They also discovered that lithium could help patients with bipolar disorder. Enthusiasm for chlorpromazine, the first ever antipsychotic medication, led to an explosion of interest in discovering new chemicals that could be used for treating mental illness. Soon after, researchers discovered the first generation of medications that could be used to relieve symptoms of depression.
The desire to develop improved antipsychotics and antidepressants with fewer side effects resulted in the birth of modern experimental psychopharmacology. Scientists used best practices for isolating the effects of different compounds in experiments.
These include placebo controls, in which a second group is administered a non-psychoactive substance without their knowing it. In this way, experimenters rule out the possibility that any effects are due to subjects’ expectations, rather than the substance itself.
These best practices were even extended to take into account the possible biasing influence of the experimenters’ expectations. Researchers developed the gold standard in experimental psychopharmacology, the double blind procedure. This practice ensures that neither the experimenter nor the participant knows who has received the placebo.
These approaches, combined with the development of accurate methods to measure the effects of the substances being studied, made it possible for the effects of any drug to be investigated in the lab before being made widely available for clinical use. Translational psychopharmacology is the attempt to unify experimental and clinical approaches to drug development. This approach takes new compounds from preclinical experimental investigation all the way to the clinic—from “benchside to bedside.” Translational psychopharmacology is inherently interdisciplinary and attempts to optimize the entire process of studying and using psychoactive compounds as medication, rather than having the process be separated into distinct research and clinical phases. In the lab, new compounds are typically tested on animal models, such as rodents. This is in order to ascertain their effectiveness and safety before testing them on humans. Animals cannot communicate the effects of the compound on their minds in the way humans can, so scientists must construct clever behavioral tests in order to gain insight into the altered mental state of the animal.
They have developed increasingly sophisticated methods for identifying the effects of different drugs on animal behavior over the last few decades, giving rise to the field of behavioral psychopharmacology.
The field of neuroscience introduced new methods that could be used to investigate the operation of the brain. Researchers began using these methods to better understand the action of different chemical compounds on the nervous system. Investigating the ways in which psychoactive chemicals interact with the neurons of the brain led to the discovery that the brain communicates using chemical signals. Rather than being sent directly, each electrical signal between neurons is actually buffered by a chemical messenger. A jolt of electricity in the first neuron causes the release of a chemical that is detected by the next neuron. In turn, that neuron generates its own jolt of electricity.
The gap between neurons where the chemical baton is passed is called the synapse. This is where many drugs have their effects upon wandering in from the bloodstream. Discovering that minuscule quantities of LSD could have profound effects on the mind was one of the major clues that led to this revolution in the way we understand the brain. Humans have always used plants containing certain compounds in order to alter their mental state. Knowledge of the psychological effects of different plants exists across the globe, from Chinese medicine to the traditional use of St.-John’s-wort for treating depression. Psychedelics in particular have been used by the vast majority of human cultures, often as a form of medicine. In the early 20th century, such practices were largely absent outside of indigenous communities in the west. However, medicinal tonics such as Coca-Cola (cocaine and caffeine) and 7 Up (Lithium) were widely consumed, in part for their psychological effects. In contemporary medicine, there is a heavy reliance on the use of chemical compounds to suppress the symptoms of psychological issues, rather than to address their root causes. On the other hand, medicinal plants are used within a holistically-based understanding of the individual.
The patient’s history, current behavior, and social and material situation are all relevant to understanding his psychological issues. With modern for-profit drug development, however, there is no incentive to spend time concerned with such matters. If a chemical can suppress a symptom it will sell, and sales are the goal. However, psychedelic medicine stands to revolutionize the field of psychopharmacology. Its mechanism seems to be addressing the root cause of suffering, rather than suppressing symptoms.
The integration of psychedelics into mainstream medicine is poised to force a confrontation and synthesis between these two perspectives on relieving psychological suffering. Since experimentation with mescaline began in the west roughly a century ago, research has documented the psychological effects of different psychedelics. Research literature originally characterized them as “psychotomimetics,z” psychosis-mimicking drugs, as a result of their hallucinogenic properties.
The term “hallucinogen” is often used for the same reason. Classical psychedelics (LSD, psilocybin, DMT, mescaline) act primarily on the serotonin system via a particular receptor found on the surface of neurons, the serotonin 2A receptor.
The chemical name for serotonin, 5-hydroxytryptamine, is typically shortened to 5-HT. So you may see this referred to as the 5-HT2A receptor. Classical psychedelics fall into two classes, the tryptamines and the phenethylamines.
The tryptamines include psilocybin and DMT, and their molecular structure resembles the serotonin molecule.
The phenethylamines include mescaline and more closely resemble dopamine, although they still exert the majority of their effects via the serotonin 2A receptor. Alexander “Sasha” Shulgin was a chemist who discovered the psychoactive effects of the 2-CB class of phenethylamines. He systematically explored the psychological effects of all known psychedelic compounds on himself. He published his reports in two volumes: PIHKAL (phenethylamines I have known and loved) and TIHKAL (tryptamines I have known and loved).
These tomes are widely considered the old and new testament of psychedelic psychopharmacology. Cannabis has been found to exert its psychological effects via the cannabinoid system, primarily via the CB1 and CB2 receptors in the brain.
The presence of receptors for molecules found in the cannabis plant is evidence of a long history of human use of cannabis, and of our coevolution with this species. Activation of these cannabinoid receptors typically produces relaxation, an increase in appetite, and a range of effects on thought patterns and perception. Rather than binding to specific sites in the brain, alcohol acts as a general nervous system depressant, reducing activity in multiple pathways. It achieves this in two ways. First, it suppresses excitatory activity by acting on NMDA receptors, cellular components that are crucial for memory formation. It also increases activity in the inhibitory GABAa pathway. This results in general impairments of central nervous system function, from memory and cognition to decision-making and movement. Opioids are derivatives of opium and include heroin, morphine, methadone, codeine, fentanyl, and oxycodone.
They act on the spinal cord and midbrain to reduce pain signals that are sent from the peripheral nervous system to the central nervous system. This results in the experience of pain relief without producing unconsciousness. As a result, morphine is considered an essential medicine by the World Health Organization (WHO). In addition, opioids also stimulate dopamine release. Dopamine mediates reward-based learning in the brain. This action of opioids is thought to account for their high addictive risk. Stimulants are defined by their psychological effects, rather than their chemical makeup. Cocaine is a common stimulant that produces an increase in alertness, energy levels, confidence, and mood. Cocaine impairs the ability of neurons to recycle three major chemicals that modulate brain activity: dopamine, norepinephrine, and serotonin. Cocaine prevents the recycling of these chemicals by neurons for later use. As a result, their action in the brain actually increases due to their lingering at receptor sites for longer than they usually would. Amphetamines and methamphetamine also increase dopamine and norepinephrine activity by the same mechanism, as well as stimulating their release. As with opiates, the dopamine pathway is thought to be responsible for their high risk of addiction. The first generation of antidepressants consisted of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants. Monoamine oxidase is an enzyme that metabolizes a range of chemicals in the brain and in other parts of the body. It is the enzyme that breaks down DMT in the gut, preventing it from being orally active unless consumed with MAOIs. (Ayahuasca, for example, is an MAOI inhibitor.) By inhibiting the activity of monoamine oxidase, MAOIs increase the amount of dopamine, norepinephrine, and serotonin available in the brain. Tricyclic antidepressants prevent norepinephrine and serotonin from being efficiently recycled, leading to their having a prolonged effect, as described for stimulants above. Modern antidepressants typically are serotonin reuptake inhibitors (SSRIs) which work by the same mechanism. However, SSRIs specifically target serotonin. It was originally speculated that SSRIs may work by correcting a preexisting chemical imbalance in the brain. But scientific evidence has not borne this out. It appears that stimulating the serotonin system may instead soothe symptoms and promote coping, rather than addressing the cause of the depression. Benzodiazepines act on the GABAa receptor that is also affected by alcohol.
They have been found to reduce anxiety and to have a sedative effect. This class of chemicals is considered a “minor tranquilizer” and can be prescribed for anxiety conditions and insomnia. Valium is the brand name for the benzodiazepine diazepam, which has been widely prescribed since 1963. Modern psychopharmacological research has two main focuses. First, it seeks to discover new chemical compounds that can be used as medicines. In addition, it reappraises older compounds for new uses. While big pharma typically emphasizes the former, as newly discovered compounds can be patented for profit, the largely university-based research of the psychedelic renaissance has focused on the latter. Modern psychedelic psychopharmacology is reassessing compounds such as psilocybin that occur in nature. It is also reexamining synthetic compounds such as MDMA that are by no means new discoveries. Research programs leverage cutting-edge imaging technology in order to study the effects on the brain.
They also hold clinical trials in order to test their use for a variety of mental health issues. This area of research looks only set to grow.
There’s never been a better time to consider becoming a psychedelic psychopharmacologist. Dr. James Cooke is a neuroscientist, writer, and speaker whose work focuses on consciousness, with a particular interest in meditative and psychedelic states. He studied Experimental Psychology and Neuroscience at Oxford University and is passionate about exploring the relationship between science and spirituality, which he does via his writing and his YouTube channel, YouTube.com/DrJamesCooke. He splits his time between London and the mountains of Portugal, where he is building a retreat center, The Surrender Homestead (@TheSurrenderHomestead on Instagram). Find him @DrJamesCooke on Instagram, Twitter, and Facebook, or at DrJamesCooke.com.
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