longo and Massa. Through the modulation of  p75NTR  activity, these compounds downregulate degenerative and upregulate trophic signaling. [ 32 ]  In particular, LM11A-31 was found to inhibit several pathophysiological mechanisms involved in AD and related to p75NTR. [ 33 ] [ 34 ]  Oral administration in AD mice models reduces degeneration of cholinergic neurites. [ 34 ]  Furthermore, by a direct activation of p75NTR signaling and inhibition of apoptotic pathway, it improves motor function in a  spinal cord injury  (SCI) mice model and leads to an antiapoptotic effect in mice after  traumatic brain injury  (TBI). [ 35 ] [ 36 ]  In February 2017, a  phase 2 clinical trial  started focusing on the evaluation of the safety of LM11A-31 in mild to moderate AD (NCT03069014). This study was completed in June 2020, but the results have not been published yet.


Another drug belonging to the class of p75NTR antagonists is THX-B, which inhibits NGF-p75NTR binding and prevents the death of RGCs in  axotomy  and glaucoma. In addition, in combination with LM22A-24, THX-B delays the loss of retinal structure, prevents RGC degeneration and preserves  ganglion cell layer - inner plexiform layer  thickness with a better efficacy compared to LM22A-24. [ 37 ]  Finally, a p75NTR antagonist, EVT901, was able to improve functional outcomes in two models of traumatic brain injury. [ 38 ]  Furthermore it was found to reduce inflammation  in vivo  in the TGFAD344 rat model of AD. [ 39 ]


There are a number of natural products with neurotrophic activity, which results from several mechanisms including enhancing BDNF  gene transcription , upregulating the expression of BDNF and TrkB, and  extracellular signal-regulated kinase  (ERK) and  CREB  signalling. [ 40 ] [ 41 ] [ 42 ]


The first discovered non-protein neurotrophic natural product was  lactacystin , isolated from a culture broth of  Streptomyces sp . [ 40 ]   Magnolol  and  honokiol , the main constituents of  Magnolia officinalis  and  Magnolia obovata  stem bark, have been reported to have neurotrophic activity in primary cultured rat cortical by enhancing the BDNF expression. [ 41 ] [ 42 ]   Merrilactone A , jiadifenin,  jiadifenolide , (1R,10S)-2-oxo-3,4-dehydroxyneomajucin, jiadifenoxolane A, (2R)-hydroxynorneomajucin, 11- O -debenzoyltashironin,tricycloillicinone, and bicycloillicinone, natural products of the  Illicium  family have been shown to promote neurite outgrowth in primary cultures of cortical neurons of fetal rats. [ 40 ] [ 41 ]  Neurotrophic properties are also possessed by several members of the  Lycopodium   alkaloids  ( huperzine A , lyconadins, complanadine A and B, and nankakurine A and B). Studies have shown that huperazine A can elevate the levels of NGF and BDNF. Synthesis of NGF can be upregulated by administration of cyathanediterpenoids specifically  erinacines ,  scabronines  and cyrneines. [ 40 ]


Some  flavonoids ,  Isoflavonoids  and  neoflavonoids  were found to have neuroprotective activity. Among the effective flavonoids,  luteolin  from  Lonicera japonica sp. ,  isorhamnetin  from  Opuntia ficus-indica ,  genistein  from  Genista tinctoria , and  calycosin  from  Astragalus membranaceus  showed the most promising effects by increasing the  mRNA expression  and  protein secretion  of NGF, GDNF, and BDNF. [ 42 ]  Paecilomycine A and spirotenuipesines A and B, members of the  trichothecenes , isolated from the  fruiting bodies  of  Paecilomycestenuipes,  have significant neurotrophic profiles especially paecilomycine A which can stimulate the synthesis of neurotrophic factors. [ 40 ]  Polyprenylatedacylphloroglucinols (PPAPs) represented by  hyperforin ,  hypericin  and garsubellin A, have neurotrophic like properties. Hyperforin, isolated from the herb  St. John's wort  ( Hypericum perforatum ), can stimulate the upregulation of the TrkB receptor. [ 40 ] [ 42 ]


Beside natural products, there are some small molecules of natural origin that exert neurotrophic activities such as:  Panaxytriol  (promotes NGF-induced neurite outgrowth in PC-12 cells); 7,8- dihydroxyflavone  (TrkB activator);  Deoxygedunin  (BDNF mimetic); Kansuinin E (promotes neurotrophic activity, most likely through TrkA activation);  Tripchlorolide  (stimulates expression of BDNF mRNA);  Fucoxanthin  (increases BDNF production and activates PKA/CREB pathway);  Silibinin  (Activate hippocampal ROS-BDNF-TrkB patway). [ 40 ] [ 42 ]


OSU-6162  ( PNU-96391 ) is a compound which acts as a  partial agonist  at both  dopamine D 2  receptors  and  5-HT 2A  receptors . It acts as a dopamine stabilizer in a similar manner to the closely related drug  pridopidine , and has  antipsychotic , anti- addictive  and anti- Parkinsonian  effects in animal studies. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ]  Both  enantiomers  show similar activity but with different ratios of effects, with the (S) enantiomer (–)-OSU-6162 that is more commonly used in research, having higher  binding affinity  to D 2  but is a weaker partial agonist at 5-HT 2A , while the (R) enantiomer (+)-OSU-6162 has higher efficacy at 5-HT 2A  but lower D 2  affinity. [ 15 ] [ 16 ]


A  psychiatric  or  psychotropic medication  is a  psychoactive drug  taken to exert an effect on the chemical makeup of the  brain  and nervous system. Thus, these medications are used to treat  mental illnesses . These medications are typically made of  synthetic   chemical compounds  and are usually prescribed in  psychiatric  settings, potentially  involuntarily  during  commitment . Since the mid-20th century, such medications have been leading treatments for a broad range of mental disorders and have decreased the need for long-term hospitalization, thereby lowering the cost of mental health care. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The  recidivism  or rehospitalization of the mentally ill is at a high rate in many countries, and the reasons for the  relapses  are under research. [ 5 ] [ 6 ] [ 7 ] [ 8 ]


Several significant psychiatric drugs were developed in the mid-20th century. In 1948,  lithium  was first used as a psychiatric medicine. One of the most important discoveries was  chlorpromazine , an  antipsychotic  that was first given to a patient in 1952. In the same decade,  Julius Axelrod  carried out research into the interaction of neurotransmitters, which provided a foundation for the development of further drugs. [ 9 ]   The popularity of these drugs have increased significantly since then, with millions prescribed annually. [ 10 ]


The introduction of these drugs brought profound changes to the treatment of mental illness. It meant that more patients could be treated without the need for confinement in a  psychiatric hospital . It was one of the key reasons why many countries moved towards  deinstitutionalization , closing many of these hospitals so that patients could be treated at home, in general hospitals and smaller facilities. [ 11 ] [ 12 ]  Use of physical restraints such as  straitjackets  also declined.


As of 2013, the 10 most prescribed psychiatric drugs by number of prescriptions were  alprazolam ,  sertraline ,  citalopram ,  fluoxetine ,  lorazepam ,  trazodone ,  escitalopram ,  duloxetine ,  bupropion XL , and  venlafaxine XR . [ 13 ]


Psychiatric medications are  prescription medications , requiring a prescription from a  physician , such as a  psychiatrist , or a psychiatric  nurse practitioner , PMHNP, before they can be obtained. Some  U.S. states  and  territories , following the creation of the  prescriptive authority for psychologists movement , have granted prescriptive privileges to  clinical psychologists  who have undergone additional specialised education and training in  medical psychology . [ 14 ]  In addition to the familiar dosage in pill form, psychiatric medications are evolving into more novel methods of drug delivery. New technologies include  transdermal ,  transmucosal ,  inhalation ,  suppository  or  depot injection  supplements. [ 15 ] [ 16 ]


Psychopharmacology studies a wide range of substances with various types of psychoactive properties. The professional and commercial fields of  pharmacology  and psychopharmacology do not typically focus on  psychedelic  or  recreational drugs , and so the majority of studies are conducted on psychiatric medication. While studies are conducted on all psychoactive drugs by both fields, psychopharmacology focuses on psychoactive and chemical interactions within the brain. Physicians who research psychiatric medications are  psychopharmacologists , specialists in the field of psychopharmacology.


Psychiatric disorders, including depression, psychosis, and bipolar disorder, are common and gaining more acceptance in the United States. The most commonly used classes of medications for these disorders are antidepressants, antipsychotics, and lithium. Unfortunately, these medications are associated with significant neurotoxicities.


Psychiatric medications carry risk for neurotoxic  adverse effects . The occurrence of neurotoxic effects can potentially reduce  drug compliance . Some adverse effects can be  treated symptomatically   by using adjunct medications such as  anticholinergics  (antimuscarinics). Some  rebound  or  withdrawal  adverse effects, such as the possibility of a sudden or severe emergence or re-emergence of  psychosis  in antipsychotic withdrawal, may appear when the drugs are discontinued, or discontinued too rapidly. [ 17 ]


While  clinical trials  of psychiatric medications, like other medications, typically test medicines separately, there is a practice in psychiatry (more so than in somatic medicine) to use  polypharmacy  in combinations of medicines that have never been tested together in clinical trials (though all medicines involved have passed clinical trials separately). It is argued that this presents a risk of adverse effects, especially  brain damage , in real-life mixed medication psychiatry that are not visible in the clinical trials of one medicine at a time (similar to mixed drug abuse causing significantly more damage than the additive effects of brain damages caused by using only one illegal drug). Outside clinical trials, there is evidence for an increase in mortality when psychiatric patients are transferred to polypharmacy with an increased number of medications being mixed. [ 18 ] [ 19 ] [ 20 ]


There are five main groups of psychiatric medications.


Antidepressants are drugs used to treat  clinical depression , and they are also often used for anxiety and other disorders. Most antidepressants will hinder the breakdown of  serotonin ,  norepinephrine , and/or  dopamine . A commonly used class of antidepressants are called  selective serotonin reuptake inhibitors  (SSRIs), which act on serotonin transporters in the brain to increase levels of serotonin in the  synaptic cleft . [ 22 ]  Another is the  serotonin-norepinephrine reuptake inhibitors  (SNRIs), which increase both serotonin and norepinephrine. Antidepressants will often take 3–5 weeks to have a noticeable effect as the regulation of receptors in the brain adapts. There are multiple classes of antidepressants which have different mechanisms of action. Another type of antidepressant is a  monoamine oxidase inhibitor  (MAOI), which is thought to block the action of  monoamine oxidase , an enzyme that breaks down serotonin and  norepinephrine . MAOIs are not used as first-line treatment due to the risk of  hypertensive crisis  related to the consumption of foods containing the amino acid  tyramine . [ 22 ]


Common antidepressants:


Antipsychotics are drugs used to treat various symptoms of psychosis, such as those caused by psychotic disorders or  schizophrenia .  Atypical antipsychotics  are also used as  mood stabilizers  in the treatment of  bipolar disorder , and they can augment the action of antidepressants in  major depressive disorder . [ 22 ]
Antipsychotics are sometimes referred to as neuroleptic drugs and some antipsychotics are branded "major tranquilizers".


There are two categories of antipsychotics:  typical antipsychotics  and  atypical antipsychotics . Most antipsychotics are available only by prescription.


Common antipsychotics:


Benzodiazepines  are effective as hypnotics, anxiolytics, anticonvulsants, myorelaxants and amnesics. [ 24 ]   Having less proclivity for overdose and toxicity, they have widely supplanted  barbiturates , although barbiturates (such as  pentobarbital ) are still used for  euthanasia . [ 25 ] [ 26 ]


Developed in the 1950s onward, benzodiazepines were originally thought to be non-addictive at therapeutic doses, but are now known to cause  withdrawal  symptoms similar to barbiturates and  alcohol . [ 27 ]  Benzodiazepines are generally recommended for short-term use. [ 24 ]


Z-drugs  are a group of drugs with effects generally similar to benzodiazepines, which are used in the treatment of insomnia.


Common benzodiazepines and z-drugs include:


In 1949, the Australian  John Cade  discovered that  lithium salts  could control  mania , reducing the frequency and severity of manic episodes. This introduced the now popular drug  lithium carbonate  to the mainstream public, as well as being the first mood stabilizer to be approved by the U.S.  Food & Drug Administration .
Besides lithium, several  anticonvulsants  and  atypical antipsychotics  have mood stabilizing activity. The mechanism of action of mood stabilizers is not well understood.


Common non-antipsychotic mood stabilizers include:


A stimulant is a drug that stimulates the central nervous system, increasing arousal, attention and endurance. Stimulants are used in psychiatry to treat  attention deficit-hyperactivity disorder . Because the medications can be addictive, patients with a history of drug abuse are typically monitored closely or treated with a non-stimulant.


Common stimulants:


Professionals, such as  David Rosenhan ,  Peter Breggin ,  Paula Caplan ,  Thomas Szasz  and  Stuart A. Kirk  sustain that psychiatry engages "in the systematic medicalization of normality". [ 28 ]  More recently these concerns have come from insiders who have worked for and promoted the APA (e.g.,  Robert Spitzer ,  Allen Frances ). [ 29 ] : 185


Scholars such as  Cooper ,  Foucalt ,  Goffman ,  Deleuze  and  Szasz  believe that pharmacological "treatment" is only a  placebo  effect, [ 30 ]  and that administration of drugs is just a  religion  in disguise and ritualistic chemistry. [ 31 ]  Other scholars [ who? ]  have argued against psychiatric medication in that significant aspects of mental illness are related to the psyche or environmental factors, but medication works exclusively on a pharmacological basis.