Different hallucinogenic drugs vary in potency but have a similar time course of action
One way of comparing the potency of various hallucinogenic drugs is to consider the typical doses taken by recreational users. Common dose ranges for LSD, psilocybin, mescaline, and DMT are presented in Table 14.1. You can see that these compounds vary widely in their potency, ranging from LSD as the most potent to mescaline as the least potent. All of the hallucinogens that are taken orally have a fairly similar time course of action. Depending on the dose and when the user last ate, the psychedelic effects of these substances generally begin within 30 to 90 minutes following ingestion. An LSD or mescaline “trip” typically lasts for 6 to 12 hours or even longer, whereas the effects of psilocybin-containing mushrooms may dissipate a bit sooner. DMT, however, presents a very different picture, at least partly due to its route of administration. The effects of smoked DMT are felt within seconds, reach a peak by 5 to 20 minutes, and are over within an hour or less. For this reason, the DMT experience is sometimes referred to as the “businessman’s trip.”
Hallucinogens produce a complex set of psychological and physiological responses
Since LSD is considered to be the prototypical hallucinogen, we will focus primarily on the psychological and physiological responses associated with this compound. Other hallucinogens may have slightly different response profiles, but the core effects are similar across drugs. The state of intoxication produced by LSD and other hallucinogens is usually called a “trip,” presumably because the user is taking a mental journey to a place different than his normal conscious awareness. The LSD trip can be divided into four phases: (1) onset; (2) plateau; (3) peak; and (4) “come-down.” Trip onset occurs about 30 minutes to an hour after one takes LSD. Visual effects begin to occur, with an intensification of colors and the appearance of geometric patterns or strange objects that can be seen with one’s eyes closed. The next 2 hours of the trip represent the plateau phase. The subjective sense of time begins to slow and the visual effects become more intense during this period.
The peak phase generally begins after about 3 hours and lasts for another 2 or 3 hours. During this phase, the user feels like he’s in another world in which time has been suspended. He sees a continuous stream of bizarre, distorted images that may be either beautiful or menacing. The user may experience synesthesia, a crossing-over of sensations in which, for example, colors are “heard” and sounds are “felt.” The peak is followed by the come-down, a phase lasting for 2 hours or more depending on the dose. Most of the drug effects are gone by the end of the come-down, although the user may still not feel completely normal until the following day. In addition to the sensory-perceptual effects just described, hallucinogenic drugs produce a wide variety of other psychological changes. These include feelings of depersonalization, emotional shifts to a euphoric or to an anxious and fearful state, and a disruption of logical thought.
A hallucinogenic trip as a whole may be experienced either as mystical and spiritually enlightening (a “good trip”) or as disturbing and frightening (a “bad trip”). Whether the user has a good or bad trip depends in part on the dose; the individual’s personality, expectations, and previous drug experiences; and the physical and social setting. But even in the best of circumstances, one cannot predict in advance the outcome of an LSD trip.
Besides their psychological effects, hallucinogens also give rise to various physiological responses. In the case of LSD, these responses reflect activation of the sympathetic nervous system and include pupil dilation and small increases in heart rate, blood pressure, and body temperature. LSD use can also lead to dizziness, nausea, and vomiting, although such reactions are more likely to occur after consumption of peyote or psilocybin-containing mushrooms.
Hallucinogenic drugs share a common indoleamine or phenethylamine structure
Most hallucinogenic drugs have either a serotonin-like or a catecholamine-like structure. The serotonin-like, or indoleamine, hallucinogens include LSD, psilocybin, psilocin, DMT, 5-MeO-DMT, and the synthetic tryptamines mentioned earlier. When the serotonin (5-HT) molecule is oriented in the proper manner, it is easy to see how its basic structure is incorporated into the structures of these hallucinogenic compounds. Important studies in the early 1950s by John Gaddum in Scotland and by Edward Wooley and David Shaw in the United States led these investigators to conclude that LSD works by antagonizing the action of 5-HT in the brain. We shall see in the next section that LSD can be understood more as an agonist than as an antagonist in the serotonergic system. Nevertheless, the linking of 5-HT with such a powerful psychoactive drug as LSD brought this recently discovered neurotransmitter into the forefront of behavioral and psychiatric research, a place that it continues to hold to the present day.
Of the hallucinogens covered in this post, the only one that is catecholamine-like is mescaline. Mescaline has structural similarities to the neurotransmitter norepinephrine (NE) as well as to the psychostimulant amphetamine. Indeed, amphetamine can produce hallucinogenic effects with prolonged administration of high doses, and several amphetamine analogs such as 2,5- dimethoxy-4-methylamphetamine (DOM, also known as “STP”) and 3,4,5-trimethoxyamphetamine (TMA) possess even greater hallucinogenic properties. Together with mescaline, these NE- and amphetamine-related compounds are known as phenethylamine hallucinogens.
Hallucinogens are 5-HT2 receptor agonists
Although we still don’t completely understand how hallucinogens produce their dramatic perceptual and cognitive effects, some progress has been made. Over time it has become clear that the serotonergic system is intimately involved in this process, but that still leaves a number of additional questions. Which serotonergic receptors are targeted by hallucinogenic drugs? Do other neurotransmitters also play a role? Do the phenethylamine hallucinogens such as mescaline work by the same mechanism as indoleamine hallucinogens like LSD, psilocybin/psilocin, and DMT? Finally, what brain circuits are activated by hallucinogenic drugs?
Beginning our exploration of hallucinogenic action with LSD, we can immediately see that this is a very complicated substance with respect to its potential effects on the serotonergic system. LSD binds with relatively high affinity to at least eight different serotonergic receptor subtypes: 5-HT1A, 5- HT1B, 5-HT1d, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT6, and 5-HTy (Nichols, 2004). There are several approaches we can take toward understanding which of these receptor interactions are important for basic hallucinogenic drug action. One approach is to compare the receptor binding properties of indoleamine hallucinogens such as LSD with those of the phenylethylamine hallucinogens. As shown in Table 14.2, such a comparison reveals that the only known common sites of interaction for both classes of compounds are the 5- HT2A and 5-HT2C receptor subtypes (Aghajanian and Marek, 1999). Moreover, the potencies of various phenethylamine hallucinogens in humans are closely correlated with their affinities for both of these subtypes (Nelson et al., 1999). Together, these findings suggest that 5-HT2A and/or 5-HT2C receptors might play a key role in the subjective and behavioral effects of hallucinogenic drugs.
Receptor binding data alone cannot determine the mechanism of action of a psychoactive drug. Behavioral studies are also needed. There is little work on the neurochemistry of LSD action in humans due to current restrictions on clinical research with this compound. However, Vollenweider and his coworkers (1998) studied the indoleamine hallucinogen psilocybin and showed that drug-induced visual illusions and hallucinations were dose-dependently blocked by ketanserin and risperidone, two compounds that antagonize 5-HT2A receptors. Because risperidone also blocks D2 receptors for dopamine (DA), it is important to note that haloperidol, an antagonist at D2 but not 5-HT2A receptors, completely failed to prevent the hallucinogenic effects of psilocybin. Thus the limited human data available at this time suggest an important role for 5-HT2A recep-tors in the mediation of drug-induced hallucinations.
Due to the scarcity of human experimental research on hallucinogens, animal studies have been extremely important in helping us understand how these drugs work. Studies using the drug-discrimination procedure have been particularly useful in this regard. An example from the work of James Appel of the University of South Carolina and his collaborators (Appel et al., 2004). The researchers first trained rats to press one lever in a Skinner box when they received an injection of LSD and a different lever when they received saline. Antagonists (A) Rats readily learned to discriminate LSD (0.08 mg/kg intraperitoneally) from saline, as shown by the progressive increase in responding on the correct lever over days. (B) In rats previously trained to discriminate this dose of LSD from saline, responding on the LSD-appropriate lever was dose-dependently reduced by pretreatment with the 5-HT2A receptor antagonists ritanserin,pirenperone,and ketanserin. (After Appel et al., 2004.) that the discriminative stimulus properties of the drug as measured by responding on the appropriate lever were acquired within about 2 weeks.
Once the animals had been trained, some were given varying doses of a 5-HT2A receptor antagonist such as ritanserin, pirenperone, or ketanserin 1 hour prior to administration of LSD. All three compounds dose-dependently reduced responding on the LSD-appropriate lever, presumably because the interoceptive cue produced by LSD was blocked by the antagonist pretreatment. Indeed, other work by Winter et al. (1999) has shown a strong correlation between the affinity of various serotonergic antagonists for the 5-HT2A receptor and their potency in blocking the LSD stimulus cue. Based on these and other findings, it appears that the discriminative stimulus procedure is consistent with the other experimental approaches discussed earlier in this section that point to the 5-HT2A receptor as a key mediator of hallucinogenic drug action.
Most hallucinogenic drugs, with the possible exception of DMT, produce rapid tolerance with repeated use. Early studies involving LSD administration to human subjects found that over a 4-day period of daily dosing, nearly complete tolerance was observed by the fourth day (Nichols, 1997). One likely mechanism underlying this tolerance is a down-regulation of 5-HT2A receptors, which has been demonstrated in rats given several daily doses of LSD or psilocybin (Buckholtz et al., 1990). Surprisingly, mescaline administration did not result in 5-HT2A receptor down-regulation, despite the fact that this compound can produce behavioral tolerance like the indoleamine hallucinogens. Therefore, there may be multiple mechanisms that can give rise to hallucinogenic drug tolerance.
What is the neural mechanism by which hallucinations are produced?
Although the above-mentioned studies have helped identify which 5-HT receptor is most important for hallucinogenic drug effects, they do not tell us where the critical receptors are located or how the activation of these receptors produces the sensory and cognitive distortions experienced during a “trip.” Due to a lack of relevant human studies, these questions have thus far been addressed mainly by various experimental approaches using animals. For example, electrophysiological studies by George Aghajanian and his colleagues have suggested an important role for the locus coeruleus (LC), a dense cluster of norepinephrine-containing neurons in the pons that is responsible for most of the noradrenergic projections to the forebrain. A key feature of the LC is that it receives and integrates input from all of the major sensory systems and sends information to all areas of the cortex including the sensory cortex.
Aghajanian’s group found that LSD, DOM, and mescaline all decreased the spontaneous firing of rat LC neurons but paradoxically enhanced the excitation of these cells by sensory stimulation (Aghajanian and Marek, 1999). This effect is caused by drug-induced activation of 5-HT2A receptors, although the receptors in question are not located directly on the LC neurons but rather on other cells that modulate LC activity. A reduction in spontaneous neuronal firing with a simultaneous enhancement of sensory responsiveness means that in the presence of hallucinogenic drugs, the LC is more sensitive to sensory input. This may be one of the key factors leading to the genesis of hallucinations, although Aghajanian and Marek discuss additional processes that may also play important roles.
Franz Vollenweider and Mark Geyer (2001) have proposed an alternative hypothesis, in which they suggest that hallucinogenic effects are produced by a disruption of normal information processing in a circuit that includes the pre- frontal cortex, striatum, and thalamus. This hypothesis argues that hallucinogenic drugs interfere with the normal “gating,” or screening, of sensory information passing through this circuit, thereby resulting in information overload at the cortical level. Vollenweider and Geyer further argue that such a mechanism accounts not only for the perceptual distortions associated with hallucinogenic drug use but also for simultaneous disturbances in cognition that these investigators consider to be psychotic-like.
Hallucinogenic drugs cause problems for some users
Hallucinogens are not thought to be addictive in the standard sense. Users do not binge on these substances, and it is rare for people to experience the kind of cravings seen with drugs such as opiates, cocaine, ethanol, and nicotine. Furthermore, hallucinogens do not produce physical dependence or withdrawal. Finally, these compounds are not effective reinforcers in animal tests such as the self-administration paradigm.
Despite this lack of addictive potential, hallucinogens can still cause serious problems for some users. As mentioned earlier, the user may have a “bad trip” in which he or she experiences an acute anxiety or panic reaction in response to the drug’s effects. Although we don’t understand the exact cause of these reactions, they are probably related to an interaction between the drug, the individual’s emotional state going into the trip, and the external environment. In most cases, friends will talk the person through the ordeal. However, if this is unsuccessful, then it may be necessary to take the person to the hospital emergency room for treatment. The incidence of bad trips is not known, but existing data from older clinical studies of LSD administration suggest that they are rare when users are prescreened for emotional stability and the environmental conditions are carefully controlled.
A second potential complication of hallucinogen use is the occurrence of flashbacks. This term is defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM- IV) as “the reexperiencing, following cessation of use of a hallucinogen, of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen” (American Psychiatric Association, 1994, p. 234). When flashbacks occur a long time after prior drug use and are sufficiently intense to cause major disturbance or impairment, then the individual is considered to be suffering from hallucinogen persisting perception disorder (HPPD). Halpern and Pope (2003) recently reviewed the literature on flashbacks and HPPD. They concluded that although some LSD users do suffer from HPPD, the prevalence of this disorder may not be very high considering the relatively few documented cases of HPPD in relation to the large number of people who have taken LSD over the years. The neural mechanisms responsible for flashbacks have not yet been studied, although it is interesting to note that the use of other psychoactive drugs such as marijuana seems to trigger flash-backs in some cases.
The most severe adverse reaction to LSD is a psychotic breakdown. At one time, LSD opponents argued that this was a major risk factor in using this substance. However, it now seems clear that prolonged psychotic episodes following LSD use almost invariably involve individuals who had already been diagnosed with a psychotic disorder such as schizophrenia or who had manifested prepsychotic symptoms before taking the drug.
Hallucinogens are substances that cause perceptual and cognitive distortions in the absence of delirium. Many hallucinogens such as mescaline, psilocybin, DMT, and 5-MeO-DMT are plant compounds that were used for hundreds or thousands of years in spiritual or religious ceremonies before their discovery by Western culture. In contrast, LSD is a synthetic drug, although it is based on a series of alkaloids found in ergot fungus.
Recognition of the powerful mind-altering properties of hallucinogenic drugs led to both clinical and recreational use beginning in the late 1950s and early 1960s. Some psychiatrists gave patients LSD in the course of psycholytic or psychedelic therapy. LSD became readily available on the street despite a federal ban on recreational use in 1967. Most hallucinogenic drugs are orally active, with a slow onset of action and a long time course of action. One exception is DMT, which is usually smoked, thereby leading to rapid drug effects and a much shorter duration of action. Of the commonly used hallucinogens, LSD is the most potent and mescaline is the least potent, based on the range of doses taken by users.
An LSD “trip” is sometimes divided into four phases: onset, plateau, peak, and come-down. During the trip, the user experiences vivid visual hallucinations, a slowing of the subjective sense of time, feelings of depersonalization, strong emotional reactions, and a disruption of logical thought. There are also physiological reactions such as pupil dilation and increased heart rate, blood pressure, and body temperature. A number of factors determine whether the user has a “good trip” or a “bad trip.”
Hallucinogenic drugs are classified chemically as either indoleamines or phenethylamines. The indoleamines are related structurally to 5-HT, whereas the phenethylamines instead share a common structure with NE. Both classes of drugs are agonists at 5-HT2 receptors, which is believed to be an essential component of their hallucinogenic properties. Activation of 5-HT2A receptors may be particularly important for hallucinogenic activity. Repeated exposure to hallucinogens leads to rapid tolerance, possibly through down- regulation of these receptors in key target cells. The specific brain areas responsible for the production of hallucinogenic drug effects have not yet been identified, but hypotheses have been proposed that focus either on the locus coeruleus or on the cortical-striatal-thalamic circuit.
Hallucinogens are not considered to be dependence forming or addictive. However, they can lead to other adverse effects such as “bad trips” and flashbacks. People who suffer from severe flashbacks long after discontinuing hallucinogenic drug use are diagnosed as having hallucinogen persisting perception disorder. At the present time, little is known about the causes or treatment of HPPD.