Nature's Pharmacopeia: A World of Medicinal Plants

Chapter 4

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The Actions of Medicinal Plants on the Nervous System

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The dendrites of neurons, here shown magnified and stained with a fluorescent dye, carry nerve impulses that control movement and generate consciousness. The signals they propagate can be influenced by plant-derived chemicals. (Micrograph by Amber Petersen and Nashaat Gerges)

The nervous system—responsible for human consciousness, cognition, sensation, and movement—is composed of a complex network of cells that together gather information from all parts of the body, integrate diverse sources of input, and then signal the appropriate responses. The system enables us to perceive our complex environment, learn, think, and have emotions.

The central nervous system consists of the brain and spinal cord. Its role is to collect and integrate sensory information, coordinate muscle movement, store memories, process language and imagery, and generate feelings. The peripheral nervous system, a nerve network that penetrates all reaches of the body, is largely responsible for gathering the sensations that an individual experiences and initiating muscle contractions according to instructions from the central nervous system. The peripheral nervous system receives input, for example, by touch or taste, and mediates responses, such as by causing muscles to move or glands to release hormones. The active principles of some herbal medicines can affect the function of the nervous system, and those that alter the behavior of the brain are called psychoactives. The basic unit of the nervous system is the nerve cell (neuron), and many medicinal compounds exert their effects by specifically interacting with these fundamental cells and the structures they form.

Neuron

A nerve cell, the basic unit of the nervous system

Psychoactive drug

A drug that produces an effect on the central nervous system, especially on the mind

CENTRAL NERVOUS SYSTEM: STRUCTURE AND FUNCTION

The brain can be considered in four regions: the brain stem, the overlying thalamus-hypothalamus structures, the cerebellum, and the cerebrum (figure 4.1). The brain stem carries sensory and motor messages between the brain and the spinal cord, acting as a conduit for information between the central nervous system and the remainder of the body. It also plays a role in generating and modulating messages. For example, the portion of the brain stem closest to the spinal cord (medulla) regulates the vital functions of heart rate, digestion, breathing, blood pressure, and coughing. Slightly above that portion is the pons, which shares information related to movement between the cerebrum and the cerebellum. The midbrain, located above the pons and near the center of the brain, processes sensory information from the eyes and ears and helps regulate movement of the body.1 Importantly, the pons and midbrain also contain neurons involved in aspects of arousal, sleep, and emotion. Drugs that act on cells in this region, such as some central stimulants, can make a person vigilant and sleepless.

Above the brain stem, the thalamus serves to distribute incoming sensory information for processing in the cerebrum, making it partly responsible for sensory awareness and attention. It also coordinates signals related to movement originating in various parts of the brain for transmission to the rest of the body. The hypothalamus governs several core biological functions, including temperature control, thirst and hunger, and aspects of sexual function and emotion. It also releases hormones into the bloodstream.2 Numerous plant-derived chemicals can affect these processes.

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FIGURE 4.1   The regions of the brain.

REGIONS AND PARTS OF THE BRAIN: FUNCTIONS OF SENSORY PERCEPTION, MOTOR CONTROL, EMOTION, AND COGNITION

Region

Part

Function

Brain stem

 

Regulates vital functions such as breathing and heart rate; transmits and processes information between spinal cord and brain; collects sensory information and provides motor control for the head

 

Medulla

Controls breathing, blood pressure, heart rate, swallowing, and respiration; contains the vomiting center, responsive to toxins in the bloodstream

 

Pons

Influences transition between sleep and wakefulness and between stages of sleep; controls breathing rates and pattern; houses neurons that govern arousal, vigilance, and attention; conveys information about movement between cerebral hemispheres and cerebrum

Thalamus and hypothalamus

Processes information between brain regions; regulates unconscious body functions and controls release of some hormones

 

Thalamus

Processes and distributes sensory information between brain stem and cerebral cortex

 

Hypothalamus

Regulates body temperature and salt–water balance; modulates hunger, thirst, and sexual behaviors

Cerebellum

 

Coordinates body movements in force and range; contributes to learning and memory

Cerebrum

 

Plans and executes movement; stores memory; enables language, reasoning, and creativity

 

Cerebral cortex

Divided into frontal, parietal, occipital, and temporal lobes; processes sensory information; site of complex reasoning, planning, personality, speech, reading, and conscious body movement

 

Basal ganglia

Regulate muscle movement

 

Amygdala

Coordinates emotional responses; generates feelings of pleasure, punishment, sexual arousal, rage, and fear

 

Hippocampus

Establishes new long-term memories

 

Limbic system

Includes the cingulate cortex, amygdala, hippocampus, and other structures; integrates emotional responses and reward; regulates motivated behavior and learning

Sources: Walter Lewis and Memory P. F. Elvin-Lewis, Medical Botany: Plants Affecting Human Health (Hoboken, N.J.: Wiley, 2003), 632; Gerard J. Tortora and Bryan H. Derrickson, Principles of Anatomy and Physiology, 11th ed. (Hoboken, N.J.: Wiley, 2009), 496–522; Eric R. Kandel et al., Principles of Neural Science, 5th ed. (New York: McGraw-Hill, 2013), 8–11.

The cerebellum is in the back of the head and connects to the brain stem. Its role is to gather sensory input regarding motion and balance and then to provide the signals to ensure smooth and coordinated muscle movements. It also plays a role in learning, particularly of motor skills. The effects of alcohol intoxication on the cerebellum are evident as staggering and slurred speech.

Occupying most of the brain’s volume is the cerebrum, comprising two hemispheres with wrinkled surfaces. This structure is responsible for sensory awareness, personality, memory storage, planning of action, and voluntary movements. Much of the cerebrum’s activities take place in the upper few millimeters of its surface (cerebral cortex), where neurons form numerous connections with one another and with other parts of the central nervous system, including cells in the brain stem, thalamus and hypothalamus, and cerebellum.3 Deep within the cerebrum are several structures (basal ganglia, amygdala, and hippocampus) involved in motor control, learning and memory storage, and motivation.4 Because the brain’s structures are intricately connected by bundles of long neurons (nerve fibers) that cross between regions, sensation, perception, and movement can be coordinated and the intriguing functions of learning, emotion, and thought can emerge.

The sensory information that comes in from the body’s extremities is channeled through the spinal cord, as are signals that go out to the muscles and other tissues, causing actions to occur. The relationship between the spinal cord and the nerve network that permeates the tissues (peripheral nervous system) is a complex one, and one that medicines can alter to great effect.

PERIPHERAL NERVOUS SYSTEM: STRUCTURE AND FUNCTION

The peripheral nervous system carries messages around the body through two nerve networks: the somatic nervous system, which controls the skeletal muscles and senses the external environment, and the autonomic nervous system, which regulates the activity of the internal organs. The somatic nervous system provides the ability to feel the heat of a cup of coffee, control the movement of hand muscles while writing, and sense vibration when a bus passes nearby. The autonomic system carries the signals that, without conscious effort, direct the heart to beat, the intestine to pass along food, and the glands to release their hormones at the appropriate times. This division of labor in the nervous system essentially distinguishes whether the movement is voluntary and the sensation conscious or whether the action is not a deliberate decision but a basic, unconscious activity of the human body. Via the central and peripheral nervous systems, nerve fibers control the function of nearly all the body systems.5

For example, the flow of blood throughout the body is regulated by the peripheral nervous system in many ways: the autonomic nervous system can increase or decrease the heart rate, depending on cues from the body and from the central nervous system; it can cause the smooth muscle lining the major blood vessels to dilate or constrict; and it can even control the ability of blood to reach the smallest of vessels in the skin, causing someone to blush. Likewise, the peripheral nervous system plays key roles in the activity of the digestive system, the reproductive system, respiration, and so forth. Indeed, a great many of the body’s functions are connected to the state of the nervous system, which may be why so many medicinal plants act there. These psychoactive drugs and peripheral nervous system modulators would not function if not for their effects on the nervous system’s basic units, the nerve cells—neurons.

Functions of the peripheral nervous system

Somatic

Conscious sensation and muscle movement

Autonomic

Unconscious control of the organs

NEURONS

Neurons, like all living cells, are self-contained units of biological activity that can synthesize myriad chemical compounds, receive input from their microenvironment, and send out signals of many types. Neurons can be quite small, on the order of one-tenth to one-twentieth of a millimeter in length, although most neurons tend to be long and thin, with multiple extensions.6 Some neurons, such as those in the spinal cord, can be tens of centimeters long but a fraction of a millimeter in diameter.

Neurons are specialized to receive, integrate, and send signals, functions that are reflected in their structure (figure 4.2). The neural cell body (soma) contains the nucleus, a repository of genetic information, and much of the machinery to sustain biological activities. The neuron gathers information, whether by sensing the environment or by communicating with other neurons, through highly branched cellular extensions called dendrites. On receipt of a signal, the neuron processes the stimulus and sends a new message to neighboring neurons along the length of an extended thin tube, the axon. The axon propagates its message electrically, which is why axons are typically coated with a sheath of the jelly-like substance myelin. Myelin serves as an insulating material to preserve the integrity of the axon’s electrical signal. The end of the axon is branched, and the tip of each branch is a presynaptic terminal, a point where the neuron communicates with the soma or dendrites of neighboring cells by converting electrical impulses into chemical messages.

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FIGURE 4.2   Neuron structure and function. Chemical messages are emitted in the form of neurotransmitter signals from the end of an axon. Transmitters are released into the synapse between cells and perceived by specialized receptors on the surface (of the dendrite, for example) of a neighboring neuron. Following their release into the synapse, structures on the presynaptic membrane take up and recycle excess neurotransmitters. (Adapted from Robert M. Julien, Claire Advokat, and Joseph E. Comaty, A Primer of Drug Action, 12th ed. [New York: Worth, 2011], fig. 3.7)

Parts of a neuron

Cell body

Contains the genetic material and most of the cell’s volume; also called the soma

Axon

Long and thin cellular extension that transmits signals electrically; axon terminals communicate chemically with neighboring cells

Dendrite

Branched extension that receives sensory input

Synapse

Point of communication between neurons

The terminus of an axon is typically separated from the dendrites and soma of neighboring cells by narrow gaps (synapses) across which neurons signal using molecules called neurotransmitters. Communication takes place when an axon end, the presynaptic terminal, sends neurotransmitters across the synapse to the receiving cell, at the postsynaptic terminal. Some neurons, such as those in the central nervous system, generate hundreds of thousands of synapses, a condition that reflects the importance of intercellular communication in nervous system function.7 Since the brain contains 100 billion or more neurons, each making an average of several thousand synaptic connections, the sensitive and specific neuronal information sharing that produces human sensation, movement, and higher-order functions owes itself to enormously complex intercellular interactions.8 Psychoactive compounds can interfere with cell-to-cell signaling at this level.

While communication along an axon and between certain specialized neurons is electrical, propagated by minute changes in voltage that can travel down the axon at speeds in the neighborhood of 100 meters per second, most intercellular signaling at synapses is mediated chemically.9 The presynaptic terminal maintains a reserve of neurotransmitters, sequestered inside the cell, that when released into the synaptic cleft between neighboring neurons, pass across to the postsynaptic cell’s membrane and are sensed by specialized neurotransmitter receptors. In some cases, the binding of a neurotransmitter to its receptor is excitatory, causing an impulse to propagate; in others, the message is inhibitory, causing the target cell to reduce its signaling activity. The diversity of known neurotransmitters reflects the complex nature of the nervous system.

At the microscopic level, the scale at which neurons operate, chemical compounds have three-dimensional structures determined by the nature of the bonding between their atoms. Most biological molecules are composed of atoms of carbon, oxygen, nitrogen, hydrogen, and a few other elements connected together to form units of distinct shapes and with unique functional properties. All the building up or breaking down of various molecules in and near cells is carried out by enzymes, specialized minuscule structures whose task is to assemble or disassemble very specific chemical configurations while leaving all others untouched. It is important that cells be able to detect with precision a wide variety of chemical compounds, for so many of these are critically important to their development and ability to communicate. To recognize the chemical signals around and within them, cells produce molecular sensors known as receptors, which are capable of receiving chemical input and informing the cell of the nature of the signal.

NEUROTRANSMITTERS

Human neurons produce a diversity of neurotransmitters that enable communication within the nervous system and between the nervous system and various tissues. These molecules fall into a handful of categories based on chemical structure, each perceived by particular receptors that are present in different subsets of cells and initiating different processes. The role of a neurotransmitter receptor is to recognize the presence of a specific neurotransmitter chemical in the fluid outside the neuron and then to signal that chemical’s presence to the interior of the neuron.

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FIGURE 4.3   Neurotransmitter agonists and antagonists. Neurotransmitters bind to specific receptors, propagating a message inside the target neuron. Neurotransmitter receptor agonists can bind to neurotransmitter receptors and provoke a similar signal inside the neuron. Neurotransmitter receptor antagonists bind to neurotransmitter receptors and block their ability to propagate a signal.

In some cases, however, molecules whose chemical structures resemble neurotransmitters can also bind to receptors and give rise to biological effects (figure 4.3). Since the receptors have an affinity for the shape of the neurotransmitter to which they normally bind, they can sometimes be activated by a closely related chemical structure (agonist) or blocked by a chemical that binds but fails to activate the receptor (antagonist). Neurotransmitter action is a function of multiple activities occurring at the synapse: signaling can be increased by releasing more neurotransmitter into the synaptic cleft or by inhibiting its degradation or reuptake; conversely, signaling can be reduced by hastening the compound’s destruction or departure from the synapse. Indeed, these and other complex phenomena serve to modulate the level of signal between neurons and are frequently engaged in the presence of psychoactive medicinal compounds.

Numerous plant products, including many potent psychoactive chemicals, function by activating or inhibiting the body’s natural (endogenous) signaling mechanisms. Herbal drugs can increase the heart rate by fooling the nervous system into a stimulated state. They can also cause numbness by preventing sensory neurons from communicating at all. Some of these chemicals function systemically; others work locally. What the plant psychoactive chemicals have in common is their direct action on the human nervous system and their propensity to perturb, hijack, or block the normal processes of cellular communication.

Neurotransmitter receptor agonist

A chemical that binds and activates a receptor in place of a neurotransmitter

Neurotransmitter receptor antagonist

A chemical that binds and blocks signaling by a receptor

Amino Acid Neurotransmitters: Glutamate, GABA, and Glycine

The amino acid neurotransmitters are active throughout the central and peripheral nervous system and serve to increase or decrease the activities of many types of neurons. As a result, they have diverse functions in the human systems. Glutamate is the principal excitatory neurotransmitter in the brain and spinal cord, and it mediates signals induced by numerous other neurotransmitters (figure 4.4).10 Among its many roles in such functions as muscle control and sensory perception, glutamate signaling is also important in forming new neural connections, such as during the process of learning.11

Gamma (γ)-aminobutyric acid (GABA), for its part, serves as an inhibitory molecule, dampening the signals generated by other neurotransmitters (see figure 4.4).12 Among GABA’s main effects are the promotion of fluid muscle movements and a sense of calm in the mind. Some natural chemical products can interfere with normal signaling via the GABA receptors, by both activating and blocking GABA responses. For example, the fly agaric (Amanita muscaria) mushroom yields muscimol, a GABA agonist that inhibits a broad range of neurotransmitter signaling (see figure 4.4). Traditional shamanic practices of eastern Siberia include the consumption of fly agaric to induce stupor and altered sensory perception.13 The fish-berry plant (Anamirta cocculus), a shrub traditionally used in India as a fishing poison and medicine, produces the highly potent central nervous system stimulant picrotoxinin, a GABA antagonist (see figure 4.4).14

Similarly to GABA, the neurotransmitter glycine has roles in maintaining a low level of nerve cell stimulation, primarily in the brain stem and spinal cord (see figure 4.4). In addition to its activity as a GABA antagonist, picrotoxinin blocks signaling via certain types of glycine receptors.15 The South Asian strychnine tree (Strychnos nuxvomica) has long been employed in indigenous medicine as a tonic and stimulant, and its seeds were traded widely in antiquity.16 Classic writers also warned of its risks. For instance, the English herbalist John Gerard (1545–1611?) described “the Vomiting Nut” as “not to be given inwardly” because “the dangers are great.”17 The seeds contain the glycine antagonist strychnine, which prevents glycine’s normally calming effects (see figure 4.4). Strychnine causes agitation at a low dose, convulsions at a moderate dose, and death through paralysis at a higher dose.

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FIGURE 4.4   Amino acid neurotransmitters: glutamate; γ-aminobutyric acid (GABA); the GABA receptor agonist muscimol, from the fly agaric mushroom; the GABA receptor antagonist picrotoxinin, from the fish-berry plant; glycine; the glycine receptor antagonist strychnine, from the strychnine tree.

Acetylcholine

The neurotransmitter acetylcholine is involved in diverse processes. In the central nervous system, nerve cells transmitting acetylcholine (called cholinergic neurons) are found in the cerebrum and midbrain, with projections that communicate with neurons throughout the cerebral cortex, cerebellum, thalamus, and other parts of the brain. In these regions, acetylcholine serves a role in learning and memory, among other functions (figure 4.5). In the periphery, acetylcholine induces muscle movement. Acetylcholine is released from the presynaptic terminals of motor neurons, binds to receptors in muscle cells, and causes them to contract.18 (In much of the body, such as in the smooth and skeletal muscles, acetylcholine initiates muscle contraction. In the heart muscle, however, acetylcholine reduces the heart rate.)19

Some plant compounds can interfere with normal acetylcholine signaling. Among the most widely known is the alkaloid nicotine (see figure 4.5), which accumulates in the leaves of the New World tobacco plant (Nicotiana tabacum and other species). Indigenous peoples of the Americas inhaled tobacco smoke, chewed its leaves, and took leaf powder into their noses for a range of spiritual-medical purposes.20Beginning in the sixteenth century, tobacco use spread to Europe, Africa, and Asia, ultimately becoming one of the most ubiquitous customs on earth. Nicotine’s effects are widespread in the body. In the periphery, the compound generally binds as an agonist to acetylcholine receptors in the nerves that control the skeletal muscles, smooth muscles, heart, and glands, although its actions are complex and depend on dose. Its broad physiological effects include increased tone of the muscles lining the gastrointestinal tract and a rise in heart rate and blood pressure, in part because of its stimulation of the adrenal gland. Nicotine also binds and activates acetylcholine receptors in the central nervous system, resulting in increased alertness and mild analgesia.21

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FIGURE 4.5   The neurotransmitter acetylcholine; the acetylcholine receptor agonist nicotine, from tobacco; the acetylcholine receptor antagonists atropine and scopolamine, from the nightshade plants; the synthetic respiratory drug tiotropium. Structural similarities are shown in purple.

In contrast to the agonist effect of nicotine on acetylcholine receptors, the alkaloid atropine, produced by the Eurasian deadly nightshade (Atropa belladonna), antagonizes acetylcholine receptors (see figures 4.5 and 4.6). This plant also goes by the name belladonna, a reference to its historic use as a cosmetic drug in Italy, dropped into the eyes to dilate ladies’ pupils (bella donna [beautiful woman]). Its effects vary greatly, depending on dose: it slows the heart rate at a low concentration and increases the heart rate at slightly higher levels. It also blocks the activity of sweat and salivary glands, slows peristalsis of the intestines, and at very high doses can disrupt coordinated signaling in the brain, resulting in hallucinations. Overdose (greater than 10 milligrams) can be lethal.22 The nightshades have long been employed in the traditional medicine of Europe. For example, the English herbalist John Parkinson (1567–1650) recommended the family of nightshade plants as cooling herbs to treat inflammation, headache, shingles, dropsy, and other complaints but warned that A. belladonna “[is] held more dangerous than any of the other,” noting the “lamentable” deaths of children who ate the plant’s black berries or drank a broth in which its leaves had soaked.23 When carefully prepared and administered, atropine remains a useful agent in medicine in the modern day. The chemical is used to dilate the pupil during eye examinations, as it relaxes the muscles of the iris.24 Atropine also blocks the constriction of smooth muscle in the lungs and can be given to ease breathing in patients with asthma and chronic obstructive pulmonary disease. In addition to atropine, the nightshade plants produce a closely related acetylcholine receptor agonist, scopolamine, which shares a number of physiological effects (see figure 4.5). Pharmacologists have developed a semisynthetic and longer-lasting drug based on the chemical structure of atropine and scopolamine, tiotropium (marketed as Spiriva), which is now considered the preferred bronchodilator for patients with chronic obstructive pulmonary disease (see figure 4.5).25

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FIGURE 4.6   Deadly nightshade, a source of the acetylcholine receptor antagonist atropine.

Monoamines: Norepinephrine, Dopamine, and Serotonin

Although the monoamine neurotransmitters are grouped together based on their structural similarity, their roles in human physiology are diverse. These chemicals broadly participate in the processing of sensory information, decision making, emotion, and many aspects of human intelligence and creativity. Produced by a relatively small number of neurons located in the central nervous system, monoamine neurotransmitters exert wide-ranging effects because of their cells’ many projections throughout the brain and (sometimes) spinal cord and their numerous synapses, which modulate signaling at a fine level.26 A great number of psychoactive plants exert their effects through signaling via these neurotransmitters’ receptors or by blocking their natural functions.

Norepinephrine neurons reside in the brain stem, and their axons project through many regions of the cerebrum, cerebellum, brain stem, and spinal cord. Together with other neurotransmitters, norepinephrine regulates alertness and focus, plays a role in the wake–sleep cycle, and is responsible in part for feelings of fear and anxiety. It is also thought to play a role in basic instinctual animal behaviors, including the search for food and water.27 The closely related compound epinephrine (also known as adrenaline) acts systemically and increases the heart rate, constricts peripheral blood vessels, opens air passages, and dampens sensations of pain. Such effects are particularly important when facing a threat and are frequently felt when one is startled.28 Both norepinephrine and epinephrine bind to the same class of neurotransmitter receptors, called the adrenergic receptors.

A number of plant-derived chemicals interact with the adrenergic system. For example, the jointfir ma huang (Ephedra sinica), employed in Chinese medicine for millennia, produces the potent stimulant alkaloid ephedrine (figures 4.7 and 4.8). Ephedrine is an agonist at adrenergic receptors in the central and peripheral nervous system, which causes an increase in heart rate and blood pressure, in addition to bronchodilation and other effects. The drug also enhances the release of norepinephrine from neurons in the periphery.29 Since it stimulates the heart rate and gives the sense of increased energy, ephedrine (in the form of pills containing jointfir herb) was marketed in the United States during the late twentieth and early twenty-first centuries as a performance-enhancing and weight-loss supplement. Most ephedrine-containing supplements were ultimately banned by the Food and Drug Administration in 2004 because of deaths associated with the use of Ephedra-containing products.30

The bark of the yohimbe tree (Pausinystalia johimbe), thought to be an aphrodisiac, contains the alkaloid yohimbine, which exerts its activities by antagonizing a subset of adrenergic receptors. Interestingly, blocking one type of adrenergic receptor induces the release of norepinephrine systemically, which increases the heart rate and blood pressure.31 Perhaps it is a combination of these physiological effects and an indirect influence on mood that gives the yohimbe herb its reputation for improving male sexual function.32

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FIGURE 4.7   The neurotransmitter norepinephrine; the adrenergic receptor agonist ephedrine, from the jointfir. Structural similarities are shown in purple.

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FIGURE 4.8   Jointfir, source of the adrenergic receptor agonist ephedrine.

The molecule reserpine from the Indian snake-root (Rauvolfia serpentina) and other plants was widely used in the twentieth century to treat high blood pressure. Reserpine binds to the storage structures inside neurons that contain norepinephrine, dopamine, and serotonin, ultimately resulting in their depletion. Reduced signaling by norepinephrine leads to a decrease in blood pressure.33

The neurotransmitter dopamine is structurally related to epinephrine and norepinephrine, but it serves distinct roles in many aspects of cognition and behavior (figure 4.9). Most dopamine-producing neurons reside in the midbrain and project into the cerebrum, where they play an important role in learning and memory, control of movement, and motivation.34 Dopamine’s contribution to voluntary movement is evident in the symptoms of Parkinson’s disease, which results from the loss of a subset of dopaminergic neurons and impairs the patient’s muscle control.35 A role for dopamine in influencing mood is revealed by the effects of reserpine, which, in addition to its function in lowering blood pressure, reduces dopamine signaling and can induce psychological depression.36

Conversely, an increase in dopamine signaling can lift a person’s mood. A striking example of this effect is the use of cocaine, the active principle of the South American coca shrub (Erythroxylum coca). The alkaloid blocks the reuptake of dopamine, norepinephrine, and serotonin at presynaptic nerve terminals and therefore artificially increases the concentration of these neurotransmitters in synapses.37 Together, these neurotransmitters produce an intense stimulation of the central nervous system, resulting in increased heart rate and blood pressure along with elevated alertness, self-confidence, and lightened mood.38Among the neurotransmitters, dopamine is most directly responsible for producing a sense of well-being (euphoria), a feeling associated with the use of a number of psychoactive drugs.

Serotonin (sometimes referred to by its alternative name, 5-hydroxytryptamine) is produced by neurons in the brain stem that project into the spinal cord, medulla, cerebrum, and cerebellum (figure 4.10). Serotonergic neurons are thought to make so many connections that essentially every neuron in the brain forms a synapse with one.39 Serotonin has an important and widespread role in human behavior and higher-order functions, as it governs attention, mood, aspects of emotion, and the integration of sensory information.40 While neurobiology researchers continue to dissect serotonin’s multiple functions, it is clear from the effects of serotonin-like drugs that this neurotransmitter is crucial in processing stimuli and creating an individual’s private reality.

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FIGURE 4.9   The neurotransmitters norepinephrine, epinephrine, and dopamine share a structural resemblance but differ in physiological properties.

Numerous plant compounds have been found to bind to serotonin receptors and induce a range of abnormal sensory experiences. For example, the ayahuasca beverage, composed of several plant ingredients including the ayahuasca vine (Banisteriopsis caapi) and chacruna (Psychotria viridis), is employed by indigenous peoples in tropical South America in spiritual healing practices. The prepared drink contains dimethyltryptamine, which closely resembles serotonin and likely acts as an agonist at its receptor (see figure 4.10).41 Among its many effects on perception, ayahuasca induces visual anomalies consisting of complex geometric patterns. Likewise, a number of fungal active principles affect the serotonin system and produce changes in mood and sensory alterations, such as the compounds psilocin and psilocybin from Psilocybe and other genera of mushrooms (see figure 4.10).42

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FIGURE 4.10   The neurotransmitter serotonin; the serotonin receptor agonists dimethyltryptamine, from the ayahuasca beverage, and psilocin, from Psilocybe and other genera of fungi. Structural similarities are shown in purple.

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FIGURE 4.11   The endogenous neuropeptide leu-enkephalin; the opioid receptor agonist morphine, from poppy. Structural similarities are shown in purple.

Endorphins

The neuropeptide (small protein) endorphins (figure 4.11) and related neurotransmitters bind to opioid receptors, which are distributed widely in the brain and spinal cord as well as in the neurons that regulate the intestinal smooth muscle and elsewhere in the periphery.43 Among their numerous roles, these chemicals inhibit the perception of pain and are produced at higher levels during stressful experiences, such as childbirth, and at physically demanding times, such as while exercising. Opioid agonists can counteract the transmission of pain sensation by blocking signals at the spinal cord or dampen pain perception in the medulla or midbrain.44 In other circumstances, opioid agonists can depress cardiac and respiratory activity, induce vomiting, reduce activity of the gastrointestinal tract, suppress the cough reflex, and interfere with motor control.45 The opium poppy (Papaver somniferum) has a long history of use for its pain-reducing, sleep-inducing, cough-suppressing activities. These properties are attributable to alkaloids, including morphine, that bind to endorphin-sensitive opioid receptors as agonists and produce analgesia, central nervous system depression, and other effects (see figure 4.11).

Endocannabinoids

Endocannabinoid neurotransmitters such as anandamide play a widespread role in modulating mood, hunger, body temperature, coordination, memory, and the perception of pain (figure 4.12). Their receptors, the cannabinoid receptors, are abundant in the central nervous system, and in many settings they function by down-regulating excitatory signals, such as by suppressing the release of glutamate from presynaptic nerve terminals. Cannabinoid receptors are found at greatest density in the cerebral cortex, basal ganglia, hippocampus, and spinal cord, where they influence thought, memory, and movement.46

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FIGURE 4.12   The neurotransmitter anandamide; the cannabinoid receptor agonist Δ9-tetrahydrocannabinol, from hemp.

Traditional medical and religious practices across Europe and Asia valued hemp (Cannabis sativa) for its effects on a person’s sensory experiences, now understood to be caused by its active principles, including the cannabinoid receptor agonist Δ9-tetrahydrocannabinol (see figure 4.12). This terpenoid compound produces symptoms of altered sensory perception, anxiety or calm (depending on dose and mental state), increased appetite, and analgesia.47

COMPLEXITY OF PSYCHOACTIVE DRUG ACTION

Since neurons of the central nervous system are intricately interconnected, making synapses with many other cells and projecting widely across regions of the brain, the multiple neurotransmitter pathways allow cells to integrate diverse sources of input and modulate signals appropriately. For example, orchestrating a simple voluntary movement such as picking up a pen requires the participation of many parts of the brain: those involved in object recognition, planning and execution of movement, and the entire motor-sensory pathway into the periphery. Ultimately, a great number of neurons are involved in such an activity, and they are spread throughout the cerebral cortex, basal ganglia, cerebellum, thalamus, spinal cord, and elsewhere, signaling through many types of neurotransmitters.48 The integration of so many brain regions and communication pathways as the basis of human experience (for example, consciousness) remains an important problem of neuroscience research.

Because of the interconnectedness of neural signals and the “cross-talk” between neurotransmitter functions, psychoactive drugs can produce a range of physical and mental changes attributable to primary actions (such as agonism and antagonism of neurotransmitter receptors) and to secondary interactions through additional neurotransmitter signaling pathways. For example, the peyote cactus (Lophophora williamsii), which grows in Mexico and the southern United States, has a long history as an aid to American Indian religious and medical practice, producing excitement and a sense of communion with the spirit world. Its active principle, mescaline, binds to a type of serotonin receptor found mostly in the frontal cerebral cortex, which is likely responsible for the altered sensory perceptions it induces. As a secondary effect, it appears to modulate the levels of glutamate and dopamine.49 Meanwhile, a sense of exhilaration and central stimulation is mediated by acetylcholine and other neurotransmitters.

While acting through diverse neurotransmitter pathways, many psychoactive drugs share the characteristic of being pleasurable. The feeling of satisfaction is closely linked to brain structures in the limbic system that integrate learning, memory, emotion, and behavior (figure 4.13). From an evolutionary perspective, it makes sense that the animal brain would develop circuitry to associate food, sex, and goal-oriented behavior with pleasure. By connecting the sense of reward with pathways of memory, animals can learn to anticipate and seek out objects and activities that will advance their chances for survival. The major components of the limbic system communicate via dopaminergic transmission and draw input from cholinergic, opioidergic, and many other neurons.50 By modulating dopamine signaling, numerous plant-derived active principles engage the brain’s responses to pleasurable stimuli.

For example, cocaine inhibits the reuptake of norepinephrine and dopamine from synapses, resulting in an intense central stimulation (mostly via norepinephrine) and feelings of euphoria caused by increased dopaminergic signaling in the limbic system. Moreover, convergent connections in the nervous system result in a great number of neurotransmitters acting in part through the dopamine pathway. The drug scopolamine, produced by jimsonweed (Datura stramonium, also called thorn apple) and its relatives, is an acetylcholine receptor antagonist that gives rise to diverse physiological effects, ranging from dry mouth and blurred vision to increased heart rate. It disrupts acetylcholine signaling in the brain, inducing sensory illusions, amnesia, and cloudy thoughts.51 It also produces euphoria by secondary effects that activate dopamine signaling.

Some active principles of the poppy, such as morphine and codeine, induce dopamine release in the limbic system.52 Nicotine, cannabinoids, alcohol, and many stimulant drugs, despite the vast differences in their physiological effects and mechanisms of action, all also provoke a sense of euphoria. It is clear that for those compounds that activate the brain’s reward center, dopamine is a key player in the pleasure of drug taking and in the development of addiction.

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FIGURE 4.13   The limbic system plays an important role in emotion, motivation, and memory. Its interconnected structures signal largely via the neurotransmitter dopamine and communicate extensively with other neurotransmitter pathways. (Some structures are not shown.) (Adapted from John P. J. Pinel, Biopsychology, 9th ed. [Boston: Pearson, 2014], fig. 3.27)

TOLERANCE, DEPENDENCE, AND ADDICTION

Many medicinal plants produce active principles that interfere with the normal biological processes of the nervous system, whether by modulating the intracellular processes of neurons, blocking synaptic communication, or substituting for the body’s own neurotransmitters and initiating abnormal signals. As a result, the effects of psychoactive drugs can be rather striking for the initiate. On repeated and long-term exposure, however, the body compensates for the drug-induced state of neural function by altering the activity of neurotransmitter receptors and neurotransmitter levels, among other changes. This condition, called tolerance, amounts to a reduced effect of the drug at a constant level of administration. Because of tolerance, some drug users ratchet their consumption upward over time simply to obtain a similar level of effect.

Since the body adjusts to increased drug levels over time, the discontinuation of a drug can unmask the compensated state, with its natural neurotransmitter systems unable to perform their full range of predrug functions. For people accustomed to drug taking, this can produce unpleasant symptoms. For example, if opiate drugs such as morphine suppress pain, cause the skin to flush, and induce euphoria, their cessation can reveal the modified physiological state, resulting in pain, chills, and dysphoria. The symptoms of withdrawal, which differ depending on the drug, dose, and individual, are hallmarks of drug dependence. For some people, the experience of withdrawal, while uncomfortable, eventually passes, and the normal physiological state returns over time.

Addiction to a drug is a pathological drive to take it despite the negative consequences. It can exist in the absence of tolerance and dependence and can persist or reappear after withdrawal symptoms have subsided, called relapse. Addiction researchers, therefore, believe that the condition is closely related to the neural processes of reward and associative learning.53

CLASSIFICATION OF PSYCHOACTIVE DRUGS

By acting on neural pathways governing cognition and sensation, herbal products can profoundly affect a person’s alertness and sensitivity to stimuli. Many plant-derived substances can excite the nervous system and give the sense of elevated mental sharpness and focus. Such compounds are known as stimulants. Conversely, drugs that dull the mind and produce the sensation of numbness are called narcotics. (It is worth bearing in mind that among government agencies and in the press, the term “narcotic” is frequently used to refer to any mind-altering drug, without distinction to its physiological effects.) Drugs that produce a feeling of well-being are euphoriants.

EFFECTS OF PSYCHOACTIVE DRUGS

Euphoriants

Create a sense of well-being and pleasure

Stimulants

Increase mental alertness and (usually) elevate physiological activity

Narcotics

Dull the senses and (usually) reduce physiological activity, induce sleepiness

Phantasticants

Alter senses such that sounds, sights, smells, and the like seem different than they actually are

Hallucinogens

Provoke sensation of stimuli that are not actually present

Psychedelics

Cause a sense of liberation from one’s mind

Entheogens

Lead to a spiritual or religious experience

A number of these outcomes can occur simultaneously, depending on the drug and the user’s subjective experience.

The central nervous system processes sensory input in the cerebrum to develop an awareness of the world. However, plant-derived chemicals that resemble neurotransmitters and act at their receptors can alter its ability to generate an accurate interpretation of reality. For instance, a number of herbal active principles create visual distortions or the impression of light, sound, or other inputs that do not exist. Such chemicals form special classes of psychoactive compounds. Phantasticants are substances that alter the sensory input in such a way that sounds, images, smells, and other stimuli seem different than they actually are. They can make colors, for example, appear more intense than under normal circumstances. In contrast, hallucinogens cause the mind to experience sensations and perceive stimuli that do not exist, such as geometric patterns in the sky and dialogue with animals. Another class of psychoactives, the psychedelics, produce feelings of liberation from one’s mind coupled with false sensory imagery. Finally, the entheogens produce experiences of spiritual or religious awakening, sometimes with visions. By altering in various ways the ability of the mind to process its complicated inputs, such chemicals can produce poignant illusions.54

PSYCHOACTIVE PLANT COMPOUNDS IN CONTEMPORARY NEUROSCIENCE

For most of human history, making sense of the mind was the domain of philosophers and theologians. With the advent of cell theory and the rise of biological chemistry, scientists employed new tools to pry apart neurons and investigate the mysteries of their communication. Yet the fragile axons and ramified dendrites did not lend themselves to surgical manipulation, and teasing apart the complexity of chemical transmission was beyond the technical capabilities of the nineteenth- and early-twentieth-century laboratory. The specific, potent actions of plant-derived compounds led investigators to search for receptors, deduce the biochemical basis of neurotransmission, and establish how synapses relay neural messages. By studying the effects of herbal active principles, neurobiologists determined how neurotransmitters function at their receptors.55 Indeed, many neurotransmitters were discovered only because a plant-derived chemical produced effects that had not been explained.

For example, a century and a half of chemical analysis from the early nineteenth century through the 1980s had identified hemp’s active principles (including Δ9-tetrahydrocannabinol) and elucidated their chemical structures. However, their mechanism of action could only be speculated on. Ultimately, investigators used plant cannabinoids as a sort of “bait” to see what they bound in brain tissue, and in 1988 they came up with the cannabinoid receptor. Surely the cannabinoid receptor did not exist solely to detect hemp consumption, researchers contended, and they set out to identify the neurotransmitter compound produced in the brain that normally signaled via the cannabinoid receptor. By the mid-1990s, several endocannabinoid (for endogenous cannabinoid) neurotransmitters had been discovered, and their functions could be described at the molecular level.56

Similarly, the identification of opioid receptors (sensitive to plant-derived opiate active principles) led investigators to seek molecules in the nervous system that acted similarly to the poppy compounds, ultimately resulting in the discovery of the endorphins and related neuropeptides.57 The action of acetylcholine in the central nervous system and periphery would be poorly understood if not for the experimental utility of nicotine, atropine, and other agents. Armed with a chemical toolkit of natural psychoactive compounds, neuroscience researchers teased apart the structure and function of the nervous system, a legacy that yielded a detailed and improving understanding of the biological nature of the mind.58

The nervous system’s basic units, the neurons, communicate with one another using chemical signals that ultimately govern the body’s ability to sense its surroundings, move its muscles, and feel emotions. The nervous system accomplishes these tasks by coordinating the activities of the central and peripheral divisions. The action of plant-derived drugs outside the brain accounts for many physiological effects.

Within the central nervous system, psychoactive compounds in medicinal plants can have a tremendous influence on a person’s perception and emotional state. Plants have evolved to produce dozens of chemicals that bind to neurotransmitter receptors, acting as agonists to promote signaling or as antagonists to block it. Through their many connections, neurons integrate diverse messages and generate an individual tableau that psychoactive compounds can distort. Many psychoactive drugs stimulate the reward center of the brain, the limbic system, providing a sensation of contentment and gratification that is highly alluring but that can lead to abuse. In addition to their long use in medicine and spiritual pursuits, plants that produce compounds acting on the nervous system have provided researchers with new tools to explore the cellular basis of sensation, perception, and the human experience.