Information

LSD and tryptamines harmless or neurotoxic?

LSD and tryptamines harmless or neurotoxic?

It's commonly stated by numerous people that LSD and trytamines like DMT and psilocin are physically harmless and not neurotoxic. Is there evidence for this?

I recently read 5-meo-Dipt which is a tryptamine might be neurotoxic. Why would 5-meo-Dipt be neurotoxic but DMT and psilocin not be? From my understanding some people micro-dose with LSD and some tryptamines to feel sharper and increase felt intelligence.

Why would one tryptamine neurotoxic and others make someone feel more intelligent? Obviously "feel" is self reported and subjective, but I'm assuming there might be some truth to this if people aren't tripping when experiencing these micro dosing effects. LSD isn't a tryptamine, but I think some people do similar things with tryptamines. I'm hoping someone with a better understand of neurology can answer this.

To restate my question are typtamines and LSD generally neurotoxic and if not, could you please link to a study on it and what mechanism makes 5-meo-dipt possibly different, could other factors might have lead to a wrong conclusion, like for example harmful environment stress on rats or do you think all tryptamines are neurotoxic?

I'm trying to understand the possible reasons or lack there of for neurotoxicity in LSD and tryptamines but there seems to be lack of reliable sources.


Short answer
All neuropsychopharmaceuticals, including the tryptamines, are potentially neurotoxic depending on the dose at which they are ingested.

Background

Neurotoxicity is, arguaby, a broad definition. According to the NIH, neurotoxicity can be caused by processes ranging from radiation to transplants, and from chemical toxins to cosmetics. NIH defines neurotoxicity as:

Neurotoxicity occurs when the exposure to natural or manmade toxic substances (neurotoxicants) alters the normal activity of the nervous system. This can eventually disrupt or even kill neurons, key cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from exposure to substances used in chemotherapy, radiation treatment, drug therapies, and organ transplants, as well as exposure to heavy metals such as lead and mercury, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances.

LSD is a tryptamine (Shulgin, & Shulgin, 1997), see Fig. 1.


Fig. 1. LSD contains the tryptamine structure (in red). source: Shroomery

Secondly, every compound is toxic when taken in large quantities. For instance, water can kill, referred to as water intoxication, for example as seen in people tripping on MDMA and taking in too much water (Ballantyne, 2007). Oxygen, another key to life, is a deadly gas when taken in artificially high concentrations for too long. Likewise, neuropharmacologically active compounds will hence eventually become neurotoxins. This, because the definition of neurotoxic is indeed quite broad (source: NIH):

Neurotoxicity occurs when the exposure to natural or manmade toxic substances (neurotoxicants) alters the normal activity of the nervous system. This can eventually disrupt or even kill neurons, key cells that transmit and process signals in the brain and other parts of the nervous system.

Thus when you ask

are tryptamines, including LSD [sic] generally neurotoxic?

Then the answer is yes, depending on the dose.

Reversely, then, every neurotoxin becomes non-toxic once taken below a certain threshold dose. If this is what you refer to by 'microdosages', then yes, even the most potent toxin becomes harmless.

To specifically answer your question with regard to LSD and psilocin: LSD is suspected to be neurotoxic at clinically applied dosages (Larsen, 2014), and psilocin can result in convulsions and death follow massive overdose (Gold et al., 2003).

References
- Ballantyne, Sci Am 2007
- Gold et al., Atlas of Clinical Neurology, Springer. pp 503-24
- Larsen, Hist Psychiatry (2016); 27(2):172-89
- Shulgin & Shulgin, Tihkal - The Continuation, pp. 490-99


Contents

Early psychopharmacology Edit

Not often mentioned or included in the field of psychopharmacology today are psychoactive substances not identified as useful in modern mental health settings or references. These substances are naturally occurring, but nonetheless psychoactive, and are compounds identified through the work of ethnobotanists and ethnomycologists (and others who study the native use of naturally occurring psychoactive drugs). However, although these substances have been used throughout history by various cultures, and have a profound effect on mentality and brain function, they have not always attained the degree of scrutinous evaluation that lab-made compounds have. Nevertheless, some, such as psilocybin and mescaline, have provided a basis of study for the compounds that are used and examined in the field today. Hunter-gatherer societies tended to favor hallucinogens, and today their use can still be observed in many surviving tribal cultures. The exact drug used depends on what the particular ecosystem a given tribe lives in can support, and are typically found growing wild. Such drugs include various psychoactive mushrooms containing psilocybin or muscimol and cacti containing mescaline and other chemicals, along with myriad other psychoactive-chemical-containing plants. These societies generally attach spiritual significance to such drug use, and often incorporate it into their religious practices. With the dawn of the Neolithic and the proliferation of agriculture, new psychoactives came into use as a natural by-product of farming. Among them were opium, cannabis, and alcohol derived from the fermentation of cereals and fruits. Most societies began developing herblores, lists of herbs which were good for treating various physical and mental ailments. For example, St. John's wort was traditionally prescribed in parts of Europe for depression (in addition to use as a general-purpose tea), and Chinese medicine developed elaborate lists of herbs and preparations. These and various other substances that have an effect on the brain are still used as remedies in many cultures. [2]

Modern psychopharmacology Edit

The dawn of contemporary psychopharmacology marked the beginning of the use of psychiatric drugs to treat psychological illnesses. It brought with it the use of opiates and barbiturates for the management of acute behavioral issues in patients. In the early stages, psychopharmacology was primarily used for sedation. With the 1950s came the establishment of lithium for mania, chlorpromazine for psychoses, and then in rapid succession, the development of tricyclic antidepressants, monoamine oxidase inhibitors, and benzodiazepines, among other antipsychotics and antidepressants. A defining feature of this era includes an evolution of research methods, with the establishment of placebo-controlled, double-blind studies, and the development of methods for analyzing blood levels with respect to clinical outcome and increased sophistication in clinical trials. The early 1960s revealed a revolutionary model by Julius Axelrod describing nerve signals and synaptic transmission, which was followed by a drastic increase of biochemical brain research into the effects of psychotropic agents on brain chemistry. [3] After the 1960s, the field of psychiatry shifted to incorporate the indications for and efficacy of pharmacological treatments, and began to focus on the use and toxicities of these medications. [4] [5] The 1970s and 1980s were further marked by a better understanding of the synaptic aspects of the action mechanisms of drugs. However, the model has its critics, too – notably Joanna Moncrieff and the Critical Psychiatry Network. [ citation needed ]

Neurotransmitters Edit

Psychoactive drugs exert their sensory and behavioral effects almost entirely by acting on neurotransmitters and by modifying one or more aspects of synaptic transmission. Neurotransmitters can be viewed as chemicals through which neurons primarily communicate psychoactive drugs affect the mind by altering this communication. Drugs may act by 1) serving as a precursor for the neurotransmitter 2) inhibiting neurotransmitter synthesis 3) preventing storage of neurotransmitter in the presynaptic vesicle 4) stimulating or inhibiting neurotransmitter release 5) stimulating or blocking post-synaptic receptors 6) stimulating autoreceptors, inhibiting neurotransmitter release 7) blocking autoreceptors, increasing neurotransmitter release 8) inhibiting neurotransmission breakdown or 9) blocking neurotransmitter reuptake by the presynaptic neuron. [1]

Hormones Edit

The other central method through which drugs act is by affecting communications between cells through hormones. Neurotransmitters can usually only travel a microscopic distance before reaching their target at the other side of the synaptic cleft, while hormones can travel long distances before reaching target cells anywhere in the body. Thus, the endocrine system is a critical focus of psychopharmacology because 1) drugs can alter the secretion of many hormones 2) hormones may alter the behavioral responses to drugs 3) hormones themselves sometimes have psychoactive properties and 4) the secretion of some hormones, especially those dependent on the pituitary gland, is controlled by neurotransmitter systems in the brain. [1]

Alcohol Edit

Alcohol is a depressant, the effects of which may vary according to dosage amount, frequency, and chronicity. As a member of the sedative-hypnotic class, at the lowest doses, the individual feels relaxed and less anxious. In quiet settings, the user may feel drowsy, but in settings with increased sensory stimulation, individuals may feel uninhibited and more confident. High doses of alcohol rapidly consumed may produce amnesia for the events that occur during intoxication. Other effects include reduced coordination, which leads to slurred speech, impaired fine-motor skills, and delayed reaction time. The effects of alcohol on the body's neurochemistry are more difficult to examine than some other drugs. This is because the chemical nature of the substance makes it easy to penetrate into the brain, and it also influences the phospholipid bilayer of neurons. This allows alcohol to have a widespread impact on many normal cell functions and modifies the actions of several neurotransmitter systems. Alcohol inhibits glutamate (a major excitatory neurotransmitter in the nervous system) neurotransmission by reducing the effectiveness at the NMDA receptor, which is related to memory loss associated with intoxication. It also modulates the function of GABA, a major inhibitory amino acid neurotransmitter. The reinforcing qualities of alcohol leading to repeated use – and thus also the mechanisms of withdrawal from chronic alcohol use – are partially due to the substance's action on the dopamine system. This is also due to alcohol's effect on the opioid systems, or endorphins, that have opiate-like effects, such as modulating pain, mood, feeding, reinforcement, and response to stress. [1]

Antidepressants Edit

Antidepressants reduce symptoms of mood disorders primarily through the regulation of norepinephrine and serotonin (particularly the 5-HT receptors). After chronic use, neurons adapt to the change in biochemistry, resulting in a change in pre- and postsynaptic receptor density and second messenger function. [1]

Monoamine oxidase inhibitors (MAOIs) are the oldest class of antidepressants. They inhibit monoamine oxidase, the enzyme that metabolizes the monoamine neurotransmitters in the presynaptic terminals that are not contained in protective synaptic vesicles. The inhibition of the enzyme increases the amount of neurotransmitter available for release. It increases norepinephrine, dopamine, and 5-HT and thus increases the action of the transmitters at their receptors. MAOIs have been somewhat disfavored because of their reputation for more serious side effects. [1]

Tricyclic antidepressants (TCAs) work through binding to the presynaptic transporter proteins and blocking the reuptake of norepinephrine or 5-HT into the presynaptic terminal, prolonging the duration of transmitter action at the synapse.

Selective serotonin reuptake inhibitors (SSRIs) selectively block the reuptake of serotonin (5-HT) through their inhibiting effects on the sodium/potassium ATP-dependent serotonin transporter in presynaptic neurons. This increases the availability of 5-HT in the synaptic cleft. [6] The main parameters to consider in choosing an antidepressant are side effects and safety. Most SSRIs are available generically and are relatively inexpensive. Older antidepressants, such as the TCAs and MAOIs usually require more visits and monitoring, and this may offset the low expense of the drugs. The SSRIs are relatively safe in overdose and better tolerated than the TCAs and MAOIs for most patients. [6]

Antipsychotics Edit

All proven antipsychotics are postsynaptic dopamine receptor blockers (dopamine antagonists). For an antipsychotic to be effective, it generally requires a dopamine antagonism of 60%–80% of dopamine D2 receptors. [6]

First generation (typical) antipsychotics: Traditional neuroleptics modify several neurotransmitter systems, but their clinical effectiveness is most likely due to their ability to antagonize dopamine transmission by competitively blocking the receptors or by inhibiting dopamine release. The most serious and troublesome side effects of these classical antipsychotics are movement disorders that resemble the symptoms of Parkinson's disease, because the neuroleptics antagonize dopamine receptors broadly, also reducing the normal dopamine-mediated inhibition of cholinergic cells in the striatum. [1]

Second-generation (atypical) antipsychotics: The concept of “atypicality” is from the finding that the second generation antipsychotics (SGAs) had a greater serotonin/dopamine ratio than did earlier drugs, and might be associated with improved efficacy (particularly for the negative symptoms of psychosis) and reduced extrapyramidal side effects. Some of the efficacy of atypical antipsychotics may be due to 5-HT2 antagonism or the blockade of other dopamine receptors. Agents that purely block 5-HT2 or dopamine receptors other than D2 have often failed as effective antipsychotics. [6]

Benzodiazepines Edit

Benzodiazepines are often used to reduce anxiety symptoms, muscle tension, seizure disorders, insomnia, symptoms of alcohol withdrawal, and panic attack symptoms. Their action is primarily on specific benzodiazepine sites on the GABAA receptor. This receptor complex is thought to mediate the anxiolytic, sedative, and anticonvulsant actions of the benzodiazepines. [6] Use of benzodiazepines carries the risk of tolerance (necessitating increased dosage), dependence, and abuse. Taking these drugs for a long period of time can lead to withdrawal symptoms upon abrupt discontinuation. [7]

Hallucinogens Edit

Hallucinogens cause perceptual and cognitive distortions without delirium. The state of intoxication is often called a “trip”. Onset is the first stage after an individual ingests (LSD, psilocybin, or mescaline) or smokes (dimethyltryptamine) the substance. This stage may consist of visual effects, with an intensification of colors and the appearance of geometric patterns that can be seen with one's eyes closed. This is followed by a plateau phase, where the subjective sense of time begins to slow and the visual effects increase in intensity. The user may experience synesthesia, a crossing-over of sensations (for example, one may “see” sounds and “hear” colors). In addition to the sensory-perceptual effects, hallucinogenic substances may induce feelings of depersonalization, emotional shifts to a euphoric or anxious/fearful state, and a disruption of logical thought. Hallucinogens are classified chemically as either indolamines (specifically tryptamines), sharing a common structure with serotonin, or as phenethylamines, which share a common structure with norepinephrine. Both classes of these drugs are agonists at the 5-HT2 receptors this is thought to be the central component of their hallucinogenic properties. Activation of 5-HT2A may be particularly important for hallucinogenic activity. However, repeated exposure to hallucinogens leads to rapid tolerance, likely through down-regulation of these receptors in specific target cells. [1]

Hypnotics Edit

Hypnotics are often used to treat the symptoms of insomnia, or other sleep disorders. Benzodiazepines are still among the most widely prescribed sedative-hypnotics in the United States today. Certain non-benzodiazepine drugs are used as hypnotics as well. Although they lack the chemical structure of the benzodiazepines, their sedative effect is similarly through action on the GABAA receptor. They also have a reputation of being less addictive than benzodiazepines. Melatonin, a naturally-occurring hormone, is often used over the counter (OTC) to treat insomnia and jet lag. This hormone appears to be excreted by the pineal gland early during the sleep cycle and may contribute to human circadian rhythms. Because OTC melatonin supplements are not subject to careful and consistent manufacturing, more specific melatonin agonists are sometimes preferred. They are used for their action on melatonin receptors in the suprachiasmatic nucleus, responsible for sleep-wake cycles. Many barbiturates have or had an FDA-approved indication for use as sedative-hypnotics, but have become less widely used because of their limited safety margin in overdose, their potential for dependence, and the degree of central nervous system depression they induce. The amino-acid L-tryptophan is also available OTC, and seems to be free of dependence or abuse liability. However, it is not as powerful as the traditional hypnotics. Because of the possible role of serotonin in sleep patterns, a new generation of 5-HT2 antagonists are in current development as hypnotics. [6]

Cannabis and the cannabinoids Edit

Cannabis consumption produces a dose-dependent state of intoxication in humans. There is commonly increased blood flow to the skin, which leads to sensations of warmth or flushing, and heart rate is also increased. It also frequently induces increased hunger. [1] Iversen (2000) categorized the subjective and behavioral effects often associated with cannabis into three stages. The first is the "buzz," a brief period of initial responding, where the main effects are lightheadedness or slight dizziness, in addition to possible tingling sensations in the extremities or other parts of the body. The "high" is characterized by feelings of euphoria and exhilaration characterized by mild psychedelia, as well as a sense of disinhibition. If the individual has taken a sufficiently large dose of cannabis, the level of intoxication progresses to the stage of being “stoned,” and the user may feel calm, relaxed, and possibly in a dreamlike state. Sensory reactions may include the feeling of floating, enhanced visual and auditory perception, visual illusions, or the perception of the slowing of time passage, which are somewhat psychedelic in nature. [8]

There exist two primary CNS cannabinoid receptors, on which marijuana and the cannabinoids act. Both the CB1 receptor and CB2 receptor are found in the brain. The CB2 receptor is also found in the immune system. CB1 is expressed at high densities in the basal ganglia, cerebellum, hippocampus, and cerebral cortex. Receptor activation can inhibit cAMP formation, inhibit voltage-sensitive calcium ion channels, and activate potassium ion channels. Many CB1 receptors are located on axon terminals, where they act to inhibit the release of various neurotransmitters. In combination, these chemical actions work to alter various functions of the central nervous system including the motor system, memory, and various cognitive processes. [1]

Opioids Edit

The opioid category of drugs – including drugs such as heroin, morphine, and oxycodone – belong to the class of narcotic analgesics, which reduce pain without producing unconsciousness but do produce a sense of relaxation and sleep, and at high doses may result in coma and death. The ability of opioids (both endogenous and exogenous) to relieve pain depends on a complex set of neuronal pathways at the spinal cord level, as well as various locations above the spinal cord. Small endorphin neurons in the spinal cord act on receptors to decrease the conduction of pain signals from the spinal cord to higher brain centers. Descending neurons originating in the periaqueductal gray give rise to two pathways that further block pain signals in the spinal cord. The pathways begin in the locus coeruleus (noradrenaline) and the nucleus of raphe (serotonin). Similar to other abused substances, opioid drugs increase dopamine release in the nucleus accumbens. [1] Opioids are more likely to produce physical dependence than any other class of psychoactive drugs, and can lead to painful withdrawal symptoms if discontinued abruptly after regular use.

Stimulants Edit

Cocaine is one of the more common stimulants and is a complex drug that interacts with various neurotransmitter systems. It commonly causes heightened alertness, increased confidence, feelings of exhilaration, reduced fatigue, and a generalized sense of well-being. The effects of cocaine are similar to those of the amphetamines, though cocaine tends to have a shorter duration of effect. In high doses and/or with prolonged use, cocaine can result in a number of negative effects as well, including irritability, anxiety, exhaustion, total insomnia, and even psychotic symptomatology. Most of the behavioral and physiological actions of cocaine can be explained by its ability to block the reuptake of the two catecholamines, dopamine and norepinephrine, as well as serotonin. Cocaine binds to transporters that normally clear these transmitters from the synaptic cleft, inhibiting their function. This leads to increased levels of neurotransmitter in the cleft and transmission at the synapses. [1] Based on in-vitro studies using rat brain tissue, cocaine binds most strongly to the serotonin transporter, followed by the dopamine transporter, and then the norepinephrine transporter. [9]

Amphetamines tend to cause the same behavioral and subjective effects of cocaine. Various forms of amphetamine are commonly used to treat the symptoms of attention deficit hyperactivity disorder (ADHD) and narcolepsy, or are used recreationally. Amphetamine and methamphetamine are indirect agonists of the catecholaminergic systems. They block catecholamine reuptake, in addition to releasing catecholamines from nerve terminals. There is evidence that dopamine receptors play a central role in the behavioral responses of animals to cocaine, amphetamines, and other psychostimulant drugs. One action causes the dopamine molecules to be released from inside the vesicles into the cytoplasm of the nerve terminal, which are then transported outside by the mesolimbic dopamine pathway to the nucleus accumbens. This plays a key role in the rewarding and reinforcing effects of cocaine and amphetamine in animals, and is the primary mechanism for amphetamine dependence. [ citation needed ]

In psychopharmacology, researchers are interested in any substance that crosses the blood–brain barrier and thus has an effect on behavior, mood or cognition. Drugs are researched for their physiochemical properties, physical side effects, and psychological side effects. Researchers in psychopharmacology study a variety of different psychoactive substances that include alcohol, cannabinoids, club drugs, psychedelics, opiates, nicotine, caffeine, psychomotor stimulants, inhalants, and anabolic-androgenic steroids. They also study drugs used in the treatment of affective and anxiety disorders, as well as schizophrenia.

Clinical studies are often very specific, typically beginning with animal testing, and ending with human testing. In the human testing phase, there is often a group of subjects: one group is given a placebo, and the other is administered a carefully measured therapeutic dose of the drug in question. After all of the testing is completed, the drug is proposed to the concerned regulatory authority (e.g. the U.S. FDA), and is either commercially introduced to the public via prescription, or deemed safe enough for over-the-counter sale.

Though particular drugs are prescribed for specific symptoms or syndromes, they are usually not specific to the treatment of any single mental disorder.

A somewhat controversial application of psychopharmacology is "cosmetic psychiatry": persons who do not meet criteria for any psychiatric disorder are nevertheless prescribed psychotropic medication. The antidepressant bupropion is then prescribed to increase perceived energy levels and assertiveness while diminishing the need for sleep. The antihypertensive compound propranolol is sometimes chosen to eliminate the discomfort of day-to-day anxiety. Fluoxetine in nondepressed people can produce a feeling of generalized well-being. Pramipexole, a treatment for restless leg syndrome, can dramatically increase libido in women. These and other off-label lifestyle applications of medications are not uncommon. Although occasionally reported in the medical literature no guidelines for such usage have been developed. [10] There is also a potential for the misuse of prescription psychoactive drugs by elderly persons, who may have multiple drug prescriptions. [11] [12]


‘Magic Mushrooms’ Can Improve Psychological Health Long Term

The psychedelic drug in magic mushrooms may have lasting medical and spiritual benefits, according to new research from Johns Hopkins School of Medicine.

The mushroom-derived hallucinogen, called psilocybin, is known to trigger transformative spiritual states, but at high doses it can also result in “bad trips” marked by terror and panic. The trick is to get the dose just right, which the Johns Hopkins researchers report having accomplished.

In their study, the Hopkins scientists were able to reliably induce transcendental experiences in volunteers, which offered long-lasting psychological growth and helped people find peace in their lives — without the negative effects.

“The important point here is that we found the sweet spot where we can optimize the positive persistent effects and avoid some of the fear and anxiety that can occur and can be quite disruptive,” says lead author Roland Griffiths, professor of behavioral biology at Hopkins.

Giffiths’ study involved 18 healthy adults, average age 46, who participated in five eight-hour drug sessions with either psilocybin — at varying doses — or placebo. Nearly all the volunteers were college graduates and 78% participated regularly in religious activities all were interested in spiritual experience.

Fourteen months after participating in the study, 94% of those who received the drug said the experiment was one of the top five most meaningful experiences of their lives 39% said it was the single most meaningful experience.

Critically, however, the participants themselves were not the only ones who saw the benefit from the insights they gained: their friends, family member and colleagues also reported that the psilocybin experience had made the participants calmer, happier and kinder.

Ultimately, Griffiths and his colleagues want to see if the same kind of psychedelic experience could help ease anxiety and fear over the long term in cancer patients or others facing death. And following up on tantalizing clues from early research on hallucinogenic drugs like LSD, mescaline and psilocybin in the 1960s (which are all now illegal), researchers are also studying whether transcendental experiences could help spur recovery from addiction and treat other psychological problems like depression and post-traumatic stress disorder.

For Griffiths’ current experiment, participants were housed in a living room-like setting designed to be calm, comfortable and attractive. While under the influence, they listened to classical music on headphones, wore eyeshades and were instructed to “direct their attention inward.”

Each participant was accompanied by two other research-team members: a “monitor” and an “assistant monitor,” who both had previous experience with people on psychedelic drugs and were empathetic and supportive. Before the drug sessions, the volunteers became acquainted enough with their team so that they felt familiar and safe. Although the experiments took place in the Hopkins hospital complex in order to ensure prompt medical attention in the event that it was needed, it never was.

As described by early advocates of the use of psychedelics — from ancient shamans to Timothy Leary and the Grateful Dead — the psilocybin experience typically involves a sense of oneness with the universe and with others, a feeling of transcending time, space and other limitations, coupled with a sense of holiness and sacredness. Overwhelmingly, these experiences are difficult to put into words, but many of Griffiths’ participants said they were left with the sense that they understood themselves and others better and therefore had greater compassion and patience.

“I feel that I relate better in my marriage. There is more empathy — a greater understanding of people and understanding their difficulties and less judgment,” said one participant. “Less judging of myself, too.”

Another said: “I have better interaction with close friends and family and with acquaintances and strangers. … My alcohol use has diminished dramatically.”

To zero in on the “sweet spot” of dosing, Griffiths started half the volunteers on a low dose and gradually increased their doses over time (with placebo sessions randomly interspersed) the other half started on a high dose and worked their way down.

Those who started on a low dose found that their experiences tended to get better as the dose increased, probably because they learned what to expect and how to handle it. But people who started with high doses were more likely to experience anxiety and fear (though these feeling didn’t last long and sometimes resolved into euphoria or a sense of transcendence).

“If we back the dose down a little, we have just as much of the same positive effects. The properties of the mystical experience remain the same, but there’s a fivefold drop in anxiety and fearfulness,” Griffiths says.

Some past experiments with psychedelics in the 󈨀s used initial high doses of the drugs — the “blast people away with a high dose” model, says Griffiths — to try to treat addiction. “Some of the early work in addictions was done with the idea of, ‘O.K., let’s model the ‘bottoming-out’ crisis and make use of the dark side of [psychedelic] compounds. That didn’t work,” Griffiths says.

It may even have backfired: other research on addictions shows that coercion, humiliation and other attempts to produce a sense of “powerlessness,” tend to increase relapse and treatment dropout, not recovery. (And the notorious naked LSD encounter sessions conducted with psychopaths made them worse, too.)

Griffiths is currently seeking patients with terminal cancer to participate in his next set of experiments (for more information on these studies, click here) because psychedelics often produce a feeling of going beyond life and death, they are thought to be especially likely to help those facing the end of life. Griffiths is also studying whether psilocybin can help smokers quit.

Griffiths and other researchers like him are hoping to bring the study of psychedelics into the future. They want to build on the promise that some of the early research showed, while avoiding the bad rep and exaggerated claims — for example, that LSD was harmless and could usher in world peace — that became associated with the drugs when people started using them recreationally in the 1960s. The resulting negative publicity helped shut down the burgeoning research.

This time around, caution may be paying off. Dr. Jerome Jaffe, America’s first drug czar, who was not involved with the research, said in a statement, “The Hopkins psilocybin studies clearly demonstrate that this route to the mystical is not to be walked alone. But they have also demonstrated significant and lasting benefits. That raises two questions: could psilocybin-occasioned experiences prove therapeutically useful, for example in dealing with the psychological distress experienced by some terminal patients?

“And should properly-informed citizens, not in distress, be allowed to receive psilocybin for its possible spiritual benefits, as we now allow them to pursue other possibly risky activities such as cosmetic surgery and mountain-climbing?”


7. Crack Cocaine

Crack cocaine, often nicknamed &ldquocrack.&rdquo is believed to have been created and made popular during the early 1980s. Because of the dangers for manufacturers of using ether to produce pure freebase cocaine, producers began to omit the step of removing the freebase precipitate from the ammonia mixture. Typically, filtration processes are also omitted. Baking soda is now most often used as a base rather than ammonia for reasons of lowered odor and toxicity however, any weak base can be used to make crack cocaine. When commonly &ldquocooked&rdquo the ratio is 1:1 to 2:3 parts cocaine/bicarbonate.

As I held the smoke in for a ten count and exhaled, I thought I felt nothing except a little excitement that was neither bad nor pleasurable. The complete rush some writers have called a &lsquowhole-body orgasm&lsquo hit me shortly after and I distinctly remember demanding &lsquomore&rsquo as soon as the realization of heaven-on-earth came. Some people say that the effects of smoking crack lasts 10 to15 minutes. For me, it was just a shortest instant of gratification. Everything afterwards was just a great increase in energy and confidence geared towards obtaining more of the drug.


Handbook of the Behavioral Neurobiology of Serotonin

Adam L. Halberstadt , David E. Nichols , in Handbook of Behavioral Neuroscience , 2020

III Chemistry and structure–activity relationships

As discussed above, the 5-HT2A receptor is now generally considered to be the key target for hallucinogens ( Nichols, 2016 ). As such, one might therefore expect the hallucinogens to bear some structural resemblance to serotonin. This relationship is quite evident with the simple tryptamines and with the tetracyclic ergoline LSD. Indeed, it was the recognition that the tryptamine fragment within the structure of LSD also was the core feature of serotonin itself, which first led to the realization that 5-HT might play a role in behavior. A comparison of the structures of 5-HT, and the hallucinogens DMT, 5-methoxytryptamine, psilocin, and LSD is presented in Fig. 43.1 below. It is not difficult to understand why all of these structures interact with 5-HT serotonin receptors, because of their close structural resemblance. Although LSD is a more complex molecule, the tryptamine core fragment is still readily apparent.

Figure 43.1 . The structures of the natural transmitter serotonin and the tryptamine-type hallucinogens psilocin, DMT, and LSD.

What is less clear, however, is how the phenethylamine type hallucinogens ( Fig. 43.2 ) interact with serotonin receptors. The only apparent similarity is a basic nitrogen atom separated by two carbon atoms from an aromatic system. Recent mutagenesis studies of the 5-HT2A receptor have, however, begun to reveal the basis for the requirement of certain structural features of the phenethylamines to interact with the receptor.

Figure 43.2 . The structures of mescaline, the prototypical phenethylamine hallucinogen, and general formulas for synthetic substituted hallucinogenic phenethylamines and “amphetamines.” For the alpha-substituted amphetamines, the stereoisomer with the R-(−)- absolute configuration (shown) is more potent.

Studies of the mutant S239A 5-HT2A receptor have demonstrated that it is this serine residue, in transmembrane helix 5, that likely hydrogen bonds to the 5-hydroxy group of 5-HT, as well as to the 5-methoxy-group of the 2,5-dimethoxy- substituted phenethylamines ( Braden & Nichols, 2007 ). Fig. 43.3 suggests possible binding modes for the 2,5-dimethoxy-substituted phenethylamines and the tryptamines, based on those studies.

Figure 43.3 . Comparison of the R-(−)- isomer of a potent difuranobenzene phenethylamine type hallucinogen (left panel) with S-(+)-α-methylserotonin. Although the stereochemistry at the carbon bearing the alpha-methyl is reversed for the phenethylamines and the tryptamines, the lengths of the ligands, differing by about 0.5 Å, could be the underlying reason for this reversal. The bicyclic aromatic indole system of the tryptamines is longer than the phenyl ring of the phenethylamines, and thus when the side chain is extended, the tryptamines will occupy a larger space in the receptor. Because the receptor evolved to accept serotonin, a tryptamine, the perspective must be one that the phenethylamines somehow adapt themselves to a binding site that prefers tryptamines.

This view could explain why a primary amine is most potent for the phenethylamines, with N-alkyl or N,N-dialkyl derivatives being essentially inert, whereas tertiary amines are potent in the tryptamine series. That is, one might envision that the binding site must “shrink” or compress to accommodate a phenethylamine. That is most readily achieved by rotation of the side chain of Asp155 in transmembrane helix 3. If this aspartate engages the amino group in an “end on” conformation for the phenethylamines, it might be speculated that N-alkyl groups would hinder that interaction. By contrast, that aspartate residue could engage the amino group of the tryptamines through an approach more perpendicular to the plane of the molecule. In that event, N-alkyl groups would be expected to have less of an effect on the ligand interaction. That argument can likely be extended to understand the binding of LSD, because its structure is so rigid that interaction of Asp155 with the protonated electron pair of the amino group can only occur through an “axial” approach to the amine moiety. That orientation is evident within the crystal structure of LSD in the 5-HT2B receptor ( Wacker et al., 2017 ).

Substitution of an alpha-methyl group on the phenethylamine side chain gives more potent compounds. There are at least three possible explanations for that finding, all of which probably make some contribution. First of all, the alpha methyl will retard metabolic deamination, giving better oral availability and increased in vivo stability. Second, the alpha methyl adds significant hydrophobicity, leading to better brain penetration. Finally, R-alpha-methyl substituted phenethylamines generally are more efficacious in activating second messenger systems than their nonalkylated congeners ( Parrish, Braden, Gundy, & Nichols, 2005 ). At least for the phenethylamines (“amphetamines”) the alpha methyl group enhances the intrinsic activity, possibly through an interaction with a critical phenylalanine residue in transmembrane helix 6. The steric limitation in this region is very strict, however, as any larger alkyl group, even an ethyl, destroys activity.

Interestingly, the stereochemistry is reversed for alpha-substituted tryptamines. One may speculate that the two classes of ligands bind in such a way as to project the alpha-methyl groups into the same general region of the receptor, but there are no data to support that supposition. The different lengths of the ligands also may be a key here. For example, Fig. 43.3 illustrates S-(+)-alpha-methyl serotonin and the more potent R-(−)- isomer of a rigid phenethylamine. In these orientations, representing potential receptor-bound conformations, the distance from the side chain amino nitrogen to the 5-oxygen atom is 6.1 and 6.6 Å for the phenethylamine and the tryptamine, respectively.

Incorporating the 2- and 5-methoxy groups into furan or dihydrofuran rings gives compounds that are more potent, but more importantly, establishes the binding orientations for the two methoxy groups. Although simulated docking experiments suggest that the 2-methoxy group of the phenethylamines could engage Ser159 through a hydrogen bond ( Braden & Nichols, 2007 ), attempts to test that hypothesis with the S159A mutant receptor, however, gave a protein that had such drastically reduced function that it was not possible to examine the effect of the presence or absence of the 2-methoxy of the ligand.

Although substitution at the 6-indole position of the tryptamines renders them inactive ( Blair et al., 2000 ), substituting the phenethylamines at the 4-position is essential to provide good activity. Again, the different sizes of the phenethylamines and tryptamines are likely at the heart of this observation. Simulating docking experiments suggest that the 4-substituent of the phenethylamines may project into a hydrophobic area of the receptor between transmembrane helices 3, 4, and 5 created by residues Phe234, Ile206, and Val156. It may be that the larger indole ring of the tryptamines projects into this space and additional bulk attached to the ligand in this region creates too large a steric footprint for the receptor to accommodate.

Phenethylamines with a 3,4,5-substitution pattern (e.g., mescaline) do not bind in the same way as 2,4,5-substituted compounds because site-specific mutations of the receptor lead to different effects on 2,4,5- versus the 3,4,5-substituted compounds ( Braden, 2007 ). Nevertheless, a hydrophobic 4-alkoxy substituent in 3,4,5-substituted compounds also gives highest activity in this series ( Nichols & Dyer, 1977 Shulgin & Shulgin, 1991 ), and simulated docking into homology models of the receptor suggests that this substituent may project into the same receptor space as the 4-substituent in the 2,4,5-substituted series.

The rigid nature of LSD limits its conformational flexibility upon binding. Mutagenesis studies suggest that the indole NH hydrogen bonds to Ser242 in transmembrane helix 5 ( Braden & Nichols, 2007 ), and the electron pair on the amine nitrogen is directed in an axial orientation toward the conserved aspartate in helix 3 ( Wacker et al., 2017 ).

Very little structural modification can be tolerated by ergolines related to LSD. The stereochemistry at both the 5- and 8-positions must be of the R configuration, shown in Fig. 43.1 and Table 43.1 . Inversion at C(8) affords iso-LSD, which is inactive. Halogenation at the 2-indole position of LSD affords antagonists such as BOL that lack hallucinogenic activity. Although N(1)-acetylation leads to an active compound, this molecule is actually a prodrug and the N-acetyl is readily cleaved in vivo to afford LSD itself. Longer N(1)-acyl groups also give active molecules, e.g., 1-propionyl-LSD (“1P-LSD”), which also appears to be a prodrug for LSD ( Brandt et al., 2016 ).

Table 43.1 . Summary of structure–activity relationships (SARs) for classes of hallucinogens.


Psychoactive drug

A psychoactive drug, psychopharmaceutical, or psychotropic drug is a chemical substance that changes nervous system function and results in alterations in perception, mood, consciousness, cognition, or behavior. [1] These substances may be used medically recreationally to purposefully improve performance or alter one's consciousness as entheogens for ritual, spiritual, or shamanic purposes or for research. Some categories of psychoactive drugs, which have therapeutic value, are prescribed by physicians and other healthcare practitioners. Examples include anesthetics, analgesics, anticonvulsant and antiparkinsonian drugs as well as medications used to treat neuropsychiatric disorders, such as antidepressants, anxiolytics, antipsychotics, and stimulant medications. Some psychoactive substances may be used in the detoxification and rehabilitation programs for persons dependent on or addicted to other psychoactive drugs.

Psychoactive substances often bring about subjective (although these may be objectively observed) changes in consciousness and mood that the user may find rewarding and pleasant (e.g., euphoria or a sense of relaxation) or advantageous in an objectively observable or measurable way (e.g. increased alertness). Substances which are rewarding and thus positively reinforcing have the potential to induce a state of addiction – compulsive drug use despite negative consequences. In addition, sustained use of some substances may produce physical or psychological dependence or both, associated with somatic or psychological-emotional withdrawal states respectively. Drug rehabilitation attempts to reduce addiction, through a combination of psychotherapy, support groups, and other psychoactive substances. Conversely, certain psychoactive drugs may be so unpleasant that the person will never use the substance again. This is especially true of certain deliriants (e.g. Jimson weed), powerful dissociatives (e.g. Salvia divinorum), and classic psychedelics (e.g. LSD, psilocybin), in the form of a "bad trip".

Psychoactive drug misuse, dependence and addiction have resulted in legal measures and moral debate. Governmental controls on manufacture, supply and prescription attempt to reduce problematic medical drug use. Ethical concerns have also been raised about over-use of these drugs clinically, and about their marketing by manufacturers. Popular campaigns to decriminalize or legalize certain recreational drug use (e.g. cannabis) are also ongoing.


This Is Your Brain on Drug Education

A man holds up an egg and says, “This is your brain.” Then, he picks up a frying pan and says, “This is drugs.” Then, he cracks open the egg, fries the contents, and says, “This is your brain on drugs.” Finally, he asks, “Any questions?” This memorable anti-drug use advertisement served as “drug education” in the 1980s.

Unfortunately, today’s drug education isn’t much better. One of the most popular anti-drug use advertisements is sponsored by the Montana Meth Project. In general, these advertisements show, in horrifying detail, a young person who uses methamphetamine for the first time and then ends up engaging in some unthinkable act such as prostitution or assaulting strangers for money to buy the drug. At the end of advertisement, printed on screen is “Meth, not even once.”

While the goal of decreasing drug abuse is a commendable one, these types of media campaigns have been shown to have no effect on drug use or abuse (Anderson, 2010). Furthermore, they do not disseminate any real facts about drug effects, but they go a long way to perpetuate false assumptions about illegal drug use and their effects. Persistent misconceptions about crack cocaine and methamphetamine are that the drugs have a unique propensity to produce dangerous effects. In the 1980s (and even now), crack cocaine, for example, was portrayed as producing unpredictable and deadly effects. And today, methamphetamine is said to cause neurotoxicity and widespread cognitive impairments.

Over the past 15 years, I have given thousands of doses of drugs such as crack cocaine and methamphetamine to people. I do this, with the informed consent of the research participant, as part of my research to understand how drugs affect the brain, behavior and physiology. Based on my studies and data from other researchers, the effects produced by crack and powder cocaine are identical they are also predictable. As the dose is increased, so are the effects. Methamphetamine, too, produces predictable effects. Indeed, the effects produced by methamphetamine are identical to those produced by d-amphetamine – the main compound in the popular Attention-Deficit Hyperactive Disorder (ADHD) treatment medication, Adderall (Kirkpatrick et al., 2012). The notion that methamphetamine users have brain deficits that lead to cognitive impairments is not supported by evidence from research (Hart et al., 2012). The bottom line is that many of the immediate and long-term harmful effects caused by methamphetamine use have been greatly exaggerated, just as the dangers of crack cocaine were overstated nearly three decades earlier (Hart, 2013).

As a result, I contend that the exaggeration of harmful effects produced by crack cocaine and methamphetamine has helped shape a political environment in which there is an unwarranted and unrealistic goal of eliminating the use of certain drugs at any cost to specific users, i.e., the poor and minorities. For example, despite the fact that there was virtually no evidence supporting claims that crack produces unique destructive effects, in the late 1980s, the U.S. Congress passed the now infamous Anti-Drug Abuse Act, setting 100 times harsher penalties for crack than for powder cocaine convictions. A whopping 85 percent of those sentenced for crack offenses are black, even though the majority of users of the drug are white (USSC, 2007). Similar racial disparities have been reported for marijuana arrests (ACLU, 2013). And now, largely because of the selective targeting of black males by drug enforcement agencies, one in three black boys born today will spend time in prison if we don’t alter our current approach (Bonczar, 2003).

  • Funding agencies could help remedy this situation by requesting research applications that focus explicitly on race—for example, trying to understand the long-term consequences of drug arrests on black people, especially as they relate to disrupting one’s life trajectory.
  • Scientists who study drugs of abuse can contribute by widening their scope such that they examine and report a broader range of drug effects and not focus exclusively on drug-related pathology.
  • Policy makers should consider drug decriminalization, in which drug sales remain illegal, but drug possessions do not lead to criminal convictions—the one thing that has prevented so many from obtaining employment, housing, governmental benefits, treatment, etc. This is crucial because each year, more than 80 percent of drug arrests involve only simple possession (FBI, 2010).

Not only am I a scientist, but I am also the father of three black sons. I recognize that there is a high probability that they, like their white counterparts and our three most recent Presidents, may one day experiment with drugs. Knowing the potential consequences if they are arrested, I cannot afford to remain silent.

Dr. Hart recently gave a presentation at APA as part of our Health Disparities seminar series entitled: Challenging the Assumptions about Drug Abuse. You can watch it below:

Dr. Carl Hart is an Associate Professor in the Departments of Psychology and Psychiatry at Columbia University. He is also a Research Scientist in the Division of Substance Abuse at the New York State Psychiatric Institute. A major focus of Dr. Hart’s research is to understand complex interactions between drugs of abuse and the neurobiology and environmental factors that mediate human behavior and physiology. Hart is a member of the National Advisory Council on Drug Abuse and on the board of directors of the College on Problems of Drug Dependence and the Drug Policy Alliance. His most recent book, High Price is a complex story of scientific achievement in the face of overwhelming odds it also highlights that U.S. drug policy is based on many false assumptions and the enforcement of such policies is racially biased.

American Civil Liberties Union (ACLU) (2013). The war on marijuana in black and white. New York, NY: Author. Retrieved from: https://www.aclu.org/criminal-law-reform/war-marijuana-black-and-white-report

Anderson, D. M. (2010). Does information matter? The effect of the Meth Project on meth use among youths. Journal of Health Economics, 29, 732-42.

Bonczar, T.P., (2003). Prevalence of imprisonment in the U.S. population, 1974-2001. U.S. Department of Justice, Bureau of Justice Statistics Special Report, NCJ 197976. Retrieved from: www.policyalmanac.org/crime/archive/prisoners_in_US_pop.pdf.

Hart,C. L., Marvin,C. B., Silver,R., Smith, E. E. (2012). Is cognitive functioning impaired in methamphetamine users? A critical review. Neuropsychopharmacology, 37, 586-608.

Hart, C. L. (2013) High Price: A neuroscientist’s journey of self-discovery that challenges everything you know about drugs and society. Harper-Collins: New York.

Kirkpatrick, M. G., Gunderson, E. W., Johanson, C. E., Levin, F. R., Foltin, R. W., Hart, C. L. (2012) Comparison of intranasal methamphetamine and d-amphetamine self-administration by humans. Addiction, 107, 783-91.


Contents

The term empathogen, meaning "generating a state of empathy", was coined in 1983–84 independently by Ralph Metzner and David E. Nichols as a term to denote a therapeutic class of drugs that includes MDMA and phenethylamine relatives. [3] Nichols later rejected this initial terminology and adopted, instead, the term entactogen, meaning "touching within", to denote this class of drugs, asserting a concern with the potential for improper association of the term empathogen with negative connotations related to the Greek root πάθος páthos ("suffering passion"). [4] Additionally, Nichols wanted to avoid any association with the term pathogenesis. [5] Nichols also thought the original term was limiting, and did not cover other therapeutic uses for the drugs that go beyond instilling feelings of empathy. [6] The hybrid word entactogen is derived from the roots en (Greek: within ), tactus (Latin: touch) and -gen (Greek: produce ). [4] Neither term is dominant in usage, and, despite their difference in connotation, they are essentially interchangeable, as they refer to precisely the same chemicals.

Both terms adopted and used in naming the class of therapeutic drugs for MDMA and related compounds were chosen with the intention of providing some reflection of the reported psychological effects associated with drugs in the classification and distinguishing these compounds from classical psychedelic drugs such as LSD, mescaline, and psilocybin and major stimulants, such as methamphetamine and amphetamine. [6] Chemically, MDMA is classified as a substituted amphetamine (which includes stimulants like dextroamphetamine and psychedelics like 2,5-dimethoxy-4-methylamphetamine), which makes MDMA a substituted phenethylamine (which includes other stimulants like methylphenidate and other psychedelics like mescaline) by the definition of amphetamine. While chemically related both to psychedelics and stimulants, the psychological effects experienced with MDMA were reported to provide obvious and striking aspects of personal relatedness, feelings of connectedness, communion with others, and ability to feel what others feel—in short an empathic resonance is consistently evoked. [7] While psychedelics like LSD may sometimes yield effects of empathic resonance, these effects tend to be momentary and likely passed over on the way to some other dimension or interest. In contrast, the main characteristic that distinguishes MDMA from LSD-type experiences is the consistency of the effects of emotional communion, relatedness, emotional openness—in short, empathy and sympathy. [6]

The chemicals below have a varying degree of entactogenic effects some of them induce additional effects, including serenic effects, stimulant effects, antidepressant effects, anxiolytic effects, and psychedelic effects. [5]

Phenethylamines Edit

Substituted amphetamines Edit

Cathinones Edit

Tryptamines Edit

Aminoindanes Edit

Psychiatrists began using empathogens as psychotherapy tools in the 1970s despite the lack of clinical trials. [8] In recent years, the scientific community has been revisiting the possible therapeutic uses of empathogens. Therapeutic models using MDMA have been studied because of its empathogenic properties. [9] This type of therapy would be applicable for treating a patient who was experiencing psychological trauma such as PTSD. Traumatic memories can be linked to fear in the patients which makes engaging with these memories difficult. Administration of an empathogen such as MDMA allows the patient to disconnect from the fear associated with the traumatic memories and engage in therapy. [9] MDMA acts by targeting the body's stress response in order to cause this therapeutic effect. In addition to reducing anxiety and a conditioned fear response, MDMA also reduces the avoidance of feelings. [9] Patients are then able to trust themselves and their therapist and engage with traumatic memories under the influence of MDMA.

Although the therapeutic effects of empathogens may be promising, drugs such as MDMA have the potential for negative effects that are counter productive in a therapy setting. For example, MDMA may make negative cognition worse. This means that a positive experience is not a guarantee and can be contingent on aspects like the setting and the patient's expectations. [10] Additionally there is no clear model of the psychopharmacological means for a positive or negative experience. [10] There is also a potential concern for the neurotoxic effects of MDMA on the fiber density of serotonin neurons in the neocortex. High doses of MDMA may cause potential depletion of serotonergic axons. The same effects may not be caused by lower doses of MDMA required for treatment, however. [11]


This Is Your Brain on Drug Education

A man holds up an egg and says, “This is your brain.” Then, he picks up a frying pan and says, “This is drugs.” Then, he cracks open the egg, fries the contents, and says, “This is your brain on drugs.” Finally, he asks, “Any questions?” This memorable anti-drug use advertisement served as “drug education” in the 1980s.

Unfortunately, today’s drug education isn’t much better. One of the most popular anti-drug use advertisements is sponsored by the Montana Meth Project. In general, these advertisements show, in horrifying detail, a young person who uses methamphetamine for the first time and then ends up engaging in some unthinkable act such as prostitution or assaulting strangers for money to buy the drug. At the end of advertisement, printed on screen is “Meth, not even once.”

While the goal of decreasing drug abuse is a commendable one, these types of media campaigns have been shown to have no effect on drug use or abuse (Anderson, 2010). Furthermore, they do not disseminate any real facts about drug effects, but they go a long way to perpetuate false assumptions about illegal drug use and their effects. Persistent misconceptions about crack cocaine and methamphetamine are that the drugs have a unique propensity to produce dangerous effects. In the 1980s (and even now), crack cocaine, for example, was portrayed as producing unpredictable and deadly effects. And today, methamphetamine is said to cause neurotoxicity and widespread cognitive impairments.

Over the past 15 years, I have given thousands of doses of drugs such as crack cocaine and methamphetamine to people. I do this, with the informed consent of the research participant, as part of my research to understand how drugs affect the brain, behavior and physiology. Based on my studies and data from other researchers, the effects produced by crack and powder cocaine are identical they are also predictable. As the dose is increased, so are the effects. Methamphetamine, too, produces predictable effects. Indeed, the effects produced by methamphetamine are identical to those produced by d-amphetamine – the main compound in the popular Attention-Deficit Hyperactive Disorder (ADHD) treatment medication, Adderall (Kirkpatrick et al., 2012). The notion that methamphetamine users have brain deficits that lead to cognitive impairments is not supported by evidence from research (Hart et al., 2012). The bottom line is that many of the immediate and long-term harmful effects caused by methamphetamine use have been greatly exaggerated, just as the dangers of crack cocaine were overstated nearly three decades earlier (Hart, 2013).

As a result, I contend that the exaggeration of harmful effects produced by crack cocaine and methamphetamine has helped shape a political environment in which there is an unwarranted and unrealistic goal of eliminating the use of certain drugs at any cost to specific users, i.e., the poor and minorities. For example, despite the fact that there was virtually no evidence supporting claims that crack produces unique destructive effects, in the late 1980s, the U.S. Congress passed the now infamous Anti-Drug Abuse Act, setting 100 times harsher penalties for crack than for powder cocaine convictions. A whopping 85 percent of those sentenced for crack offenses are black, even though the majority of users of the drug are white (USSC, 2007). Similar racial disparities have been reported for marijuana arrests (ACLU, 2013). And now, largely because of the selective targeting of black males by drug enforcement agencies, one in three black boys born today will spend time in prison if we don’t alter our current approach (Bonczar, 2003).

  • Funding agencies could help remedy this situation by requesting research applications that focus explicitly on race—for example, trying to understand the long-term consequences of drug arrests on black people, especially as they relate to disrupting one’s life trajectory.
  • Scientists who study drugs of abuse can contribute by widening their scope such that they examine and report a broader range of drug effects and not focus exclusively on drug-related pathology.
  • Policy makers should consider drug decriminalization, in which drug sales remain illegal, but drug possessions do not lead to criminal convictions—the one thing that has prevented so many from obtaining employment, housing, governmental benefits, treatment, etc. This is crucial because each year, more than 80 percent of drug arrests involve only simple possession (FBI, 2010).

Not only am I a scientist, but I am also the father of three black sons. I recognize that there is a high probability that they, like their white counterparts and our three most recent Presidents, may one day experiment with drugs. Knowing the potential consequences if they are arrested, I cannot afford to remain silent.

Dr. Hart recently gave a presentation at APA as part of our Health Disparities seminar series entitled: Challenging the Assumptions about Drug Abuse. You can watch it below:

Dr. Carl Hart is an Associate Professor in the Departments of Psychology and Psychiatry at Columbia University. He is also a Research Scientist in the Division of Substance Abuse at the New York State Psychiatric Institute. A major focus of Dr. Hart’s research is to understand complex interactions between drugs of abuse and the neurobiology and environmental factors that mediate human behavior and physiology. Hart is a member of the National Advisory Council on Drug Abuse and on the board of directors of the College on Problems of Drug Dependence and the Drug Policy Alliance. His most recent book, High Price is a complex story of scientific achievement in the face of overwhelming odds it also highlights that U.S. drug policy is based on many false assumptions and the enforcement of such policies is racially biased.

American Civil Liberties Union (ACLU) (2013). The war on marijuana in black and white. New York, NY: Author. Retrieved from: https://www.aclu.org/criminal-law-reform/war-marijuana-black-and-white-report

Anderson, D. M. (2010). Does information matter? The effect of the Meth Project on meth use among youths. Journal of Health Economics, 29, 732-42.

Bonczar, T.P., (2003). Prevalence of imprisonment in the U.S. population, 1974-2001. U.S. Department of Justice, Bureau of Justice Statistics Special Report, NCJ 197976. Retrieved from: www.policyalmanac.org/crime/archive/prisoners_in_US_pop.pdf.

Hart,C. L., Marvin,C. B., Silver,R., Smith, E. E. (2012). Is cognitive functioning impaired in methamphetamine users? A critical review. Neuropsychopharmacology, 37, 586-608.

Hart, C. L. (2013) High Price: A neuroscientist’s journey of self-discovery that challenges everything you know about drugs and society. Harper-Collins: New York.

Kirkpatrick, M. G., Gunderson, E. W., Johanson, C. E., Levin, F. R., Foltin, R. W., Hart, C. L. (2012) Comparison of intranasal methamphetamine and d-amphetamine self-administration by humans. Addiction, 107, 783-91.


What are the effects of LSD (acid)?

This assumes pure acid, i.e. 100% LSD.

Acid feels like &ldquoseeing the world for the first time,&rdquo with stimulated and profound seeming thoughts, and sort of a dreamlike feeling. 12 Hallucinations also exist, though it would be more accurate to think of them as visual distortions - i.e. seeing extra patterns in the grass, a photo of a waterfall might look like the water is moving when it&rsquos actually not - but don&rsquot think of it as you&rsquoll be seeing green leprechauns that will talk to you.

See the first few images on this page for an accurate depiction of low to moderate acid dosage visual effects.

Read more on the effects of LSD here.

How long does LSD last?

8-13 hours, 13 though it&rsquos wise to plan for

During and after use

Side effects during use

Possible side effects during use include: anxiety, paranoid thinking, discomfort, temporary moderate increases in blood pressure. 14

Side effects after use

&ldquoCohen (1960) reported that only a single case of a psychotic reaction lasting more than 48 hours occurred in 1200 experimental (non-patient) research participants (a rate of 0.8 per 1000). Notably, the individual was an identical twin of a schizophrenic patient and thus would have been excluded under the proposed guidelines.&rdquo 5

If you have close schizophrenic relatives, you should not take LSD. This will be discussed futher in the safety section below.

Desirable effects during use

Possible desirable effects during use: joy/intense happiness and peace/harmony. 14

Desirable long-term benefits

Users following a specific guided trip protocol experienced a variety of benefits including increased purpose, more energy for work, more initiative, getting more work done, increased self-confidence, marriage satisfaction, and more friends at and outside work. 15 16

&ldquoBad&rdquo trips

What is the probability of having a bad trip on LSD?

This depends heavily on the dosage, your mindstate going into the trip, and the environment where you take LSD.

We can approximate from a psilocybin mushroom study:

    At a dosage of 200 micrograms of LSD 17 in a therapeutic clinical environment, we might expect 86% of people to experience some extreme fear, 18 for an LSD-adjusted (increase time to account for longer trip with LSD vs psilocybin) average of around

22 minutes of strong anxiety 19 , and we might expect around

4 minutes of strong anxiety 19 , and we might expect around

2 minutes of strong anxiety 19 , and we might expect around

Bad trips can increase long-term well-being, so call them &ldquochallenging trips&rdquo instead

Challenging or &ldquobad&rdquo acid trips can be most beneficial if they are short, but difficult. 8

&ldquoMultiple regression analysis showed degree of difficulty was positively associated, and duration was negatively associated, with enduring increases in well-being.&rdquo 8

Are you currently having a bad trip?

Medical benefits

&ldquoFor example, a recent meta-analysis of six randomized clinical trials of treatment for alcoholism conducted between 1966–1970 found that a single dose of LSD [acid] reduced the probability of alcohol misuse almost two-fold relative to comparison conditions (Krebs and Johansen, 2012).&rdquo 9 20

There is less medical research into LSD (acid) vs psilocybin (shrooms), because psilocybin is less stigmatized, and psilocybin also has a shorter duration, which is easier for researchers as with psilocybin they can spend more like 8 hours with a participant instead of having to spend

16 hours with the participant.

Researchers are also interested in studying LSD microdosing, which involves taking around 10 micrograms of LSD, often with the goal of boosting mood or boosting productivity / entering a flow state. See this article for more.

With psilocybin (we would expect similar results for LSD) for cancer-related emotional distress, &ldquo83 percent said it [psilocybin + psychotherapy] increased their well-being or life satisfaction moderately or very much, and 89 percent said it lead to moderate, strong, or extreme improvements in their behaviors. Of the 90 total sessions conducted during the study, none were rated as having decreased well-being or life satisfaction.&rdquo 11

Watch this video, this video, or this video to get a sense for the therapeutic uses of LSD - these videos are using psilocybin, but they should be useful to anyone evaluating LSD, too.

Psychedelic retreats

While not LSD, magic mushrooms are decently similar in effects and therapeutic potential to LSD.

It is our understanding that magic truffles are legal in the Netherlands, and in Jamaica magic mushrooms are either outright legal or the laws don&rsquot seem to be enforced.


The "safest" Rc's?

Which do you consider the safest or the RC with the least side efffects?

Of course, do look up and read about the specific chems you plan on researching but you can pretty much just follow the rules of normal drug classes to get an idea, with the exception of an extreme outlier (which the community collectively warns about things like hexen's extreme fiendishness).

Tryptamines/Lysergamides: Physically, the safest. Psychologically, maybe the most risky (also most rewarding in a lot of researchers' opinions).

Benzodiazepenes: Physically, mostly harmless unless you mix with other downers or you let habituation creep in on you, then withdrawals are potentially deadly. Psychologically, can cause memory gaps, rebound anxiety, and some people have a paradoxical reaction that makes them angry and aggressive.

Amphetamines: Physically, going to be doing some damage on your cardiovascular system and be neurotoxic to some degree, dependent on dose and duration of use. Psychologically, probably safe until you binge long enough to go into sleep deprivation induced psychosis.

Mostly, just don't touch RC opioids or RC cannabinoids. The opioids are way too fucking potent, and for whatever reason the -noids have a hundred terrible side effects that you would never get from the natural cannabinoids in weed.

How are psychedelics psychologically super risky?

Thanks for breaking it down for me! I was only curious, as I lurk around here often man. I appreciate it, i didnt think id get much replies :)!

And yet at the right doses the fentanyl analogs should be very safe other than the whole addiction (and technically that's safe too since sudden withdrawal while extremely uncomfortable isn't lethal) thing just like most opis are. O-dmt should be too. U-47700 and it's relatives are questionable since their structure is too different from anything with a long history of human use. And MT-45 is toxic.

What is your definition of safe?

If you mean well studied about effects on humans then right now there is only one such chemical and that is Etizolam.

Been approved by Japan and a few other countries as a legitamate medicine for a while now. I would trust Japan's regulations.

You question is really vague.

Etizolam may be well studied, but I certainly wouldn't call it safe. I'm gonna be ignoring the quibbling over the definition of safe and going with what one would intuitively consider safe. I consider addiction to be a threat worthy of regarding a drug as riskier, and for that reason Etizolam isn't high on the list of safe RCs simply by virtue of being a benzo. And you can overdose on it, which isn't a problem exactly, but it would seem to preclude it from being the safest when there are drugs that can be reasonably expected to have lethal doses far in excess of what anyone would ever have access to, maybe in excess of what's ever been synthesized. If it's possible at all.

The chemicals I'm speaking of there are the lysergamides, which, by all indications, are every bit as safe as LSD. Which is to say, for all intents and purposed completely safe. No neurotoxicity, no possibility for lethal overdose, and no addiction.

I suppose, what can be taken regularly and maybe even rec. that would not have serious adverse effects.

The lysergamides, 1p-LSD, ETH-LAD, AL-LAD, etc. Their effects are so close to LSD that it's a nigh certainty that they'll be every bit as safe as LSD is, which is to say, completely and utterly safe. Can't overdose (lethally), no neurotoxicity, and not addictive at all. 1P is the closest to LSD, so it's the surest bet with regards to safety, but Iɽ be extremely surprised if any of them turned out to have significant toxicity.

The tryptamines come close, with the exception of the alpha-substituted tryptamines like AMT and AET, and their 5-MeO and 4-HO counterparts. All the rest of the tryptamines are very safe at all doses previously tried. I'm not aware of any overdose deaths from tryptamines, but some of them are definitely safer than others. DPT has such a horrible bodyload that Iɽ guess it's likely to prove dangerous at extremely high doses. But I don't think ANY of them are likely to be dangerous except at doses far higher than anyone's likely to take, even accidentally. As far as safety goes, the 5-MeOs seem a lot rougher and harder on the body than the others, so Iɽ bet on them being more dangerous in overdose. I find that the 4-HOs tend to have less body load as a general rule, but unlike the 5-MeOs (Which are pretty much universally harder on the body), there are exceptions with the 4-HOs. For example, I find psilocin to provoke nausea a great deal more readily than DMT itself (not that those two are RCs, but they are tryptamines).


Damage caused by MDMA neurotoxicity and how it manifests physically

MDMA is a known neurotoxin and that's why we're advised to follow the 3 month rule.

I've educated myself enough on the subject and I'm well aware of the havoc mdma abuse can wreck on the system. however, say someone abused mdma daily for a month, according to the studies this person might have caused irreversible damage to their serotonin receptors site more specifically. Few studies claim that this damage is irreversible but this can be debated due to lack of studies on human test subjects. And recent advancements in neurochemistry has proven that neurogenisis is possible under the right conditions though it might take a long time

Iɽ like to understand how this would manifest physically and cause problems to the person who abused mdma. How would their life be different? What brain function might be reduced, etc. What are the repercussions of damaging your serotonin receptors?

I know some guys who have abused mdma daily, some for a period of months. This obviously might have done some damage, but when you talk to these people after they've abstained for a while they seem to hold a normal conversation, laugh, cry etc like how a normal human does. so then, what are the physical manifestations of this damage. Some things I can think of are loss of memory/poor memory, anxiety etc. but Iɽ like to know for certain what mdma abuse would cause to the abuser.

I was retarded when I was younger and did mdma everyday for a whole week, while I've not noticed any thing different after abstaining from mdma for more than a year, I can't tell what kind of damage I might have done, if i did. I still feel the same, can't notice any kind of permanent damage that I might have done. though I occasionally have panic attacks, a poor memory which I'll instantly blame it on abusing mdma, but I also see my friends who have never touched drugs facing similar issues.

One thing for certain i've noticed is a poor memory and learning things doesn't stick in my memory like before. I can learn things with the same ease as before, just that after a few weeks I'll completly forget what I learnt and have to practically re-learn it. I don't know if I should blame this on mdma.

If I can get a detailed explanation on this subject, it would surely ease my mind so I can't stop blaming anything wrong with me on that time I abused mdma long ago.


Contents

Early psychopharmacology Edit

Not often mentioned or included in the field of psychopharmacology today are psychoactive substances not identified as useful in modern mental health settings or references. These substances are naturally occurring, but nonetheless psychoactive, and are compounds identified through the work of ethnobotanists and ethnomycologists (and others who study the native use of naturally occurring psychoactive drugs). However, although these substances have been used throughout history by various cultures, and have a profound effect on mentality and brain function, they have not always attained the degree of scrutinous evaluation that lab-made compounds have. Nevertheless, some, such as psilocybin and mescaline, have provided a basis of study for the compounds that are used and examined in the field today. Hunter-gatherer societies tended to favor hallucinogens, and today their use can still be observed in many surviving tribal cultures. The exact drug used depends on what the particular ecosystem a given tribe lives in can support, and are typically found growing wild. Such drugs include various psychoactive mushrooms containing psilocybin or muscimol and cacti containing mescaline and other chemicals, along with myriad other psychoactive-chemical-containing plants. These societies generally attach spiritual significance to such drug use, and often incorporate it into their religious practices. With the dawn of the Neolithic and the proliferation of agriculture, new psychoactives came into use as a natural by-product of farming. Among them were opium, cannabis, and alcohol derived from the fermentation of cereals and fruits. Most societies began developing herblores, lists of herbs which were good for treating various physical and mental ailments. For example, St. John's wort was traditionally prescribed in parts of Europe for depression (in addition to use as a general-purpose tea), and Chinese medicine developed elaborate lists of herbs and preparations. These and various other substances that have an effect on the brain are still used as remedies in many cultures. [2]

Modern psychopharmacology Edit

The dawn of contemporary psychopharmacology marked the beginning of the use of psychiatric drugs to treat psychological illnesses. It brought with it the use of opiates and barbiturates for the management of acute behavioral issues in patients. In the early stages, psychopharmacology was primarily used for sedation. With the 1950s came the establishment of lithium for mania, chlorpromazine for psychoses, and then in rapid succession, the development of tricyclic antidepressants, monoamine oxidase inhibitors, and benzodiazepines, among other antipsychotics and antidepressants. A defining feature of this era includes an evolution of research methods, with the establishment of placebo-controlled, double-blind studies, and the development of methods for analyzing blood levels with respect to clinical outcome and increased sophistication in clinical trials. The early 1960s revealed a revolutionary model by Julius Axelrod describing nerve signals and synaptic transmission, which was followed by a drastic increase of biochemical brain research into the effects of psychotropic agents on brain chemistry. [3] After the 1960s, the field of psychiatry shifted to incorporate the indications for and efficacy of pharmacological treatments, and began to focus on the use and toxicities of these medications. [4] [5] The 1970s and 1980s were further marked by a better understanding of the synaptic aspects of the action mechanisms of drugs. However, the model has its critics, too – notably Joanna Moncrieff and the Critical Psychiatry Network. [ citation needed ]

Neurotransmitters Edit

Psychoactive drugs exert their sensory and behavioral effects almost entirely by acting on neurotransmitters and by modifying one or more aspects of synaptic transmission. Neurotransmitters can be viewed as chemicals through which neurons primarily communicate psychoactive drugs affect the mind by altering this communication. Drugs may act by 1) serving as a precursor for the neurotransmitter 2) inhibiting neurotransmitter synthesis 3) preventing storage of neurotransmitter in the presynaptic vesicle 4) stimulating or inhibiting neurotransmitter release 5) stimulating or blocking post-synaptic receptors 6) stimulating autoreceptors, inhibiting neurotransmitter release 7) blocking autoreceptors, increasing neurotransmitter release 8) inhibiting neurotransmission breakdown or 9) blocking neurotransmitter reuptake by the presynaptic neuron. [1]

Hormones Edit

The other central method through which drugs act is by affecting communications between cells through hormones. Neurotransmitters can usually only travel a microscopic distance before reaching their target at the other side of the synaptic cleft, while hormones can travel long distances before reaching target cells anywhere in the body. Thus, the endocrine system is a critical focus of psychopharmacology because 1) drugs can alter the secretion of many hormones 2) hormones may alter the behavioral responses to drugs 3) hormones themselves sometimes have psychoactive properties and 4) the secretion of some hormones, especially those dependent on the pituitary gland, is controlled by neurotransmitter systems in the brain. [1]

Alcohol Edit

Alcohol is a depressant, the effects of which may vary according to dosage amount, frequency, and chronicity. As a member of the sedative-hypnotic class, at the lowest doses, the individual feels relaxed and less anxious. In quiet settings, the user may feel drowsy, but in settings with increased sensory stimulation, individuals may feel uninhibited and more confident. High doses of alcohol rapidly consumed may produce amnesia for the events that occur during intoxication. Other effects include reduced coordination, which leads to slurred speech, impaired fine-motor skills, and delayed reaction time. The effects of alcohol on the body's neurochemistry are more difficult to examine than some other drugs. This is because the chemical nature of the substance makes it easy to penetrate into the brain, and it also influences the phospholipid bilayer of neurons. This allows alcohol to have a widespread impact on many normal cell functions and modifies the actions of several neurotransmitter systems. Alcohol inhibits glutamate (a major excitatory neurotransmitter in the nervous system) neurotransmission by reducing the effectiveness at the NMDA receptor, which is related to memory loss associated with intoxication. It also modulates the function of GABA, a major inhibitory amino acid neurotransmitter. The reinforcing qualities of alcohol leading to repeated use – and thus also the mechanisms of withdrawal from chronic alcohol use – are partially due to the substance's action on the dopamine system. This is also due to alcohol's effect on the opioid systems, or endorphins, that have opiate-like effects, such as modulating pain, mood, feeding, reinforcement, and response to stress. [1]

Antidepressants Edit

Antidepressants reduce symptoms of mood disorders primarily through the regulation of norepinephrine and serotonin (particularly the 5-HT receptors). After chronic use, neurons adapt to the change in biochemistry, resulting in a change in pre- and postsynaptic receptor density and second messenger function. [1]

Monoamine oxidase inhibitors (MAOIs) are the oldest class of antidepressants. They inhibit monoamine oxidase, the enzyme that metabolizes the monoamine neurotransmitters in the presynaptic terminals that are not contained in protective synaptic vesicles. The inhibition of the enzyme increases the amount of neurotransmitter available for release. It increases norepinephrine, dopamine, and 5-HT and thus increases the action of the transmitters at their receptors. MAOIs have been somewhat disfavored because of their reputation for more serious side effects. [1]

Tricyclic antidepressants (TCAs) work through binding to the presynaptic transporter proteins and blocking the reuptake of norepinephrine or 5-HT into the presynaptic terminal, prolonging the duration of transmitter action at the synapse.

Selective serotonin reuptake inhibitors (SSRIs) selectively block the reuptake of serotonin (5-HT) through their inhibiting effects on the sodium/potassium ATP-dependent serotonin transporter in presynaptic neurons. This increases the availability of 5-HT in the synaptic cleft. [6] The main parameters to consider in choosing an antidepressant are side effects and safety. Most SSRIs are available generically and are relatively inexpensive. Older antidepressants, such as the TCAs and MAOIs usually require more visits and monitoring, and this may offset the low expense of the drugs. The SSRIs are relatively safe in overdose and better tolerated than the TCAs and MAOIs for most patients. [6]

Antipsychotics Edit

All proven antipsychotics are postsynaptic dopamine receptor blockers (dopamine antagonists). For an antipsychotic to be effective, it generally requires a dopamine antagonism of 60%–80% of dopamine D2 receptors. [6]

First generation (typical) antipsychotics: Traditional neuroleptics modify several neurotransmitter systems, but their clinical effectiveness is most likely due to their ability to antagonize dopamine transmission by competitively blocking the receptors or by inhibiting dopamine release. The most serious and troublesome side effects of these classical antipsychotics are movement disorders that resemble the symptoms of Parkinson's disease, because the neuroleptics antagonize dopamine receptors broadly, also reducing the normal dopamine-mediated inhibition of cholinergic cells in the striatum. [1]

Second-generation (atypical) antipsychotics: The concept of “atypicality” is from the finding that the second generation antipsychotics (SGAs) had a greater serotonin/dopamine ratio than did earlier drugs, and might be associated with improved efficacy (particularly for the negative symptoms of psychosis) and reduced extrapyramidal side effects. Some of the efficacy of atypical antipsychotics may be due to 5-HT2 antagonism or the blockade of other dopamine receptors. Agents that purely block 5-HT2 or dopamine receptors other than D2 have often failed as effective antipsychotics. [6]

Benzodiazepines Edit

Benzodiazepines are often used to reduce anxiety symptoms, muscle tension, seizure disorders, insomnia, symptoms of alcohol withdrawal, and panic attack symptoms. Their action is primarily on specific benzodiazepine sites on the GABAA receptor. This receptor complex is thought to mediate the anxiolytic, sedative, and anticonvulsant actions of the benzodiazepines. [6] Use of benzodiazepines carries the risk of tolerance (necessitating increased dosage), dependence, and abuse. Taking these drugs for a long period of time can lead to withdrawal symptoms upon abrupt discontinuation. [7]

Hallucinogens Edit

Hallucinogens cause perceptual and cognitive distortions without delirium. The state of intoxication is often called a “trip”. Onset is the first stage after an individual ingests (LSD, psilocybin, or mescaline) or smokes (dimethyltryptamine) the substance. This stage may consist of visual effects, with an intensification of colors and the appearance of geometric patterns that can be seen with one's eyes closed. This is followed by a plateau phase, where the subjective sense of time begins to slow and the visual effects increase in intensity. The user may experience synesthesia, a crossing-over of sensations (for example, one may “see” sounds and “hear” colors). In addition to the sensory-perceptual effects, hallucinogenic substances may induce feelings of depersonalization, emotional shifts to a euphoric or anxious/fearful state, and a disruption of logical thought. Hallucinogens are classified chemically as either indolamines (specifically tryptamines), sharing a common structure with serotonin, or as phenethylamines, which share a common structure with norepinephrine. Both classes of these drugs are agonists at the 5-HT2 receptors this is thought to be the central component of their hallucinogenic properties. Activation of 5-HT2A may be particularly important for hallucinogenic activity. However, repeated exposure to hallucinogens leads to rapid tolerance, likely through down-regulation of these receptors in specific target cells. [1]

Hypnotics Edit

Hypnotics are often used to treat the symptoms of insomnia, or other sleep disorders. Benzodiazepines are still among the most widely prescribed sedative-hypnotics in the United States today. Certain non-benzodiazepine drugs are used as hypnotics as well. Although they lack the chemical structure of the benzodiazepines, their sedative effect is similarly through action on the GABAA receptor. They also have a reputation of being less addictive than benzodiazepines. Melatonin, a naturally-occurring hormone, is often used over the counter (OTC) to treat insomnia and jet lag. This hormone appears to be excreted by the pineal gland early during the sleep cycle and may contribute to human circadian rhythms. Because OTC melatonin supplements are not subject to careful and consistent manufacturing, more specific melatonin agonists are sometimes preferred. They are used for their action on melatonin receptors in the suprachiasmatic nucleus, responsible for sleep-wake cycles. Many barbiturates have or had an FDA-approved indication for use as sedative-hypnotics, but have become less widely used because of their limited safety margin in overdose, their potential for dependence, and the degree of central nervous system depression they induce. The amino-acid L-tryptophan is also available OTC, and seems to be free of dependence or abuse liability. However, it is not as powerful as the traditional hypnotics. Because of the possible role of serotonin in sleep patterns, a new generation of 5-HT2 antagonists are in current development as hypnotics. [6]

Cannabis and the cannabinoids Edit

Cannabis consumption produces a dose-dependent state of intoxication in humans. There is commonly increased blood flow to the skin, which leads to sensations of warmth or flushing, and heart rate is also increased. It also frequently induces increased hunger. [1] Iversen (2000) categorized the subjective and behavioral effects often associated with cannabis into three stages. The first is the "buzz," a brief period of initial responding, where the main effects are lightheadedness or slight dizziness, in addition to possible tingling sensations in the extremities or other parts of the body. The "high" is characterized by feelings of euphoria and exhilaration characterized by mild psychedelia, as well as a sense of disinhibition. If the individual has taken a sufficiently large dose of cannabis, the level of intoxication progresses to the stage of being “stoned,” and the user may feel calm, relaxed, and possibly in a dreamlike state. Sensory reactions may include the feeling of floating, enhanced visual and auditory perception, visual illusions, or the perception of the slowing of time passage, which are somewhat psychedelic in nature. [8]

There exist two primary CNS cannabinoid receptors, on which marijuana and the cannabinoids act. Both the CB1 receptor and CB2 receptor are found in the brain. The CB2 receptor is also found in the immune system. CB1 is expressed at high densities in the basal ganglia, cerebellum, hippocampus, and cerebral cortex. Receptor activation can inhibit cAMP formation, inhibit voltage-sensitive calcium ion channels, and activate potassium ion channels. Many CB1 receptors are located on axon terminals, where they act to inhibit the release of various neurotransmitters. In combination, these chemical actions work to alter various functions of the central nervous system including the motor system, memory, and various cognitive processes. [1]

Opioids Edit

The opioid category of drugs – including drugs such as heroin, morphine, and oxycodone – belong to the class of narcotic analgesics, which reduce pain without producing unconsciousness but do produce a sense of relaxation and sleep, and at high doses may result in coma and death. The ability of opioids (both endogenous and exogenous) to relieve pain depends on a complex set of neuronal pathways at the spinal cord level, as well as various locations above the spinal cord. Small endorphin neurons in the spinal cord act on receptors to decrease the conduction of pain signals from the spinal cord to higher brain centers. Descending neurons originating in the periaqueductal gray give rise to two pathways that further block pain signals in the spinal cord. The pathways begin in the locus coeruleus (noradrenaline) and the nucleus of raphe (serotonin). Similar to other abused substances, opioid drugs increase dopamine release in the nucleus accumbens. [1] Opioids are more likely to produce physical dependence than any other class of psychoactive drugs, and can lead to painful withdrawal symptoms if discontinued abruptly after regular use.

Stimulants Edit

Cocaine is one of the more common stimulants and is a complex drug that interacts with various neurotransmitter systems. It commonly causes heightened alertness, increased confidence, feelings of exhilaration, reduced fatigue, and a generalized sense of well-being. The effects of cocaine are similar to those of the amphetamines, though cocaine tends to have a shorter duration of effect. In high doses and/or with prolonged use, cocaine can result in a number of negative effects as well, including irritability, anxiety, exhaustion, total insomnia, and even psychotic symptomatology. Most of the behavioral and physiological actions of cocaine can be explained by its ability to block the reuptake of the two catecholamines, dopamine and norepinephrine, as well as serotonin. Cocaine binds to transporters that normally clear these transmitters from the synaptic cleft, inhibiting their function. This leads to increased levels of neurotransmitter in the cleft and transmission at the synapses. [1] Based on in-vitro studies using rat brain tissue, cocaine binds most strongly to the serotonin transporter, followed by the dopamine transporter, and then the norepinephrine transporter. [9]

Amphetamines tend to cause the same behavioral and subjective effects of cocaine. Various forms of amphetamine are commonly used to treat the symptoms of attention deficit hyperactivity disorder (ADHD) and narcolepsy, or are used recreationally. Amphetamine and methamphetamine are indirect agonists of the catecholaminergic systems. They block catecholamine reuptake, in addition to releasing catecholamines from nerve terminals. There is evidence that dopamine receptors play a central role in the behavioral responses of animals to cocaine, amphetamines, and other psychostimulant drugs. One action causes the dopamine molecules to be released from inside the vesicles into the cytoplasm of the nerve terminal, which are then transported outside by the mesolimbic dopamine pathway to the nucleus accumbens. This plays a key role in the rewarding and reinforcing effects of cocaine and amphetamine in animals, and is the primary mechanism for amphetamine dependence. [ citation needed ]

In psychopharmacology, researchers are interested in any substance that crosses the blood–brain barrier and thus has an effect on behavior, mood or cognition. Drugs are researched for their physiochemical properties, physical side effects, and psychological side effects. Researchers in psychopharmacology study a variety of different psychoactive substances that include alcohol, cannabinoids, club drugs, psychedelics, opiates, nicotine, caffeine, psychomotor stimulants, inhalants, and anabolic-androgenic steroids. They also study drugs used in the treatment of affective and anxiety disorders, as well as schizophrenia.

Clinical studies are often very specific, typically beginning with animal testing, and ending with human testing. In the human testing phase, there is often a group of subjects: one group is given a placebo, and the other is administered a carefully measured therapeutic dose of the drug in question. After all of the testing is completed, the drug is proposed to the concerned regulatory authority (e.g. the U.S. FDA), and is either commercially introduced to the public via prescription, or deemed safe enough for over-the-counter sale.

Though particular drugs are prescribed for specific symptoms or syndromes, they are usually not specific to the treatment of any single mental disorder.

A somewhat controversial application of psychopharmacology is "cosmetic psychiatry": persons who do not meet criteria for any psychiatric disorder are nevertheless prescribed psychotropic medication. The antidepressant bupropion is then prescribed to increase perceived energy levels and assertiveness while diminishing the need for sleep. The antihypertensive compound propranolol is sometimes chosen to eliminate the discomfort of day-to-day anxiety. Fluoxetine in nondepressed people can produce a feeling of generalized well-being. Pramipexole, a treatment for restless leg syndrome, can dramatically increase libido in women. These and other off-label lifestyle applications of medications are not uncommon. Although occasionally reported in the medical literature no guidelines for such usage have been developed. [10] There is also a potential for the misuse of prescription psychoactive drugs by elderly persons, who may have multiple drug prescriptions. [11] [12]


‘Magic Mushrooms’ Can Improve Psychological Health Long Term

The psychedelic drug in magic mushrooms may have lasting medical and spiritual benefits, according to new research from Johns Hopkins School of Medicine.

The mushroom-derived hallucinogen, called psilocybin, is known to trigger transformative spiritual states, but at high doses it can also result in “bad trips” marked by terror and panic. The trick is to get the dose just right, which the Johns Hopkins researchers report having accomplished.

In their study, the Hopkins scientists were able to reliably induce transcendental experiences in volunteers, which offered long-lasting psychological growth and helped people find peace in their lives — without the negative effects.

“The important point here is that we found the sweet spot where we can optimize the positive persistent effects and avoid some of the fear and anxiety that can occur and can be quite disruptive,” says lead author Roland Griffiths, professor of behavioral biology at Hopkins.

Giffiths’ study involved 18 healthy adults, average age 46, who participated in five eight-hour drug sessions with either psilocybin — at varying doses — or placebo. Nearly all the volunteers were college graduates and 78% participated regularly in religious activities all were interested in spiritual experience.

Fourteen months after participating in the study, 94% of those who received the drug said the experiment was one of the top five most meaningful experiences of their lives 39% said it was the single most meaningful experience.

Critically, however, the participants themselves were not the only ones who saw the benefit from the insights they gained: their friends, family member and colleagues also reported that the psilocybin experience had made the participants calmer, happier and kinder.

Ultimately, Griffiths and his colleagues want to see if the same kind of psychedelic experience could help ease anxiety and fear over the long term in cancer patients or others facing death. And following up on tantalizing clues from early research on hallucinogenic drugs like LSD, mescaline and psilocybin in the 1960s (which are all now illegal), researchers are also studying whether transcendental experiences could help spur recovery from addiction and treat other psychological problems like depression and post-traumatic stress disorder.

For Griffiths’ current experiment, participants were housed in a living room-like setting designed to be calm, comfortable and attractive. While under the influence, they listened to classical music on headphones, wore eyeshades and were instructed to “direct their attention inward.”

Each participant was accompanied by two other research-team members: a “monitor” and an “assistant monitor,” who both had previous experience with people on psychedelic drugs and were empathetic and supportive. Before the drug sessions, the volunteers became acquainted enough with their team so that they felt familiar and safe. Although the experiments took place in the Hopkins hospital complex in order to ensure prompt medical attention in the event that it was needed, it never was.

As described by early advocates of the use of psychedelics — from ancient shamans to Timothy Leary and the Grateful Dead — the psilocybin experience typically involves a sense of oneness with the universe and with others, a feeling of transcending time, space and other limitations, coupled with a sense of holiness and sacredness. Overwhelmingly, these experiences are difficult to put into words, but many of Griffiths’ participants said they were left with the sense that they understood themselves and others better and therefore had greater compassion and patience.

“I feel that I relate better in my marriage. There is more empathy — a greater understanding of people and understanding their difficulties and less judgment,” said one participant. “Less judging of myself, too.”

Another said: “I have better interaction with close friends and family and with acquaintances and strangers. … My alcohol use has diminished dramatically.”

To zero in on the “sweet spot” of dosing, Griffiths started half the volunteers on a low dose and gradually increased their doses over time (with placebo sessions randomly interspersed) the other half started on a high dose and worked their way down.

Those who started on a low dose found that their experiences tended to get better as the dose increased, probably because they learned what to expect and how to handle it. But people who started with high doses were more likely to experience anxiety and fear (though these feeling didn’t last long and sometimes resolved into euphoria or a sense of transcendence).

“If we back the dose down a little, we have just as much of the same positive effects. The properties of the mystical experience remain the same, but there’s a fivefold drop in anxiety and fearfulness,” Griffiths says.

Some past experiments with psychedelics in the 󈨀s used initial high doses of the drugs — the “blast people away with a high dose” model, says Griffiths — to try to treat addiction. “Some of the early work in addictions was done with the idea of, ‘O.K., let’s model the ‘bottoming-out’ crisis and make use of the dark side of [psychedelic] compounds. That didn’t work,” Griffiths says.

It may even have backfired: other research on addictions shows that coercion, humiliation and other attempts to produce a sense of “powerlessness,” tend to increase relapse and treatment dropout, not recovery. (And the notorious naked LSD encounter sessions conducted with psychopaths made them worse, too.)

Griffiths is currently seeking patients with terminal cancer to participate in his next set of experiments (for more information on these studies, click here) because psychedelics often produce a feeling of going beyond life and death, they are thought to be especially likely to help those facing the end of life. Griffiths is also studying whether psilocybin can help smokers quit.

Griffiths and other researchers like him are hoping to bring the study of psychedelics into the future. They want to build on the promise that some of the early research showed, while avoiding the bad rep and exaggerated claims — for example, that LSD was harmless and could usher in world peace — that became associated with the drugs when people started using them recreationally in the 1960s. The resulting negative publicity helped shut down the burgeoning research.

This time around, caution may be paying off. Dr. Jerome Jaffe, America’s first drug czar, who was not involved with the research, said in a statement, “The Hopkins psilocybin studies clearly demonstrate that this route to the mystical is not to be walked alone. But they have also demonstrated significant and lasting benefits. That raises two questions: could psilocybin-occasioned experiences prove therapeutically useful, for example in dealing with the psychological distress experienced by some terminal patients?

“And should properly-informed citizens, not in distress, be allowed to receive psilocybin for its possible spiritual benefits, as we now allow them to pursue other possibly risky activities such as cosmetic surgery and mountain-climbing?”


7. Crack Cocaine

Crack cocaine, often nicknamed &ldquocrack.&rdquo is believed to have been created and made popular during the early 1980s. Because of the dangers for manufacturers of using ether to produce pure freebase cocaine, producers began to omit the step of removing the freebase precipitate from the ammonia mixture. Typically, filtration processes are also omitted. Baking soda is now most often used as a base rather than ammonia for reasons of lowered odor and toxicity however, any weak base can be used to make crack cocaine. When commonly &ldquocooked&rdquo the ratio is 1:1 to 2:3 parts cocaine/bicarbonate.

As I held the smoke in for a ten count and exhaled, I thought I felt nothing except a little excitement that was neither bad nor pleasurable. The complete rush some writers have called a &lsquowhole-body orgasm&lsquo hit me shortly after and I distinctly remember demanding &lsquomore&rsquo as soon as the realization of heaven-on-earth came. Some people say that the effects of smoking crack lasts 10 to15 minutes. For me, it was just a shortest instant of gratification. Everything afterwards was just a great increase in energy and confidence geared towards obtaining more of the drug.


Handbook of the Behavioral Neurobiology of Serotonin

Adam L. Halberstadt , David E. Nichols , in Handbook of Behavioral Neuroscience , 2020

III Chemistry and structure–activity relationships

As discussed above, the 5-HT2A receptor is now generally considered to be the key target for hallucinogens ( Nichols, 2016 ). As such, one might therefore expect the hallucinogens to bear some structural resemblance to serotonin. This relationship is quite evident with the simple tryptamines and with the tetracyclic ergoline LSD. Indeed, it was the recognition that the tryptamine fragment within the structure of LSD also was the core feature of serotonin itself, which first led to the realization that 5-HT might play a role in behavior. A comparison of the structures of 5-HT, and the hallucinogens DMT, 5-methoxytryptamine, psilocin, and LSD is presented in Fig. 43.1 below. It is not difficult to understand why all of these structures interact with 5-HT serotonin receptors, because of their close structural resemblance. Although LSD is a more complex molecule, the tryptamine core fragment is still readily apparent.

Figure 43.1 . The structures of the natural transmitter serotonin and the tryptamine-type hallucinogens psilocin, DMT, and LSD.

What is less clear, however, is how the phenethylamine type hallucinogens ( Fig. 43.2 ) interact with serotonin receptors. The only apparent similarity is a basic nitrogen atom separated by two carbon atoms from an aromatic system. Recent mutagenesis studies of the 5-HT2A receptor have, however, begun to reveal the basis for the requirement of certain structural features of the phenethylamines to interact with the receptor.

Figure 43.2 . The structures of mescaline, the prototypical phenethylamine hallucinogen, and general formulas for synthetic substituted hallucinogenic phenethylamines and “amphetamines.” For the alpha-substituted amphetamines, the stereoisomer with the R-(−)- absolute configuration (shown) is more potent.

Studies of the mutant S239A 5-HT2A receptor have demonstrated that it is this serine residue, in transmembrane helix 5, that likely hydrogen bonds to the 5-hydroxy group of 5-HT, as well as to the 5-methoxy-group of the 2,5-dimethoxy- substituted phenethylamines ( Braden & Nichols, 2007 ). Fig. 43.3 suggests possible binding modes for the 2,5-dimethoxy-substituted phenethylamines and the tryptamines, based on those studies.

Figure 43.3 . Comparison of the R-(−)- isomer of a potent difuranobenzene phenethylamine type hallucinogen (left panel) with S-(+)-α-methylserotonin. Although the stereochemistry at the carbon bearing the alpha-methyl is reversed for the phenethylamines and the tryptamines, the lengths of the ligands, differing by about 0.5 Å, could be the underlying reason for this reversal. The bicyclic aromatic indole system of the tryptamines is longer than the phenyl ring of the phenethylamines, and thus when the side chain is extended, the tryptamines will occupy a larger space in the receptor. Because the receptor evolved to accept serotonin, a tryptamine, the perspective must be one that the phenethylamines somehow adapt themselves to a binding site that prefers tryptamines.

This view could explain why a primary amine is most potent for the phenethylamines, with N-alkyl or N,N-dialkyl derivatives being essentially inert, whereas tertiary amines are potent in the tryptamine series. That is, one might envision that the binding site must “shrink” or compress to accommodate a phenethylamine. That is most readily achieved by rotation of the side chain of Asp155 in transmembrane helix 3. If this aspartate engages the amino group in an “end on” conformation for the phenethylamines, it might be speculated that N-alkyl groups would hinder that interaction. By contrast, that aspartate residue could engage the amino group of the tryptamines through an approach more perpendicular to the plane of the molecule. In that event, N-alkyl groups would be expected to have less of an effect on the ligand interaction. That argument can likely be extended to understand the binding of LSD, because its structure is so rigid that interaction of Asp155 with the protonated electron pair of the amino group can only occur through an “axial” approach to the amine moiety. That orientation is evident within the crystal structure of LSD in the 5-HT2B receptor ( Wacker et al., 2017 ).

Substitution of an alpha-methyl group on the phenethylamine side chain gives more potent compounds. There are at least three possible explanations for that finding, all of which probably make some contribution. First of all, the alpha methyl will retard metabolic deamination, giving better oral availability and increased in vivo stability. Second, the alpha methyl adds significant hydrophobicity, leading to better brain penetration. Finally, R-alpha-methyl substituted phenethylamines generally are more efficacious in activating second messenger systems than their nonalkylated congeners ( Parrish, Braden, Gundy, & Nichols, 2005 ). At least for the phenethylamines (“amphetamines”) the alpha methyl group enhances the intrinsic activity, possibly through an interaction with a critical phenylalanine residue in transmembrane helix 6. The steric limitation in this region is very strict, however, as any larger alkyl group, even an ethyl, destroys activity.

Interestingly, the stereochemistry is reversed for alpha-substituted tryptamines. One may speculate that the two classes of ligands bind in such a way as to project the alpha-methyl groups into the same general region of the receptor, but there are no data to support that supposition. The different lengths of the ligands also may be a key here. For example, Fig. 43.3 illustrates S-(+)-alpha-methyl serotonin and the more potent R-(−)- isomer of a rigid phenethylamine. In these orientations, representing potential receptor-bound conformations, the distance from the side chain amino nitrogen to the 5-oxygen atom is 6.1 and 6.6 Å for the phenethylamine and the tryptamine, respectively.

Incorporating the 2- and 5-methoxy groups into furan or dihydrofuran rings gives compounds that are more potent, but more importantly, establishes the binding orientations for the two methoxy groups. Although simulated docking experiments suggest that the 2-methoxy group of the phenethylamines could engage Ser159 through a hydrogen bond ( Braden & Nichols, 2007 ), attempts to test that hypothesis with the S159A mutant receptor, however, gave a protein that had such drastically reduced function that it was not possible to examine the effect of the presence or absence of the 2-methoxy of the ligand.

Although substitution at the 6-indole position of the tryptamines renders them inactive ( Blair et al., 2000 ), substituting the phenethylamines at the 4-position is essential to provide good activity. Again, the different sizes of the phenethylamines and tryptamines are likely at the heart of this observation. Simulating docking experiments suggest that the 4-substituent of the phenethylamines may project into a hydrophobic area of the receptor between transmembrane helices 3, 4, and 5 created by residues Phe234, Ile206, and Val156. It may be that the larger indole ring of the tryptamines projects into this space and additional bulk attached to the ligand in this region creates too large a steric footprint for the receptor to accommodate.

Phenethylamines with a 3,4,5-substitution pattern (e.g., mescaline) do not bind in the same way as 2,4,5-substituted compounds because site-specific mutations of the receptor lead to different effects on 2,4,5- versus the 3,4,5-substituted compounds ( Braden, 2007 ). Nevertheless, a hydrophobic 4-alkoxy substituent in 3,4,5-substituted compounds also gives highest activity in this series ( Nichols & Dyer, 1977 Shulgin & Shulgin, 1991 ), and simulated docking into homology models of the receptor suggests that this substituent may project into the same receptor space as the 4-substituent in the 2,4,5-substituted series.

The rigid nature of LSD limits its conformational flexibility upon binding. Mutagenesis studies suggest that the indole NH hydrogen bonds to Ser242 in transmembrane helix 5 ( Braden & Nichols, 2007 ), and the electron pair on the amine nitrogen is directed in an axial orientation toward the conserved aspartate in helix 3 ( Wacker et al., 2017 ).

Very little structural modification can be tolerated by ergolines related to LSD. The stereochemistry at both the 5- and 8-positions must be of the R configuration, shown in Fig. 43.1 and Table 43.1 . Inversion at C(8) affords iso-LSD, which is inactive. Halogenation at the 2-indole position of LSD affords antagonists such as BOL that lack hallucinogenic activity. Although N(1)-acetylation leads to an active compound, this molecule is actually a prodrug and the N-acetyl is readily cleaved in vivo to afford LSD itself. Longer N(1)-acyl groups also give active molecules, e.g., 1-propionyl-LSD (“1P-LSD”), which also appears to be a prodrug for LSD ( Brandt et al., 2016 ).

Table 43.1 . Summary of structure–activity relationships (SARs) for classes of hallucinogens.


Psychoactive drug

A psychoactive drug, psychopharmaceutical, or psychotropic drug is a chemical substance that changes nervous system function and results in alterations in perception, mood, consciousness, cognition, or behavior. [1] These substances may be used medically recreationally to purposefully improve performance or alter one's consciousness as entheogens for ritual, spiritual, or shamanic purposes or for research. Some categories of psychoactive drugs, which have therapeutic value, are prescribed by physicians and other healthcare practitioners. Examples include anesthetics, analgesics, anticonvulsant and antiparkinsonian drugs as well as medications used to treat neuropsychiatric disorders, such as antidepressants, anxiolytics, antipsychotics, and stimulant medications. Some psychoactive substances may be used in the detoxification and rehabilitation programs for persons dependent on or addicted to other psychoactive drugs.

Psychoactive substances often bring about subjective (although these may be objectively observed) changes in consciousness and mood that the user may find rewarding and pleasant (e.g., euphoria or a sense of relaxation) or advantageous in an objectively observable or measurable way (e.g. increased alertness). Substances which are rewarding and thus positively reinforcing have the potential to induce a state of addiction – compulsive drug use despite negative consequences. In addition, sustained use of some substances may produce physical or psychological dependence or both, associated with somatic or psychological-emotional withdrawal states respectively. Drug rehabilitation attempts to reduce addiction, through a combination of psychotherapy, support groups, and other psychoactive substances. Conversely, certain psychoactive drugs may be so unpleasant that the person will never use the substance again. This is especially true of certain deliriants (e.g. Jimson weed), powerful dissociatives (e.g. Salvia divinorum), and classic psychedelics (e.g. LSD, psilocybin), in the form of a "bad trip".

Psychoactive drug misuse, dependence and addiction have resulted in legal measures and moral debate. Governmental controls on manufacture, supply and prescription attempt to reduce problematic medical drug use. Ethical concerns have also been raised about over-use of these drugs clinically, and about their marketing by manufacturers. Popular campaigns to decriminalize or legalize certain recreational drug use (e.g. cannabis) are also ongoing.