The present study used TMS to investigate motor cortical excitability in schizophrenia patients with and without comorbid SUD (cannabis). The TMS technique allows noninvasive testing of inhibitory and excitatory intracortical networks in the human brain. In contrast to most animal research, TMS can describe alterations at the system level of the human cerebral cortex; this level typically has a closer relation to the clinical context (Lang et al. 2008).

In a previous study, we were able to identify an SICI reduction in a sample of first-episode schizophrenia patients relative to healthy control subjects. This suggested that a GABAergic deficit may be involved in schizophrenic pathophysiology, which would support the functional dysconnectivity hypothesis (Wobrock et al. 2008). Functional disconnectivity in schizophrenia—as indexed by TMS measures—has also been found between posterior parietal cortex and ipsilateral motor cortex (Koch et al. 2008). To our knowledge, our study is the first to use TMS to explore the effects of accompanying cannabis abuse on cortical excitability in schizophrenia.

The main result of our study is that schizophrenia patients with a history of cannabis abuse (SZ-SUD) showed a reduced GABA_A-mediated SICI and an enhanced ICF compared to patients with no cannabis abuse history (SZ-NSUD). The GABA_B-mediated CSP and parameters of corticospinal excitability such as RMT and SI1mV did not differ between the groups. We found no significant hemispheric differences in TMS measures (after Bonferroni correction).

In our study, SZ-SUD patients were significantly younger and less educated than SZ-NSUD patients. This is in accordance with other cross-sectional studies (Cantor-Graae et al. 2001; Mueser et al. 1990; Wobrock and Soyka 2008); therefore, our patient samples seem to be representative for this special patient population. Importantly, psychopathology and disease severity did not differ between the two schizophrenia subgroups.

A number of TMS studies have now found reduced intracortical inhibition and enhanced ICF in schizophrenia patients (Daskalakis et al. 2002; Eichhammer et al. 2004; Fitzgerald et al. 2002a,b,c; Pascual-Leone et al. 2002; Wobrock et al. 2008). SICI seems to be induced by GABAergic interneurons via α2- or α3-GABA_A receptors (Di Lazzaro et al. 2007; Siebner et al. 1998), whereas ICF relates to the excitability of excitatory neuronal circuits in motor cortex; these circuits are at least partially dissociable from the SICI network (Ziemann 2004). In schizophrenia, GABAergic dysfunction, decreased levels of the mRNA expression of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67), and a reduction of GABAergic interneurons are all observed (Benes 1998; Knable et al. 2002; Lewis et al. 2005). Furthermore, expression levels of seven GABA-related transcripts have been found to be reduced in subjects with schizophrenia in four cortical regions (including the motor cortex); these changes may cause cortical dysfunction in schizophrenia patients (Hashimoto et al. 2008).

These neuropathological and neurobiological findings are in line with the reduced SICI observed in schizophrenia. Our results most likely reflect an amplified GABAergic deficit and a distinct functional intracortical disconnectivity in cannabis-abusing schizophrenia patients. Our data demonstrate, for the first time, the influence of previous cannabis abuse on cortical GABAergic function in schizophrenia patients.

The influence of cannabis consumption on TMS measures in subjects not suffering from schizophrenia was investigated in a recently published study by Fitzgerald et al. (2009). These authors examined 42 chronic cannabis users (both heavy and light users) and observed reduced SICI relative to healthy controls, without any differences in CSP. This finding corroborates our view that chronic cannabis use may cause a GABA_A-mediated reduction of intracortical inhibition without any influence on GABA_B activity.

In summary, there is convincing evidence for a link between cannabis, schizophrenia, and the GABAergic system. In this vein, our results are also in line with studies reporting a reduction of event-related potentials—such as the auditory evoked P50 or P300—in both schizophrenia, including its prodrominal states, and after cannabis use (Adler et al. 1982; Coburn et al. 1998; Frommann et al. 2008; Ozgürdal et al. 2008; Roser et al. 2008), probably also reflecting reduced inhibition in a cortico-subcortical loop.

The active compound of herbal cannabis, delta-9-tetrahydrocannabinol (THC), exerts all of its known central effects through CB1Rs. Cannabinoids, via CB1Rs, influence the release of glutamate, dopamine, acetylcholine, and GABA primarily presynaptically. In contrast, the cellular mechanisms involved in the inhibition of neurotransmitter release by cannabinoids are still not fully understood (Iversen 2003). Several mechanisms are suspected to be engaged in these inhibitory effects of CB1R activation, including activation of N-type Ca2⁺ currents (Caulfield and Brown 1992), a reduction of the frequency of Ca2⁺-independent excitatory or inhibitory synaptic currents (Schlicker and Kathmann 2001), and decreased phosphorylation of A-type K⁺ channels by the cAMP-dependent enzyme protein kinase A (Deadwyler et al. 1995). In the rodent hippocampus, a specific class of GABAergic interneurons was detected to express CB1Rs, and moreover, endogenous and exogenous cannabinoids were shown to inhibit GABA release in CA1 pyramidal cells (Hoffman and Lupica 2000; Katona et al. 1999, 2000) and pyramidal cells of the ventral tegmental area (Pistis et al. 2001).

In our study, patients with a double diagnosis showed an enhanced ICF. Likewise, atropine, a cholinergic antagonist, has been found to enhance ICF (Liepert et al. 2001), while NMDA antagonists and chronic nicotine exposure have been associated with an ICF reduction (Lang et al. 2008; Schwenkreis et al. 1999; Ziemann et al. 1998). The enhanced ICF in schizophrenia patients with comorbid cannabis abuse might hence best be explained by an increased glutamatergic input and reduced GABA_Aergic neurotransmission, while a disturbance in cholinergic intracortical neuronal circuits may also play a role.

Previous studies investigating the action of addictive drugs (other than cannabis) on cortical excitability have revealed partially conflicting results. Chronic nicotine abuse, acute alcohol exposure, and alcohol dependence have been associated with enhanced inhibition and reduced facilitation in specific neuronal circuits in motor cortex (Conte et al. 2007; Lang et al. 2008; Ziemann et al. 1996b). Cocaine addicts showed decreased excitability of the motor cortex (Boutros et al. 2005), whereas ecstasy users demonstrated increased excitability of the visual cortex (Oliveri and Calvo 2003). Apart from the specific type of drug under investigation, there are two likely reasons why the observed effects of drug modulation contrast with the effects reported in the present study: First, effects may critically depend on specific neurodevelopmental brain abnormalities in schizophrenia patients (Falkai et al. 2008). Secondly, most of the TMS studies investigating addictive drug effects on cortical excitability have looked at acute drug effects or have tested subjects that were under the influence of the drug at the time of TMS measurement. In our sample, we assessed patients in a drug-free interval, to investigate the pathophysiology of this double diagnosis condition without the influence of acute drug effects or long-lasting intoxication effects.

However, our study has several limitations. Although we collected data about the pattern of substance abuse, we did not differentiate between different types of cannabis or the average amount of cannabis per use. The content of psychoactive THC varies widely across different types of cannabis (Potter et al. 2008). This complicates the exploration of dose–response relationships, although in our sample, we found no correlation between TMS parameters and the amount of cannabis consumption (lifetime days of use).

Secondly, antipsychotic medication could be a considerable confounding factor in TMS paradigms (Davey et al. 1997). For instance, one study found a difference in RMT between patients treated with risperidone (increased RMT) and olanzapine (decreased RMT; Fitzgerald et al. 2002c). For paired-pulse measurements, medication influencing GABA, glutamate, serotonin, or dopamine transmission could be potentially relevant because the interneuronal-pyramidal circuits are mediated via these pathways. However, according to the literature, one would expect that antipsychotics should compensate for the reduced inhibition or increased facilitation and should not produce it, as there are no studies available showing increased cortical inhibition in medicated (or unmedicated) schizophrenia and only one study demonstrating reduced cortical inhibition exclusively in medicated patients (Pascual-Leone et al. 2002). In our study, we could not rule out an influence of antipsychotic dosing on ICF completely, as we detected a positive correlation between the extent of facilitation (MEP ratio) and the cumulative antipsychotic dosage in the SZ-SUD patient group.

Furthermore, although we consider our patient sample to be quite representative, groups differed in central demographic parameters (gender, age, and education). This may have affected our main results, although we consider this unlikely, as we adjusted our analyses for confounding variables. Another limitation is that we did not determine the concentration of endogenous cannabinoids (e.g., anandamide) in the CSF, as it has been done in previous studies with cannabis abusing schizophrenia patients (Leweke et al. 2007). It would have been interesting to see if dysregulations of the endogenous cannabinoid system contributed to the observed GABAergic dysfunction as assessed by TMS.

Finally, we did not administer THC in a controlled fashion and therefore cannot conclude directly that the cortical excitability differences between the groups under investigation were caused by cannabis consumption. Alternatively, the excitability differences could represent a kind of brain dysfunction that precedes clinical diagnosis of schizophrenia and increases the risk for SUDs. We do not consider this alternative interpretation likely.

The strength of our study is that we were able to investigate a sample of first-episode patients that was both well-characterized and representative for this patient population in a clinical setting. Due to disease severity and the clinical necessity for medication, it was of course not possible to test these patients in a neuroleptic-naive setting.

Summing up, this study affords novel insights into the cortical physiology of schizophrenia patients with comorbid cannabis use disorder. The etiological relationship between the two diagnoses is not yet fully understood, but this study supports the theory that cannabis abuse acts as a distinct vulnerability factor for schizophrenia through an increase in GABAergic dysfunction. Alternatively, our results support the hypothesis of an increased sensitivity to the effects of drugs in this special population.